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HELLO TO EVERYONE HERE IN

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LIPSETT, AND TO EVERYONE JOINING

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ONLINE.

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IT'S MY DISTINCT PLEASURE TO

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INTRODUCE DR. LEI WANG TODAY.

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ONE QUICK NOTE BEFORE WE GET

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STARTED THE CME CODE IS 57654.

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IF YOU HAVE A QUESTION DURING

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THE SEMINAR OR AFTER THE SEMINAR

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THESE CAN BE SUBMITTED VIA THE

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SUBMIT FEEDBACK BUTTON ONLINE.

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AND FOR THOSE IN PERSON, THERE

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WILL BE A RECEPTION THAT FOLLOWS

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THE LECTURE OUTSIDE IN THE

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SEMINAR HALL.

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CURRENTLY PROFESSOR WANG IS A

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PROFESSOR AT UCSF WHERE HE'S

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BEEN SINCE 2014.

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HE   PERFORMED HIS BACHELOR'S

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AND MASTERS STUDIES AT PEKING

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UNIVERSITY BEFORE MOVING TO HIS

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Ph.D. STUDIES IN THE LAB OF

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PETER SCHULTZ WHERE HE PIONEERED

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METHODS TO EXPAND GENETIC CODE

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FOR TRANSFORMING AND

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INCORPORATION OF NONAMINO ACIDS.

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HE THEN   PERFOR THE PURPOSED

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HIS POST DOC STUDIES WITH

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DR. CHEN AT UCSD, AND HE BEGAN

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HIS INDEPENDENT CAREER AS AN

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ASSISTANT PROFESSOR, AND THEN IN

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2014 HE JOINED UCSF.

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DR. WANG HAS RECEIVED SEVERAL

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AWARDS INCLUDING THE KAISER

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AWARD FROM THE PROTEIN SOCIETY

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FOR SIGNIFICANT CONTRIBUTIONS TO

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THE STUDY OF PROTEINS AS WELL AS

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NIH DIRECTOR'S INNOVATION AWARD

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AMONGST MANY OTHERS.

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AS DR. WANG WILL TELL YOU TODAY,

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HIS LAB DEVELOPS NEW METHODS

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BASED ON GENETIC INCORPORATION

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OF NONNATURAL AMINO ACIDS TO

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INTRODUCE NOVEL FUNCTIONALITY

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INTO PROTEINS TO INVESTIGATE

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BIOLOGICAL PROCESSES, IN VIVO,

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WHICH HE WILL COVER DURING HIS

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TALK TODAY.

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SO YOIN ME IN WELCOMING

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DR. WANG.

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[ APPLAUSE ]

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>> THANK YOU VERY MUCH,
ROSS,

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FOR THE KIND INVITATION AND

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GENEROUS INTRODUCTION.

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I HAD A GREAT TIME MEETING WITH

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THE OUTSTANDING PIs AND

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TRAINEES HERE, REALLY ENJOYED

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THE VISIT.

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IT'S A GREAT HONOR AND PLEASURE

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TO BE HERE.

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MY TALK TODAY WILL BE

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BIOSPECIFIC CHEMISTRY FOR

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COVALENT LINKING OF

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BIOMACROMOLECULES.

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BEFORE WE PROCEED, I WOULD LIKE

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TO DISCLOSE POTENTIAL CONFLICT

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OF INTEREST EMPLOY I SERVE AS

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SCIENTIFIC ADVISOR TO ANOTHER

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THEOR PUTTICS BIOTECH COMPANY

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FOCUSING ON DEVELOPING COVID AND

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BIOLOGICS.

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JUST TESTING MY CURSOR AS YOU

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CAN SEE.

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OKAY, GREAT.

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IN NEARLY ALL LIFE FORMS PROTEIN

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INTERACTING WITH PROTEINS AND

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OTHER CLASSES OF BIOMOLECULES TO

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  PERFORM THE ESSENTIAL

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BIOLOGICAL FUNCTIONS.

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THIS INTERACTIONS INCLUDING

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ELECTROSTATIC FORCES,

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[INDISCERNIBLE] AND CARBOHYDRATE

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ACTIONS ARE NONCOVALENT IN

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NATURE.

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AS A RESULT IT TENDS TO BE WEAK,

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TRANSIENT AND REVERSIBLE.

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ALTHOUGH IT'S TRYING TO ENGINEER

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SUCH NONCOVALENT INTERACTIONS

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INTO COVALENT BONDS CREATING

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STRONG, STABLE AND IRREVERSIBLE

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CONNECTICUT NEKSS FOR

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BIOMOLECULES TO STUDY SPECIAL

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HARNESS BIOLOGICAL ACTIVITIES.

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PROTEINS HAVE A LIMITED ABILITY

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TO FORM COVALENT BOUNDS, A KEY

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EXAMPLE IS THE [INDISCERNIBLE]

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FORMED BETWEEN 2 CYSTINE

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RESIDUES SPONTANEOUSLY.

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CONCRUCIAL FOR PROTEIN STRUCTURE

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AND FUNCTION, THE DISULPHIDE

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BOND IS  IS REVERSIBLE AND NOW A

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ANOTHER MAJOR FACTOR IS CATTAL

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SIS, OR THE ATTACHMENT OF

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UBIQUITIN THROUGH OTHER PROTEINS

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THROUGH THE ENZYME MEDIATED

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CATTAL SIS.

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AS YOU CAN SEE THIS WILL REQUIRE

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MULTIPLE RESIDUES IN A SPECIAL

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MICROENVIRONMENT.

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AND HOWEVER RATIONALLY DESIGNING

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THIS BOUNDS REMAINS CHALLENGING

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DUE TO THE COMPLEXISITY OF THE

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PROCESSES.

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THE CHEMISTRY HAS REVOLUTIONED

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THE BIOMARK ROUGH ATOM

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MOLECULES, TO THIS RESULT, 2

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GROUPS ARE SEPARATED AND

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INTRODUCED TO A SMALL COLKIEWL,

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WHICH THEN LINK TO FORM THE

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CONNECTION.

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BECAUSE THE TALKATIVE

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BIOMOLECULE MUST BE MODIFIED

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WITH A BIOORTHOGONAL FUNCTIONAL

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GROUP, IMPLEMENTING THIS

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APPROACH IN VIVO IS CHALLENGING

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IN PARTICULAR ESPECIALLY FOR

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THERAPEUTIC APPLICATIONS WHERE

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THE TARGETED MOLECULE ARE VERY

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DIFFICULT TO BE ALTERED.

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TO ADDRESS THIS, WE PROPOSE

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BIOSPECIFIC CHEMISTRY, THIS

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APPROACH INTRODUCED A SINGLE

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BIOREACTIVE GROUP INTO A

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BIOMOLECULE WHICH THEN REACTED

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WITH ANOTHER BIOMOLECULE WITHOUT

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THE NEED TO MODIFY THE LATTER.

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THIS ABLE TO COVALENTLY MODIFY

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BIOMOLECULES SHOULD MAKE BI

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SPECIFIC CHEMISTRY IDEAL FOR IN

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VIVO STUDIES IN THERAPEUTIC

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APPLICATIONS.

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WE BEGAN EXPLORING BIOSPECIFIC

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CHEMISTRY TO ENABLE PROTEINS TO

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COVID AND TARGET ANOTHER PROTEIN

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BEYOND THE DISULPHIDE BOUNDS WE

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ENVISIONED WHETHER ADDITIONAL

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COVALENT LINKAGES COULD FORM

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BETWEEN THE UNNATURAL AND

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NATURAL RESIDUE.

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THIS BIOREACTIVE ACID IF

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SUCCESSFUL WOULD BREAK THE

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NATURAL BARRIER INTRODUCING NEW

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COVID AND ABOUNDING CAPABILITIES

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INTO PROTEINS.

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UNNATURAL ANALYSIS CAN BE

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SPECIFICALLY INTRODUCED THROUGH

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PROTEINS THROUGH GENETIC CODE

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EXPANSION USING A ORTHOGONAL

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[INDISCERNIBLE] PAIR TO SUPPRESS

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A STOP CODON INTRODUCED

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ARTIFICIALLY INTO THE RNA. 

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HOWEVER THE INCORPORATION OF THE

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00:07:05,066 --> 00:07:07,936
PROTEIN INTO THE CELLS HAS LONG

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BEEN CONSIDERED INFEASIBLE.

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FOR A BIOREACTIVE AUTOIMMUNE

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REACTIVE TO FUNCTION, IT MUST

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REACT WITH BIOMOLECULES INSIDE

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THE CELLS, BUT IS SUCH REACTION

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RISK CYTOTOXICITY AND COULD

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STORE TRANSLATION IF IT WILL

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REACT WITH THE TRANSLATION

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MACHINERY.

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ADDITIONALLY THE ABUNDANCE OF

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THE TERMINUS IS IN PROTEIN ANDS

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IN CELLS POSE A CHALLENGE FOR

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NONSELECTIVE REACTIONS WHICH CAN

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COMPROMISE SPECIFICITY.

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TO ADDRESS THESE CHALLENGES WE

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DEVELOP A STRATEGY CALLED

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PROXIMITY ENABLED BIOREACTIVITY.

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IN THIS APPROACH THE UAA, NOW

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REFER NATURAL [INDISCERNIBLE], I

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WILL NOW REFER TO THIS AS UAA,

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THE U,A APAYS IS DESIGNED TO BE

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LATENT INSIDE THE CELLS

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PREVENTING UNWANTED REACTIONS

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WITH AN INTRACELLULAR MOLECULES

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AND THEN ALLOWING FOR GENETIC

189
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INCORPORATION.

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ONCE INCORPORATING TO PROTEIN

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AND THE BROADER COAST TO THE

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TARGETED RESIDUE, THE

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UAA ACTIVITY IS TRIGGERED BY THE

194
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PROXIMITY EFFECT WHICH REDUCES

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THE ENTROPY OF ACTIVATION AND

196
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INCREASE THE EFFECTIVE

197
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CONCENTRATION ENABLING A

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[INDISCERNIBLE] BOND TO FORM

199
00:08:35,690 --> 00:08:36,524
SELECTIVELY BETWEEN THE

200
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[INDISCERNIBLE] AND THE TARGETED

201
00:08:45,433 --> 00:08:45,733
RESIDUE.

202
00:08:45,733 --> 00:08:47,969
THE REACTIONS WE AIM TO DEVELOP

203
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MUST BOTH BE BIOCOMPATIBLE AND

204
00:08:50,772 --> 00:08:51,873
EFFICIENT UNDER PHYSIOLOGICAL

205
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CONDITIONS WHICH IS A CHALLENGE

206
00:08:55,510 --> 00:08:57,712
IN VALENCE TO,A CHIEF.

207
00:08:57,712 --> 00:09:00,114
THE FOCUSED INITIALLY ON

208
00:09:00,114 --> 00:09:02,417
TARGETED ASSISTIVE RESIDUE DUE

209
00:09:02,417 --> 00:09:04,686
TO HIGH FOLLICULAR

210
00:09:04,686 --> 00:09:06,087
[INDISCERNIBLE].

211
00:09:06,087 --> 00:09:07,288
OUR HYPOTHESIS WAS THAT

212
00:09:07,288 --> 00:09:11,025
[INDISCERNIBLE] COULD STAY INERT

213
00:09:11,025 --> 00:09:13,094
IN ITSELF, BUT EFFECTIVELY ASHES

214
00:09:13,094 --> 00:09:15,463
CYSTING WHEN BROUGHT INTO CLOSE

215
00:09:15,463 --> 00:09:15,797
PROXIMITY.

216
00:09:15,797 --> 00:09:19,133
TO TEST THIS WE CHOOSE A FLORAL

217
00:09:19,133 --> 00:09:19,734
METHOD [INDISCERNIBLE] AND THE

218
00:09:19,734 --> 00:09:25,740
DESIGN OF THE UNNATURAL TERMINAL

219
00:09:25,740 --> 00:09:28,209
[INDISCERNIBLE] AFFECT.

220
00:09:28,209 --> 00:09:29,677
WE INCORPORATE FFACT INTO A

221
00:09:29,677 --> 00:09:32,480
[INDISCERNIBLE] AND EXPRESS THIS

222
00:09:32,480 --> 00:09:32,880
IN E.COLI.

223
00:09:32,880 --> 00:09:34,782
AFTER PURIFICATION MASS PECK

224
00:09:34,782 --> 00:09:36,417
VERIFIED IN COOPERATION WITH

225
00:09:36,417 --> 00:09:37,585
THIS AMINO ACID AND THAT WE

226
00:09:37,585 --> 00:09:42,523
DON'T SEE ANY ADDITIONAL

227
00:09:42,523 --> 00:09:45,059
MODIFICATION TO THE FFACT.

228
00:09:45,059 --> 00:09:49,263
INCLUDING OUR INTENDED REACTIONS

229
00:09:49,263 --> 00:09:51,065
WITH INTRACELLULAR ASSISTINE

230
00:09:51,065 --> 00:09:51,966
GLUTEA THIGH OWN.

231
00:09:51,966 --> 00:09:54,102
THIS INDICATING IT STAYS

232
00:09:54,102 --> 00:10:00,341
INACTIVE DURING THE BIOSYNTHESIS

233
00:10:00,341 --> 00:10:01,576
AND PURIFICATION.

234
00:10:01,576 --> 00:10:03,177
TO TEST WHETHER IF EFFECT CAN

235
00:10:03,177 --> 00:10:06,381
FORM A COVID AND BOUND WITH THE

236
00:10:06,381 --> 00:10:11,085
CYSTINE IN PROTEINS, WE

237
00:10:11,085 --> 00:10:12,820
INCORPORATE FFACT INTO A BODY

238
00:10:12,820 --> 00:10:14,989
AND PLACE ASSISTING RESIDUE INTO

239
00:10:14,989 --> 00:10:16,958
THE PROTEINS AND BINDING AT THE

240
00:10:16,958 --> 00:10:19,127
INTERFACE AND THESE 2 PROTEINS

241
00:10:19,127 --> 00:10:20,662
WILL PURIFY AND INCUBATE IT AND

242
00:10:20,662 --> 00:10:24,832
WE THEN RUN AN SDS PAGE UNDER

243
00:10:24,832 --> 00:10:27,902
THE NATURE AND CONDITIONS TO

244
00:10:27,902 --> 00:10:30,938
TEST WHETHER THIS TOO ACTIVATES

245
00:10:30,938 --> 00:10:31,572
EACH OTHER.

246
00:10:31,572 --> 00:10:35,777
IT SHOWS A COMPLEX OF

247
00:10:35,777 --> 00:10:37,779
[INDISCERNIBLE] Z WAS FORMED.

248
00:10:37,779 --> 00:10:41,649
HOWEVER IF WE REPLACE THE FFACT,

249
00:10:41,649 --> 00:10:43,785
WITH THE NON[INDISCERNIBLE]

250
00:10:43,785 --> 00:10:46,220
FFACT, OR PLACE THE CYSTINE WITH

251
00:10:46,220 --> 00:10:49,190
OTHER AMIN ACID RESIDUES OR PUT

252
00:10:49,190 --> 00:10:51,492
THE CYSTINE INTO DIFFERENT

253
00:10:51,492 --> 00:10:52,860
POSITIONS, NO COVID COMPLEX

254
00:10:52,860 --> 00:10:55,229
FORMED SO THIS RESULT I HAD

255
00:10:55,229 --> 00:10:57,565
BEENICATING THAT THE COVALENT

256
00:10:57,565 --> 00:11:00,868
BOUNDING FORMATION BETWEEN THESE

257
00:11:00,868 --> 00:11:02,303
2 PROTEINS DEPENDS ON THE

258
00:11:02,303 --> 00:11:04,772
PROXIMITY OF THE FFACT AND

259
00:11:04,772 --> 00:11:05,740
CYSTINE.

260
00:11:05,740 --> 00:11:11,646
NEXT WE TESTED THE INTRA

261
00:11:11,646 --> 00:11:13,748
MOLECULAR REACTIVITY IN THE

262
00:11:13,748 --> 00:11:14,449
FLUORESCENT PROTEIN.

263
00:11:14,449 --> 00:11:17,351
WE PLACED THE [INDISCERNIBLE] 67

264
00:11:17,351 --> 00:11:21,155
OF THE FLORA FORWITH THE FFACT

265
00:11:21,155 --> 00:11:23,491
AND REPLACED SERIES POINTSINE

266
00:11:23,491 --> 00:11:24,459
WITH CYSTINE.

267
00:11:24,459 --> 00:11:26,427
WE THEN EXPRESS IN MUTANT

268
00:11:26,427 --> 00:11:30,298
PROTEIN IN E.COLI, PURIFIED IT

269
00:11:30,298 --> 00:11:34,602
AND MASS SPEC CONFIRMED NEARLY A

270
00:11:34,602 --> 00:11:35,703
HUNDRED PERCENT EFFICIENT IN THE

271
00:11:35,703 --> 00:11:37,739
SINGLE FORMATION AND A SINGLE

272
00:11:37,739 --> 00:11:39,807
ACCOUNT OF THIS PROTEIN SHOWED

273
00:11:39,807 --> 00:11:42,009
THAT THERAY A SINGLE COVALENT

274
00:11:42,009 --> 00:11:43,611
BOND DOUBLED THE LIFE SPAN AND

275
00:11:43,611 --> 00:11:44,879
[INDISCERNIBLE] OF THIS MUTANT

276
00:11:44,879 --> 00:11:46,647
FOR US IN PROTEIN.

277
00:11:46,647 --> 00:11:49,884
THIS BENEFITS THAT ARE VERY

278
00:11:49,884 --> 00:11:58,126
DIFFICULT TO ACHIEVE USING ONLY

279
00:11:58,126 --> 00:11:58,793
NATURAL AMINO ACIDS.

280
00:11:58,793 --> 00:12:00,161
CONTINUING  ON THIS BREAK

281
00:12:00,161 --> 00:12:01,429
THROUGH, WE AND SEVERAL OTHER

282
00:12:01,429 --> 00:12:03,898
RESEARCH GROUPS HAVE SINCE

283
00:12:03,898 --> 00:12:05,133
DESIGNED AND GENETICALLY

284
00:12:05,133 --> 00:12:09,270
INCORPORATED A VARIETY OF LATENT

285
00:12:09,270 --> 00:12:11,773
BIOREACTIVE TERMINAL ASSETS TO

286
00:12:11,773 --> 00:12:13,407
TARGET DIFFERENT AMINO ACID

287
00:12:13,407 --> 00:12:13,975
RESIDUES.

288
00:12:13,975 --> 00:12:15,743
HERE ARE SOME REPRESENTED

289
00:12:15,743 --> 00:12:16,010
EXAMPLES.

290
00:12:16,010 --> 00:12:19,080
AS YOU CAN SEE BESIDES CYSTIN,

291
00:12:19,080 --> 00:12:22,617
WE'RE ABLE TO COAST AND TARGET

292
00:12:22,617 --> 00:12:26,788
SEVERAL OTHER RESIDUES.

293
00:12:26,788 --> 00:12:28,389
THROUGH THIS [INDISCERNIBLE]

294
00:12:28,389 --> 00:12:30,324
MECHANISM, HIGHLIGHTING THE

295
00:12:30,324 --> 00:12:36,931
GENERALITY OF THIS APPROACH.

296
00:12:36,931 --> 00:12:39,200
ONE VERSATILE UAA, WE HAVE

297
00:12:39,200 --> 00:12:42,470
DEVELOPED THIS FSY FOR ITS

298
00:12:42,470 --> 00:12:44,839
EXCEPTIONAL BIOCOMPATIBILITY AND

299
00:12:44,839 --> 00:12:48,242
MULTITALKATIVE AFFINITY WITHIN

300
00:12:48,242 --> 00:12:48,743
LIVE CELLS.

301
00:12:48,743 --> 00:12:53,047
IN SPITE OF THE PIONEERING WORK

302
00:12:53,047 --> 00:12:54,816
OF BARRY SHARPLESS ON THE

303
00:12:54,816 --> 00:12:56,050
CHEMISTRY WE DESIGNED THIS

304
00:12:56,050 --> 00:12:57,718
[INDISCERNIBLE] TO FORM A

305
00:12:57,718 --> 00:13:00,288
FUNCTIONAL GROUP.

306
00:13:00,288 --> 00:13:02,023
WE INCORPORATE FSY INTO THE

307
00:13:02,023 --> 00:13:06,694
BINDING FACE OF F-BODY Z AND

308
00:13:06,694 --> 00:13:08,029
INTRODUCE DIFFERENT NUCLEAPHILIC

309
00:13:08,029 --> 00:13:09,330
RESIDUES TO TEST WEATHER FS1 CAN

310
00:13:09,330 --> 00:13:13,534
REACT WITH THEM THROUGH THE

311
00:13:13,534 --> 00:13:14,135
SUFEX CHEMISTRY.

312
00:13:14,135 --> 00:13:16,304
AND WE EXPRESS THESE PROTEINS

313
00:13:16,304 --> 00:13:19,240
DWECT DREKING E.COLI WITHOUT

314
00:13:19,240 --> 00:13:21,375
PURIFYING THEM WITH THE CELLS

315
00:13:21,375 --> 00:13:22,844
WHERE THEY ANALYZE THE CELL

316
00:13:22,844 --> 00:13:23,177
LIAISON SAIT.

317
00:13:23,177 --> 00:13:26,547
AS YOU CAN SEE HERE, BOTH ON THE

318
00:13:26,547 --> 00:13:29,984
WESTERN BLOT AND SDS PAGE TO

319
00:13:29,984 --> 00:13:32,954
RESULT SHOWED THAT THE FSY WAS

320
00:13:32,954 --> 00:13:36,791
ABLE TO REACTIVATE WITH LYSINE,

321
00:13:36,791 --> 00:13:39,093
HISTODINE AND TYROSEEN.

322
00:13:39,093 --> 00:13:41,028
AND THIS REACTION SPECIFICITY

323
00:13:41,028 --> 00:13:46,067
WAS FURTHER VERIFIED BY MASS

324
00:13:46,067 --> 00:13:46,634
SPEC.

325
00:13:46,634 --> 00:13:51,505
SINCE THESE ARE ABUNDANT AT MANY

326
00:13:51,505 --> 00:13:53,608
PROTEIN INTERACTION PHASES, SO

327
00:13:53,608 --> 00:13:59,680
FSC HAS THE POTENTIAL TO TARGET

328
00:13:59,680 --> 00:14:00,815
VIRTUALLY ANY PROTEIN.

329
00:14:00,815 --> 00:14:04,118
ANOTHER VERSE TIE REACTION IS

330
00:14:04,118 --> 00:14:05,853
PFEX, THE PHOSPHOROUS FLUORIDE

331
00:14:05,853 --> 00:14:08,723
EXTEND TO REACTION, WHILE PFEX

332
00:14:08,723 --> 00:14:11,225
TYPICALLY REQUIRES A CATALYST OF

333
00:14:11,225 --> 00:14:13,227
FULL REACTIONS BETWEEN SMALL

334
00:14:13,227 --> 00:14:14,629
MOLECULES, WE DISCOVERED THROUGH

335
00:14:14,629 --> 00:14:17,098
GENETIC INCORPORATION OF THIS,

336
00:14:17,098 --> 00:14:18,633
TOO, END TERMINAL SIS INTO

337
00:14:18,633 --> 00:14:20,134
PROTEINS, WE FOUND IN THE

338
00:14:20,134 --> 00:14:21,869
PROTEIN ENVIRONMENT, THE PFEX

339
00:14:21,869 --> 00:14:23,638
REACTION CAN NOW BE ACTIVATED

340
00:14:23,638 --> 00:14:26,807
SIMPLY BY THE PROXIMITY EFFECT.

341
00:14:26,807 --> 00:14:34,248
AND THIS ALLOWS, WE USE PFEX TO

342
00:14:34,248 --> 00:14:36,250
TARGET HISTIDINE, LIESINE AND

343
00:14:36,250 --> 00:14:36,918
ADDITIONAL CELLS.

344
00:14:36,918 --> 00:14:38,019
ADDITIONALLY IT'S REALLY

345
00:14:38,019 --> 00:14:43,758
INTERESTING, WHEN WE REACTS WITH

346
00:14:43,758 --> 00:14:45,626
EFTHIMIOS DINE IT DISPLACES

347
00:14:45,626 --> 00:14:48,396
THERMAL ACTIVITY AS WELL.

348
00:14:48,396 --> 00:14:51,999
WHAT CAN WE ACHIEVE WITH THIS

349
00:14:51,999 --> 00:14:53,134
NEW COVALENT BONDING ABILITIES?

350
00:14:53,134 --> 00:14:55,703
FIRST I WOULD LIKE TO INTRODUCE

351
00:14:55,703 --> 00:15:00,107
GENETIC ENCODED CHEMICAL CROSS

352
00:15:00,107 --> 00:15:06,514
LINKING OR GECX TO IDENTIFY

353
00:15:06,514 --> 00:15:07,214
PROTEIN-PROTEIN INTERACTIONS.

354
00:15:07,214 --> 00:15:09,050
ONE APPLICATION WE DEVELOPED IS

355
00:15:09,050 --> 00:15:13,721
TRYING TO USE THIS TO PROBE

356
00:15:13,721 --> 00:15:15,890
LIGAND RECEPTOR INTERACTIONOT

357
00:15:15,890 --> 00:15:17,358
[INDISCERNIBLE] CELL SURFACE.

358
00:15:17,358 --> 00:15:19,860
WHEN WE EXPERIENCE STRESS, THE

359
00:15:19,860 --> 00:15:21,696
HYPOTHALAMUS WILL RECEASE

360
00:15:21,696 --> 00:15:24,765
CORTICALE RELEASE FACTOR CRF, A

361
00:15:24,765 --> 00:15:32,373
PEPTIDE HORMONE THAT BINDS TO

362
00:15:32,373 --> 00:15:35,676
CLASS TPC R, [INDISCERNIBLE]

363
00:15:35,676 --> 00:15:37,712
TRIGGERING A CASCADE OF BRAIN

364
00:15:37,712 --> 00:15:41,115
AND MUSCLE RESULT NOTHING STRESS

365
00:15:41,115 --> 00:15:41,649
RESPONSE.

366
00:15:41,649 --> 00:15:42,616
HOWEVER CHRONIC STRESS CAN LEAD

367
00:15:42,616 --> 00:15:46,320
TO ANXIOUS AND DEPRESSION.

368
00:15:46,320 --> 00:15:49,423
AND BLOCKING THE CRF RECEPTOR

369
00:15:49,423 --> 00:15:51,392
INTERACTION COULD POTENTIALLY

370
00:15:51,392 --> 00:15:52,860
TREAT THIS CONDITIONS BUT AT THE

371
00:15:52,860 --> 00:15:56,964
TIME IT WAS UNCLEAR HOW THE CRF

372
00:15:56,964 --> 00:16:00,434
PEPTIDE HORMONE BINDS AND

373
00:16:00,434 --> 00:16:02,003
ACTIVATES THE RECEPTOR.

374
00:16:02,003 --> 00:16:04,405
THEN AS ASSISTANT PROFESSOR

375
00:16:04,405 --> 00:16:07,308
UNDER THE PRESSURE OF THE NIH

376
00:16:07,308 --> 00:16:08,843
STUDY PANELS, SEEKING PROMOTION

377
00:16:08,843 --> 00:16:11,445
IN THE PUBLISHING, I WAS

378
00:16:11,445 --> 00:16:13,381
IMMEDIATELY INTRIGUED BY THE

379
00:16:13,381 --> 00:16:15,416
POSSIBILITY OF CREATING A

380
00:16:15,416 --> 00:16:20,254
HAPPILY EVER AFTER PILL BY

381
00:16:20,254 --> 00:16:21,622
BLOCKING THIS INTERACTION.

382
00:16:21,622 --> 00:16:24,392
SO MY GROUP STARTED MAPPING

383
00:16:24,392 --> 00:16:27,661
BINDING SIZEOT GPCR USING THE

384
00:16:27,661 --> 00:16:31,399
CROSS LINKING U,A,A, WE USED THE

385
00:16:31,399 --> 00:16:33,100
[INDISCERNIBLE] CALLED AZI, WE

386
00:16:33,100 --> 00:16:35,603
CAN INCORPORATE AZI INTO VARIOUS

387
00:16:35,603 --> 00:16:37,238
DIFFERENT POSITIONS INTO THE TPC

388
00:16:37,238 --> 00:16:39,974
R, WHICH WAS EXPRESSED THERE

389
00:16:39,974 --> 00:16:41,042
FROM THE MAMMALIAN CELLS AND

390
00:16:41,042 --> 00:16:43,911
THEN WE THROW IN THE PEPTIDE

391
00:16:43,911 --> 00:16:44,645
HORMONE,   PERFORM THE CROSS

392
00:16:44,645 --> 00:16:47,281
LINKING ON THE MAMMALIAN CELL

393
00:16:47,281 --> 00:16:48,783
SURFACE, AFTER WHICH WE JUST

394
00:16:48,783 --> 00:16:52,053
ANALYZE THE CELL LIAISON SAIT TO

395
00:16:52,053 --> 00:16:54,155
DETECT WHETHER LIGAND IS CROSS

396
00:16:54,155 --> 00:16:56,123
LINKED WITH THE GBCR.

397
00:16:56,123 --> 00:16:59,794
AS YOU CAN SEE IN THIS PANEL A,

398
00:16:59,794 --> 00:17:03,964
THEY INCORPORATE ACI INTO

399
00:17:03,964 --> 00:17:04,865
SPECIFIC SIZE THAT IT CAN

400
00:17:04,865 --> 00:17:06,300
CAPTURE THE LIAISON GAPPED AND

401
00:17:06,300 --> 00:17:09,937
COMPLEX OF LIGAND DETECTED HERE,

402
00:17:09,937 --> 00:17:12,440
AND THIS SLIDES ARE POTENTIALLY

403
00:17:12,440 --> 00:17:16,644
THE LIGAND OF BYPASSING SITES

404
00:17:16,644 --> 00:17:20,414
AND OF MARKETING MAGENTA HERE ON

405
00:17:20,414 --> 00:17:21,816
THE GBCR MEMBRANE STRUCTURE BUT

406
00:17:21,816 --> 00:17:23,250
WE WERE VERY HAPPY AND AT THAT

407
00:17:23,250 --> 00:17:25,786
TIME, WE REALIZED THIS STILL

408
00:17:25,786 --> 00:17:29,490
CANNOT HELP US TO CRACK THE

409
00:17:29,490 --> 00:17:31,258
POSITION FOR CI INTO LIGAND FOR

410
00:17:31,258 --> 00:17:33,427
THE BINDING POCKET OF THIS PC R

411
00:17:33,427 --> 00:17:34,428
BECAUSE OF PHOTO CROSS LINKING

412
00:17:34,428 --> 00:17:37,364
IS NOT A RESIDUE SELECTIVE SO WE

413
00:17:37,364 --> 00:17:38,766
CANNOT KNOW THE DISTANCE

414
00:17:38,766 --> 00:17:40,401
CONSTRAINTS BETWEEN THE PEPTIDE

415
00:17:40,401 --> 00:17:45,072
LIGAND IS THE GPCR RECEPTOR.

416
00:17:45,072 --> 00:17:46,373
AND HERE GEX PROVIDED THE

417
00:17:46,373 --> 00:17:48,642
SOLUTION, SINCE WE ALL KNOW, GEX

418
00:17:48,642 --> 00:17:50,211
IS THE RESIDUE AND THE DISTANCE

419
00:17:50,211 --> 00:17:52,980
SPECIFIC, WE COULD USE THE 2

420
00:17:52,980 --> 00:17:54,748
PINPOINT THE EXACT CONTACT

421
00:17:54,748 --> 00:17:57,952
POINTS BETWEEN THE CRF AND THE

422
00:17:57,952 --> 00:17:58,219
RECEPTOR.

423
00:17:58,219 --> 00:18:00,821
SO WHAT WE DID IS INTRODUCE THIS

424
00:18:00,821 --> 00:18:02,490
EFFECT ON END TERMINAL ACID ON

425
00:18:02,490 --> 00:18:04,458
DIFFERENT POSITIONS OF THIS CIF

426
00:18:04,458 --> 00:18:07,428
1 R, AND ASSISTING IN THE

427
00:18:07,428 --> 00:18:07,795
PEPTIDE LIGAND.

428
00:18:07,795 --> 00:18:09,497
WE THROW IN THIS PEPTIDE LIGAND

429
00:18:09,497 --> 00:18:12,399
INTO THE LIVE CELLS, AND THEN

430
00:18:12,399 --> 00:18:13,901
ANALYZE, IF THE RECEPTOR

431
00:18:13,901 --> 00:18:15,703
CAPTURED A LIGAND USING WESTERN

432
00:18:15,703 --> 00:18:18,038
BLOT ANALYSIS OF THE CELL

433
00:18:18,038 --> 00:18:19,740
LIAISON SAIT.

434
00:18:19,740 --> 00:18:21,475
AND THIS RESULT TELLS US WHICH

435
00:18:21,475 --> 00:18:23,644
RESIDUE IN THE RECEPTOR IS IN

436
00:18:23,644 --> 00:18:24,612
CONTACT WITH THE SPECIFIC

437
00:18:24,612 --> 00:18:27,214
RESIDUE IN THE PEPTIDE LIGAND AS

438
00:18:27,214 --> 00:18:31,352
SHOWN BY THE MATCHING COLOR IN

439
00:18:31,352 --> 00:18:31,886
THIS DIAGRAM HERE.

440
00:18:31,886 --> 00:18:33,587
SO BASED ON THIS CONSTRAINT

441
00:18:33,587 --> 00:18:37,892
INFORMATION AS WELL AS THE

442
00:18:37,892 --> 00:18:40,861
STRUCTURE OF INDIVIDUAL GBCR

443
00:18:40,861 --> 00:18:41,929
SEPARATELY, NOWY WERE ABLE TO

444
00:18:41,929 --> 00:18:45,266
BUILD A MODEL FOR THE CRF LIGAND

445
00:18:45,266 --> 00:18:48,269
BINDING TO THE FULL LENGTH TPC

446
00:18:48,269 --> 00:18:49,904
R, PROVIDING THIS INSIGHT INTO

447
00:18:49,904 --> 00:18:52,006
RECEPTOR ACTIVATION AND

448
00:18:52,006 --> 00:18:52,306
INHIBITION.

449
00:18:52,306 --> 00:18:55,676
AS YOU CAN SEE HERE, ALL THE

450
00:18:55,676 --> 00:18:57,745
INFORMATION WE HAVE IS ON THE

451
00:18:57,745 --> 00:19:00,214
CELL SURFACE WHICH CAN

452
00:19:00,214 --> 00:19:01,682
COMPLEMENT WHAT PEOPLE CAN

453
00:19:01,682 --> 00:19:07,188
PORTEND LATER USING THIS OR

454
00:19:07,188 --> 00:19:07,755
CRYOEM STRUCTURES.

455
00:19:07,755 --> 00:19:09,323
TAKING A BOLDER STEP BEYOND THE

456
00:19:09,323 --> 00:19:13,694
CELL SURFACE, WE NEXT APPLY GEX

457
00:19:13,694 --> 00:19:14,528
INSIDE LIVE CELLS TO KACCT

458
00:19:14,528 --> 00:19:16,597
TININE PATHWAY IRB

459
00:19:16,597 --> 00:19:17,998
PROTEIN-PROTEIN INTERACTIONS SO

460
00:19:17,998 --> 00:19:20,367
THE STRATEGY IS TO INCORPORATE

461
00:19:20,367 --> 00:19:22,703
THE LATENT END TERMINAL INTO OUR

462
00:19:22,703 --> 00:19:23,871
TARGET PROTEIN WHICH IS

463
00:19:23,871 --> 00:19:27,908
EXPRESSED WITHIN LIVE CELLS.

464
00:19:27,908 --> 00:19:29,343
WHENEVER AN UNKNOWN PROTEIN

465
00:19:29,343 --> 00:19:31,278
ACTIVATES PROTEIN OF INTEREST,

466
00:19:31,278 --> 00:19:34,148
THEN THE BIO'S ACTIVE TERMINAL

467
00:19:34,148 --> 00:19:36,650
ACID REACT WITH FLRL RESIDUE ON

468
00:19:36,650 --> 00:19:39,186
TO THIS UNKNOWN PROTEIN

469
00:19:39,186 --> 00:19:40,120
IRREVERSIBLY CAPTURE IT AND

470
00:19:40,120 --> 00:19:41,956
ALLOW US TO DO SUBSEQUENT

471
00:19:41,956 --> 00:19:44,858
PROCESSING AND IDENTIFY THIS

472
00:19:44,858 --> 00:19:45,859
UNKNOWN PROTEIN USING MASS SPEC.

473
00:19:45,859 --> 00:19:47,928
AS CAN YOU SEE, YOU KNOW IN

474
00:19:47,928 --> 00:19:51,398
ADDITION TO WORKING IN LIVE

475
00:19:51,398 --> 00:19:54,468
CELLS, OUR GEX MECHANISM HAS A

476
00:19:54,468 --> 00:19:56,403
MAJOR ADVANTAGE AS SPONTANEOUS

477
00:19:56,403 --> 00:19:57,471
REACTION AND LONG REACTION

478
00:19:57,471 --> 00:20:00,207
WINDOW WHICH ALLOW IT TO ENRICH,

479
00:20:00,207 --> 00:20:04,712
WEAK AND INTRENSENT PROTEIN ISHT

480
00:20:04,712 --> 00:20:11,619
ACTIONS INIMPROVING SENSITIVITY

481
00:20:11,619 --> 00:20:12,353
FOR IDENTICTION.

482
00:20:12,353 --> 00:20:15,322
THIOREDOXIN IS AN ENZYME THAT

483
00:20:15,322 --> 00:20:17,691
CAN REDUCE THE DISULPHIDE BOUNDS

484
00:20:17,691 --> 00:20:18,959
OF THE PROTEINS.

485
00:20:18,959 --> 00:20:20,728
TO IDENTIFY THIS IN THE PROTEIN

486
00:20:20,728 --> 00:20:25,532
IN OH COAL I WE INCORPORATE THIS

487
00:20:25,532 --> 00:20:33,474
UAA BPRY INTO NEAR THE ACTIVE

488
00:20:33,474 --> 00:20:36,110
SITE AND PROTEIN, WE EXPRESS

489
00:20:36,110 --> 00:20:38,846
THIS CONTINUOUS REDOXON IN

490
00:20:38,846 --> 00:20:40,447
E.COLI, AND WESTERN BLOT AND

491
00:20:40,447 --> 00:20:42,750
ACID OF THE CELL LIAISON SAIT TO

492
00:20:42,750 --> 00:20:44,885
SHOW THE MULTIPLE BENS WITH

493
00:20:44,885 --> 00:20:47,454
HIGHER MOLECULAR WEIGHT AND

494
00:20:47,454 --> 00:20:49,857
REDOXON AND THIS BEN WILL PULL

495
00:20:49,857 --> 00:20:52,593
DOWN AND IDENTIFY MASS

496
00:20:52,593 --> 00:20:53,861
SPECTROMETRY.

497
00:20:53,861 --> 00:20:54,962
THIS SCHEMA HAS 205 PROTEINS

498
00:20:54,962 --> 00:20:56,930
THAT DIRECTLY BINDS TO THE

499
00:20:56,930 --> 00:21:00,434
THIOREDOXIN AND THE RESULTING

500
00:21:00,434 --> 00:21:02,703
PROTEIN ISHT ACTION NETWORK

501
00:21:02,703 --> 00:21:04,305
PROVIDES NEW SIZE INTO THE

502
00:21:04,305 --> 00:21:06,707
REDUCTION ROW IN REGULATING

503
00:21:06,707 --> 00:21:11,645
METABOLISM, DNA DAMAGE REPAIR

504
00:21:11,645 --> 00:21:12,646
AND OTHER PROCESSES.

505
00:21:12,646 --> 00:21:14,615
OF COURSE, THE SYSTEM IS NOT

506
00:21:14,615 --> 00:21:17,484
ALWAYS AVAILABLE FOR TARGETING.

507
00:21:17,484 --> 00:21:19,820
AND THAT WHY WE DEVELOP THE FSY

508
00:21:19,820 --> 00:21:22,990
AND FSK ON THESE 2 END TERMINAL

509
00:21:22,990 --> 00:21:26,293
ASIT TO TARGET THE MORE ABUNDANT

510
00:21:26,293 --> 00:21:27,194
TYROSEEN AND EFTHIMIOSINE

511
00:21:27,194 --> 00:21:28,729
RESIDUE, WE SHOULD HAVE A BROAD

512
00:21:28,729 --> 00:21:30,597
RANGE OF PROTEINS SO WE CAN

513
00:21:30,597 --> 00:21:31,398
CAPTURE.

514
00:21:31,398 --> 00:21:33,167
ADDITIONALLY, WE THINK FSY, AND

515
00:21:33,167 --> 00:21:35,035
FSK CAN BE PLACED INTO THE

516
00:21:35,035 --> 00:21:37,871
PERIPHERY OF THE PROTEIN INSTEAD

517
00:21:37,871 --> 00:21:39,740
OF THE BINDING IRPT FACE OR THE

518
00:21:39,740 --> 00:21:43,344
ACTIVE SITE TO MINIMIZE

519
00:21:43,344 --> 00:21:43,677
INTERFERENCE.

520
00:21:43,677 --> 00:21:46,914
SO TO TEST THIS IDEA, WE

521
00:21:46,914 --> 00:21:49,049
INCORPORATE FSY AND FSK AGAIN

522
00:21:49,049 --> 00:21:50,517
INTO THIOREDOXIN BUT THIS TIME

523
00:21:50,517 --> 00:21:53,454
FURTHER AWAY FROM THE ACTIVE

524
00:21:53,454 --> 00:21:53,687
SITE.

525
00:21:53,687 --> 00:21:55,556
WOE THEN EXPRESS THIS MUTANT

526
00:21:55,556 --> 00:21:57,658
PROTEINS IN E.COLI AND NOW YOU

527
00:21:57,658 --> 00:22:00,461
CAN SEE ON WESTERN BLOT, WOO WE

528
00:22:00,461 --> 00:22:02,596
CAN ADENTIFY MORE SUBSTRATE

529
00:22:02,596 --> 00:22:04,565
PROTEINS OF THIOREDOXIN COMPARED

530
00:22:04,565 --> 00:22:10,604
TO USING THE BPRY OUT OF THE

531
00:22:10,604 --> 00:22:11,672
ACTIVE SITE.

532
00:22:11,672 --> 00:22:14,341
IN ADDITION TO COVALENT, THE

533
00:22:14,341 --> 00:22:16,944
PROTEINS WE RECENTLY ENABLED

534
00:22:16,944 --> 00:22:18,812
GENETIC ENCODED CHEMICAL CROSS

535
00:22:18,812 --> 00:22:20,547
LINKING OF RNA, AND OTHER

536
00:22:20,547 --> 00:22:31,091
DIFFERENT CLASS OF BIOMOLECULES.

537
00:22:32,025 --> 00:22:33,327
PROTEIN INTERACTIONS REGULATE

538
00:22:33,327 --> 00:22:37,598
NEAR ALL ASPECTS OF RNA

539
00:22:37,598 --> 00:22:38,999
INCLUDING PRERNA SPICING, RNA

540
00:22:38,999 --> 00:22:41,201
MODIFICATION TRANSLATION AND

541
00:22:41,201 --> 00:22:41,702
DEGRADATION.

542
00:22:41,702 --> 00:22:43,804
RECENT STUDIES HAVE ALSO

543
00:22:43,804 --> 00:22:46,407
REVEALED THAT ON THE BINDING

544
00:22:46,407 --> 00:22:48,742
PROTEINS, CAN BIND RNA THROUGH

545
00:22:48,742 --> 00:22:50,644
THE INTRINSIC DISORDER REGIONS

546
00:22:50,644 --> 00:22:54,047
SO TO FULLY UNDERSTAND THIS

547
00:22:54,047 --> 00:22:56,350
COMPLEX REGULATORY MECHANISM,

548
00:22:56,350 --> 00:22:57,418
AND UNCOVER NEW INSIGHTS, IT IS

549
00:22:57,418 --> 00:23:01,755
CRUCIAL TO IESHES DENTIFY

550
00:23:01,755 --> 00:23:03,123
PROTEIN INTERACTIONS IN VIVO,

551
00:23:03,123 --> 00:23:05,192
OOH DIALLY WITH SINGLE

552
00:23:05,192 --> 00:23:11,432
NUCLEOTIDE AND A SINGLE  IMMUNO

553
00:23:11,432 --> 00:23:11,832
RESOLUTION.

554
00:23:11,832 --> 00:23:16,303
THE MOST WIDELY USED METHOD

555
00:23:16,303 --> 00:23:18,839
CURRENTLY IS THE NUCLEICIDE

556
00:23:18,839 --> 00:23:19,273
BASED CROSS LINKING.

557
00:23:19,273 --> 00:23:21,642
WHEN EXPOSED TO UV LIGHT, THE

558
00:23:21,642 --> 00:23:23,710
BASEOT NUCLEOICIDE CAN GENERATE

559
00:23:23,710 --> 00:23:26,914
RADICALS, WHICH CAN CROSS LINK

560
00:23:26,914 --> 00:23:29,550
AMINO ACID RESIDUES COMBINED

561
00:23:29,550 --> 00:23:30,717
WITH THE IMMUNOPRECIPITATION AND

562
00:23:30,717 --> 00:23:32,753
HIGH THROUGH PUT SEQUENCING WE

563
00:23:32,753 --> 00:23:34,521
CAN IDENTIFY THE TARGETS OF THE

564
00:23:34,521 --> 00:23:40,294
SPECIFIC RNA BYPASSING PROTEINS.

565
00:23:40,294 --> 00:23:45,332
UNFORTUNATELY, CROSS LINKING AS

566
00:23:45,332 --> 00:23:47,568
BIAS PREFERENCE FOR THE

567
00:23:47,568 --> 00:23:49,036
[INDISCERNIBLE] MAKING IT

568
00:23:49,036 --> 00:23:51,572
DIFFICULT TO STUDY REGIONS OF

569
00:23:51,572 --> 00:23:51,939
[INDISCERNIBLE].

570
00:23:51,939 --> 00:23:54,908
AS I MENTIONED EARLIER IT IS

571
00:23:54,908 --> 00:23:56,243
NONRESIDUE SELECTIVE AND

572
00:23:56,243 --> 00:23:57,177
THEREFORE MAKING IT A CHALLENGE

573
00:23:57,177 --> 00:24:01,782
TO ACHIEVE AMINO ACID RESOLUTION

574
00:24:01,782 --> 00:24:05,519
EMPLOY AND, BECAUSE THE REACTION

575
00:24:05,519 --> 00:24:07,788
IS NONSPECIFIC, THEREFORE, IT'S

576
00:24:07,788 --> 00:24:09,323
INFEASIBLE TO ENGINEER PRECISE

577
00:24:09,323 --> 00:24:19,766
COVALENT LINKAGES BETWEEN

578
00:24:20,334 --> 00:24:22,603
PROTEINS AND RNA.

579
00:24:22,603 --> 00:24:27,641
AND THIS UAA, WILL REACTIVE WITH

580
00:24:27,641 --> 00:24:29,676
NUCLEOTIDEOT RNA WHEN THE RNA

581
00:24:29,676 --> 00:24:30,744
BINDING PROTEIN IRPT ACT WITH

582
00:24:30,744 --> 00:24:30,978
THE RNA.

583
00:24:30,978 --> 00:24:32,980
AS CAN YOU SEE, NOW THE

584
00:24:32,980 --> 00:24:35,148
REACTIVITY COMES FROM THE

585
00:24:35,148 --> 00:24:37,651
PROTEIN INSTEAD OF COMING FROM

586
00:24:37,651 --> 00:24:38,018
THE RNA.

587
00:24:38,018 --> 00:24:44,124
IF WE ARE ABLE TO TALK AT A 2

588
00:24:44,124 --> 00:24:47,160
PRIME HYDROXYL GROUP ON THE

589
00:24:47,160 --> 00:24:47,828
[INDISCERNIBLE], THEN WE SHOULD

590
00:24:47,828 --> 00:24:51,865
BE ABLE TO ELIMINATE THE

591
00:24:51,865 --> 00:24:54,368
NUCLEOTIDE BIAS, AND SINCE

592
00:24:54,368 --> 00:24:54,902
APPROXIMATELY ENABLED

593
00:24:54,902 --> 00:24:56,270
REACTIVITY, DOESN'T REQUIRE AN

594
00:24:56,270 --> 00:24:59,473
EXTERNAL TRIGGER, SO WE THINK

595
00:24:59,473 --> 00:25:00,874
THIS IS--SHOULD HAVE WORKED BOTH

596
00:25:00,874 --> 00:25:02,376
IN CELLS AND IN VIVO.

597
00:25:02,376 --> 00:25:05,546
IN ADIG THE REACTION OCCURS

598
00:25:05,546 --> 00:25:08,749
EXCLUSIVELY BETWEEN THE UNEND

599
00:25:08,749 --> 00:25:10,417
TERMINAL AND THE BIONUCLEOTIDE

600
00:25:10,417 --> 00:25:12,319
AND THEREFORE SHOULD PROVIDE A

601
00:25:12,319 --> 00:25:22,095
SINGLE AMINO ACID RESOLUTION AND

602
00:25:22,095 --> 00:25:29,736
SINGLE NUCLEOTIDE RESOLUTION.

603
00:25:29,736 --> 00:25:33,140
WE USE THE [INDISCERNIBLE]

604
00:25:33,140 --> 00:25:35,676
MATURE RNA, TO STUDY MATURE RNA.

605
00:25:35,676 --> 00:25:41,214
ON THE CRYSTAL STRUCTURE, NEAR

606
00:25:41,214 --> 00:25:43,450
THE CLEAVAGE SIDE POSITIONS IN

607
00:25:43,450 --> 00:25:45,786
THE SITE TO [INDISCERNIBLE] THE

608
00:25:45,786 --> 00:25:48,322
BOWPPED RNA.

609
00:25:48,322 --> 00:25:54,528
AFTER INCUBATING THIS MUTANT

610
00:25:54,528 --> 00:25:57,531
CAS13 B, WE FOWBD IT WAS ABLE TO

611
00:25:57,531 --> 00:26:01,168
CAPTURE THE PRECURSOR RNA

612
00:26:01,168 --> 00:26:01,702
REGARDLESS OF NUCLEOTIDE

613
00:26:01,702 --> 00:26:04,371
IDENTITY OUT OF THE CLEAVAGE

614
00:26:04,371 --> 00:26:06,306
SITE.

615
00:26:06,306 --> 00:26:09,076
THIS DEMONSTRATES THAT GECX-RNA

616
00:26:09,076 --> 00:26:15,849
CAN TARGET THE RTHIS,A WITHOUT

617
00:26:15,849 --> 00:26:16,617
THE NUCLEOTIDE BIAS.

618
00:26:16,617 --> 00:26:23,857
TO DEMON TRAIT THE UTILITY OF

619
00:26:23,857 --> 00:26:27,027
GECX- RNA, WE DEVELOP THE

620
00:26:27,027 --> 00:26:28,829
TECHNOLOGY TO MAP THE

621
00:26:28,829 --> 00:26:30,030
MODIFICATION ACROSS THE

622
00:26:30,030 --> 00:26:34,735
TRANSCRIPT ORDER OF MICRONS.

623
00:26:34,735 --> 00:26:36,269
IT REGULATES MRNA FUNCTION.

624
00:26:36,269 --> 00:26:39,072
WHILE SEVERAL DETECTION METHODS

625
00:26:39,072 --> 00:26:41,541
ALREADY EXIST THEY EITHER LACK

626
00:26:41,541 --> 00:26:43,076
SINGLE NUCLEOTIDE RESOLUTION OR

627
00:26:43,076 --> 00:26:44,311
LACK OF PROTEIN SPECIFICITY OR

628
00:26:44,311 --> 00:26:48,315
THEY RELY ON THE ANTIBODY FOR

629
00:26:48,315 --> 00:26:48,782
INVITRO RECOGNITION.

630
00:26:48,782 --> 00:26:53,754
OUR GOAL IS TRYING TO DETECT THE

631
00:26:53,754 --> 00:26:55,956
M6A DIRECT IN SALES WITH BOTH

632
00:26:55,956 --> 00:27:05,499
SINGLE NUCLEOTIDE RESOLUTION AND

633
00:27:05,499 --> 00:27:06,800
PROTEIN SPECIFICITY.

634
00:27:06,800 --> 00:27:08,969
OUR STRATEGY INVOLVES EXPRESSING

635
00:27:08,969 --> 00:27:11,638
THE M6A READER PROTEIN IN LIVE

636
00:27:11,638 --> 00:27:15,509
CELLS TO RECOGNIZE M6A.

637
00:27:15,509 --> 00:27:17,244
AND LATENT BIOREACTIVE END

638
00:27:17,244 --> 00:27:18,111
TERMINAL ACID IS INCORPORATED

639
00:27:18,111 --> 00:27:20,180
INTO THE READER PROTEIN NEAR THE

640
00:27:20,180 --> 00:27:22,683
M6 A BINDING SITE.

641
00:27:22,683 --> 00:27:24,951
ONCE THE READER PROTEIN

642
00:27:24,951 --> 00:27:31,124
RECOGNIZE THE M6 A THROUGH THE

643
00:27:31,124 --> 00:27:33,427
GECX-RNA MECHANISM, THEN WE

644
00:27:33,427 --> 00:27:34,928
CROSS LINK THIS NUCLEI O TIDEOT

645
00:27:34,928 --> 00:27:36,830
RNA OF THE AND THEN THIS COMPLEX

646
00:27:36,830 --> 00:27:38,665
IS PULLED DOWN AND THE PROTEIN

647
00:27:38,665 --> 00:27:40,400
WAS DIGESTED TO RELEASE THE

648
00:27:40,400 --> 00:27:41,768
CAPTURED RNA.

649
00:27:41,768 --> 00:27:43,904
THIS CAPTURED RNA, IS THEN

650
00:27:43,904 --> 00:27:45,739
REVERSE TRANSCRIBED WITH THE

651
00:27:45,739 --> 00:27:48,709
PROCESS TERMINATED AT THE CROSS

652
00:27:48,709 --> 00:27:49,142
LINKING SITE.

653
00:27:49,142 --> 00:27:52,045
DUE TO THE PRESENCE OF THE END

654
00:27:52,045 --> 00:27:54,247
TERMINAL ACID, AND THIS RNA

655
00:27:54,247 --> 00:27:55,782
TRANSCRIPTS WILL BE PC R

656
00:27:55,782 --> 00:27:57,150
AMPLIFIED AND THEN SEQUENCED IN

657
00:27:57,150 --> 00:28:00,220
HIGH THROUGH PUT AND THIS WILL

658
00:28:00,220 --> 00:28:03,156
REVEAL ALL THE CROSS LINKING

659
00:28:03,156 --> 00:28:05,225
SITES, THEN WOANS WE KNOW THE

660
00:28:05,225 --> 00:28:07,694
CROSS LINKING SITES WE THEN

661
00:28:07,694 --> 00:28:09,596
EXPECT THE M6A SITE SHOULD BE

662
00:28:09,596 --> 00:28:11,131
ADJACENT TO THE IDENTIFY THE

663
00:28:11,131 --> 00:28:15,202
CROSS LINK IN SIZE, SO FOR THIS

664
00:28:15,202 --> 00:28:16,937
EXPERIMENT, WE USED THE WIDE

665
00:28:16,937 --> 00:28:20,173
URGE OF THE MEN OF THE M6A

666
00:28:20,173 --> 00:28:24,478
READER PROTEIN, AS M6 A READER

667
00:28:24,478 --> 00:28:24,978
PROTEIN.

668
00:28:24,978 --> 00:28:26,913
AND WE INCORPORATE END TERMINAL

669
00:28:26,913 --> 00:28:30,117
ACID FSY INTO THE M6A BINDING

670
00:28:30,117 --> 00:28:31,885
SITE OF THIS YTH DEMAND AND

671
00:28:31,885 --> 00:28:34,588
PUTTING IT CLOSE TO THE M6A

672
00:28:34,588 --> 00:28:43,597
SHOWN IN BLUE HERE.

673
00:28:43,597 --> 00:28:48,535
WE TESTED THAT TESTED THIS

674
00:28:48,535 --> 00:28:49,436
[INDISCERNIBLE] TECHNOLOGY IN

675
00:28:49,436 --> 00:28:50,737
THE CELLS.

676
00:28:50,737 --> 00:28:52,472
HERE IT SHOWS THE PEAKS OF 1

677
00:28:52,472 --> 00:28:55,776
EXAMPLE AS YOU CAN SEE THE PEAKS

678
00:28:55,776 --> 00:28:57,277
TERMINATED ALREADY, SOME OF THEM

679
00:28:57,277 --> 00:28:59,412
AT THE M6A SITE, WE THEN

680
00:28:59,412 --> 00:29:02,516
ANALYZED ALL THE NUCLEOTIDES

681
00:29:02,516 --> 00:29:05,385
SURROUNDING THIS TERMINATION

682
00:29:05,385 --> 00:29:06,686
PEAKS AND FOUND THEY ARE

683
00:29:06,686 --> 00:29:09,422
ENRICHED WITH THIS DARK MOTIF

684
00:29:09,422 --> 00:29:12,125
WHICH IS CONSISTENT WITH THE

685
00:29:12,125 --> 00:29:13,794
CONSENT MOTIVE OF M6A, AND IN

686
00:29:13,794 --> 00:29:16,997
ADDITION WE FOUND THAT CROSS

687
00:29:16,997 --> 00:29:18,632
LINKING SITE, PRIMARILY AT THE

688
00:29:18,632 --> 00:29:20,333
MINUS STARTER POSITION RELATIVE

689
00:29:20,333 --> 00:29:22,068
TO THE M6A MODEL

690
00:29:22,068 --> 00:29:22,736
CITIZENIFICATION INDICATING THIS

691
00:29:22,736 --> 00:29:27,207
APPROACH GAVE US A SINGLE

692
00:29:27,207 --> 00:29:28,675
NUCLEOTIDE RESOLUTION EMPLOY SO

693
00:29:28,675 --> 00:29:31,645
USING THIS APPROACH WE PREDICTED

694
00:29:31,645 --> 00:29:38,285
A TOTAL OF ALMOST 14,000 M6 A

695
00:29:38,285 --> 00:29:39,619
SIDE FOR DEMAND.

696
00:29:39,619 --> 00:29:42,756
AND 6000 ISA A KNOWN M6A SITE

697
00:29:42,756 --> 00:29:47,794
APPROACH AND THE REST ALMOST

698
00:29:47,794 --> 00:29:48,628
8000 NEWLY IDENTIFIED.

699
00:29:48,628 --> 00:29:53,033
IN SUMMARY AS YOU CAN SEE, OUR

700
00:29:53,033 --> 00:29:54,734
METHOD CAN RECOGNIZE M6A

701
00:29:54,734 --> 00:29:58,238
DIRECTING LIVE CELLS HAS

702
00:29:58,238 --> 00:29:58,839
PROTEIN--READER PROTEIN

703
00:29:58,839 --> 00:30:00,273
SPECIFICITY, AND THEREFORE WE

704
00:30:00,273 --> 00:30:01,908
ANTICIPATE THIS CAN BE SIMILARLY

705
00:30:01,908 --> 00:30:05,011
BE USED TO MAP ALL THE OTHER

706
00:30:05,011 --> 00:30:06,847
MODISHS IN CELLS AS LONG AS YOU

707
00:30:06,847 --> 00:30:14,788
HAVE A PROTEIN TO RECOGNIZE THE

708
00:30:14,788 --> 00:30:15,188
RNA MODIFICATION.

709
00:30:15,188 --> 00:30:17,958
NEXT I WOULD LIKE TO DISCUSS

710
00:30:17,958 --> 00:30:19,226
GENETIC ENCODED CHEMICAL CROSS

711
00:30:19,226 --> 00:30:20,861
LINKING OF CARBON HYDRATES AND

712
00:30:20,861 --> 00:30:30,503
METHOD WE REFER TO AS

713
00:30:30,503 --> 00:30:30,837
GECX SUGAR.

714
00:30:30,837 --> 00:30:32,205
PROTEIN GLYCAN INTERACTIONS PLAY

715
00:30:32,205 --> 00:30:35,108
A CRUCIAL ROLE IN VARIOUS

716
00:30:35,108 --> 00:30:37,277
BIOLOGICAL PROCESSES, RAINCHLING

717
00:30:37,277 --> 00:30:38,812
FROM INTERSPECIES COMMUNICATION

718
00:30:38,812 --> 00:30:40,080
TO INTERSPECIES RECOGNITION

719
00:30:40,080 --> 00:30:45,619
EMPLOY FOR INITANCE, THE BINDING

720
00:30:45,619 --> 00:30:49,923
OF C-GLYCOPROTEIN TO THE FLI

721
00:30:49,923 --> 00:30:52,225
COLSIS CAN AND REACH THE

722
00:30:52,225 --> 00:30:53,593
SELF-RECOGNITION IN OUR IMMUNE

723
00:30:53,593 --> 00:30:57,097
SYSTEM. 

724
00:30:57,097 --> 00:30:59,866
AND IN FACT, VIRAL PATHOIENS CAN

725
00:30:59,866 --> 00:31:02,669
EXPLOIT THE [INDISCERNIBLE] TO

726
00:31:02,669 --> 00:31:05,171
INHIBITOR C-GLAC ON THE CELLS

727
00:31:05,171 --> 00:31:08,975
THEREFORE TO EVADE IMMUNE

728
00:31:08,975 --> 00:31:09,242
DETECTION.

729
00:31:09,242 --> 00:31:12,145
SIMILARLY TUMOR CELLS CAN

730
00:31:12,145 --> 00:31:13,346
UPREGULATE THE SALIC GLUE

731
00:31:13,346 --> 00:31:15,115
MARIOUS GAND ON THE SURFACE AND

732
00:31:15,115 --> 00:31:19,619
USE THIS TO ENGAGE THE SIGLEC ON

733
00:31:19,619 --> 00:31:21,588
THE IMMUNE CELLS'DING TO IMMUNE

734
00:31:21,588 --> 00:31:28,695
ESCAPE AND CANCER PROGRESSION

735
00:31:28,695 --> 00:31:29,362
AND METASTASIS.

736
00:31:29,362 --> 00:31:32,232
>> DESPITE THE ESSENTIAL
ROLE IN

737
00:31:32,232 --> 00:31:34,267
MOLECULAR RECOGNITION, THE

738
00:31:34,267 --> 00:31:35,101
PROTEIN GLYCAN INTERACTIONS HAVE

739
00:31:35,101 --> 00:31:39,172
BEEN VERY DIFFICULT TO STUDY,

740
00:31:39,172 --> 00:31:41,207
MANY OTHER DIFFICULTIES IN MAJOR

741
00:31:41,207 --> 00:31:42,542
CHALLENGE OF 1 HIGHLIGHTER HERE

742
00:31:42,542 --> 00:31:46,279
IS THE LO AFFINITY BETWEEN A

743
00:31:46,279 --> 00:31:50,016
SINGLE GLYCAN, A SINGLE SUGAR

744
00:31:50,016 --> 00:31:52,185
PROTEIN RECOGNITION WITH KD,

745
00:31:52,185 --> 00:31:54,020
DISASSOCIATION CONITANT OFTEN IN

746
00:31:54,020 --> 00:31:59,125
THE HIGH MICROMOLAR AND IN THE

747
00:31:59,125 --> 00:32:00,293
MINIMOLER RANGE.

748
00:32:00,293 --> 00:32:01,995
SINCE THE BINDING AFFINITY IS SO

749
00:32:01,995 --> 00:32:05,365
LOW, SO WE THOUGHT CAN WE ON

750
00:32:05,365 --> 00:32:07,701
COVALENTLY STABILIZE PROTEIN FLI

751
00:32:07,701 --> 00:32:08,535
COLSIS KAN--KANA INTERACTION

752
00:32:08,535 --> 00:32:10,603
THEREFORE TO BETTER STUDY IT?

753
00:32:10,603 --> 00:32:15,108
HOWEVER, WE FOUND THERE WAS NO

754
00:32:15,108 --> 00:32:16,609
REACTION THAT CAN REACT WITH

755
00:32:16,609 --> 00:32:18,311
GLYCAN UNDER VERY MILD

756
00:32:18,311 --> 00:32:20,880
CONDITIONS, SO WE HAVE TO TART

757
00:32:20,880 --> 00:32:22,282
TO IDENTIFY A FUVENGZAL GROUP

758
00:32:22,282 --> 00:32:24,684
THAT IT CAN REACTIVE WITH FLI

759
00:32:24,684 --> 00:32:26,519
COLSIS KAN--KANA UNDER

760
00:32:26,519 --> 00:32:29,289
BIOCOMPATIBLE CONDITIONS. 

761
00:32:29,289 --> 00:32:30,924
TO DO THIS, WE DEVELOP A PLAN

762
00:32:30,924 --> 00:32:35,261
AND A PLAN, AND A CROSS LINK

763
00:32:35,261 --> 00:32:35,628
[INDISCERNIBLE].

764
00:32:35,628 --> 00:32:40,333
WE FIRST INCUBATE THE

765
00:32:40,333 --> 00:32:44,170
C-GLYCOPROTEIN THE LIGAND OF

766
00:32:44,170 --> 00:32:45,572
GD3, WHEN THEY BIND WITH EACH

767
00:32:45,572 --> 00:32:47,007
OTHER, THEN WE THROW IN A BUNCH

768
00:32:47,007 --> 00:32:48,908
OF CROSS LISTEN INCHINGERS.

769
00:32:48,908 --> 00:32:51,378
ONE END REACTS RAPIDLY WITH THE

770
00:32:51,378 --> 00:32:53,013
PROTEIN, PRIOR TO THE CROSS

771
00:32:53,013 --> 00:32:54,414
LINKING OF THE PROTEIN AND CAST

772
00:32:54,414 --> 00:32:56,483
AT THE OTHER END TOWARD THE

773
00:32:56,483 --> 00:32:57,684
BOUND TBLI KAN--KANA, IF THIS

774
00:32:57,684 --> 00:33:00,420
END REACTIVE WITH OUR GLYCAN,

775
00:33:00,420 --> 00:33:03,156
THEN COVALENT COMPLEX OF A

776
00:33:03,156 --> 00:33:04,491
GLYCAN PROTEIN WILL BE FORMED

777
00:33:04,491 --> 00:33:07,894
AND,A LOW DETECTION EMPLOY SO WE

778
00:33:07,894 --> 00:33:09,829
DECIDED AND THE SLIDE TO SEVERAL

779
00:33:09,829 --> 00:33:14,534
CROSS LINKERS AND DORPHED THAT

780
00:33:14,534 --> 00:33:16,202
THIS FUNCTIONAL GROUP,

781
00:33:16,202 --> 00:33:16,870
[INDISCERNIBLE] FLUORIDE WAS

782
00:33:16,870 --> 00:33:18,571
ABLE TO REACT WITH TBLI

783
00:33:18,571 --> 00:33:19,639
KAN--KANAS WITH MILD CONDITIONS

784
00:33:19,639 --> 00:33:27,380
AND IT'S THE ONLY POSITIVE SPOT

785
00:33:27,380 --> 00:33:28,014
WE DETECTED.

786
00:33:28,014 --> 00:33:33,086
NEXT WE THEN DETERMINED THIS FSY

787
00:33:33,086 --> 00:33:34,454
TO CONTEND TO IDENTIFY THE

788
00:33:34,454 --> 00:33:36,423
FLUORIDE FUMPLEG ALGORITHMS UPON

789
00:33:36,423 --> 00:33:38,224
GROUP AND TO IPT GREATER

790
00:33:38,224 --> 00:33:39,726
CORPORATE THIS END TERMINAL ACID

791
00:33:39,726 --> 00:33:44,064
INTO THE BYPASSING PROTEIN.

792
00:33:44,064 --> 00:33:45,765
AND WE FOUND ONCE THIS END

793
00:33:45,765 --> 00:33:47,534
TERMINAL IS INCORPORATED INTO

794
00:33:47,534 --> 00:33:51,504
THIS SPECIFIC SIZE, IT ENABLED

795
00:33:51,504 --> 00:33:55,008
TO BYPASSED THE SUITE

796
00:33:55,008 --> 00:33:55,608
COVALENTLY.

797
00:33:55,608 --> 00:33:57,644
NEXT WE THEN INCUBATED THE

798
00:33:57,644 --> 00:33:59,946
CANCER CELL LINE THAT HAS HIGH

799
00:33:59,946 --> 00:34:03,583
LEVEL OF THE TBLI CAN WITH THE

800
00:34:03,583 --> 00:34:06,219
[INDISCERNIBLE] OR COVALENT 7

801
00:34:06,219 --> 00:34:06,419
FSY.

802
00:34:06,419 --> 00:34:10,323
AS YOU CAN SEE THE COVALENT

803
00:34:10,323 --> 00:34:13,093
VERSION OF SIGLEC 7 HAS DRAMATIC

804
00:34:13,093 --> 00:34:14,928
INCREASE CELL BINDING COMPARED

805
00:34:14,928 --> 00:34:17,230
TO THE WILD-TYPE SIGLEC 7, AS

806
00:34:17,230 --> 00:34:18,331
SHOWN IN THIS GRAPH HERE,

807
00:34:18,331 --> 00:34:21,568
FURTHER MODEL CITIZEN IF WE

808
00:34:21,568 --> 00:34:24,838
PRETREAT THE CELLS WITH

809
00:34:24,838 --> 00:34:28,441
[INDISCERNIBLE] TO REMOVE THE

810
00:34:28,441 --> 00:34:30,510
SIALOGLYCAN, NOW YOU CAN SEE

811
00:34:30,510 --> 00:34:32,779
IT'S REDUCED TO 1 TENTH OF THE

812
00:34:32,779 --> 00:34:36,116
ORIGINAL LEVEL.

813
00:34:36,116 --> 00:34:38,017
THAT SUPPORTS THE SIGLEC 7 V,

814
00:34:38,017 --> 00:34:46,025
SFY, FOR THIS CANCER CELL

815
00:34:46,025 --> 00:34:47,293
SURFACE.

816
00:34:47,293 --> 00:34:49,329
MANY TUMORS UPREGULATE CELL

817
00:34:49,329 --> 00:34:51,731
SURFACE GLYCAN AND THIS DPLI

818
00:34:51,731 --> 00:34:54,200
KAN--KANA CAN ENGAGE WITH THE

819
00:34:54,200 --> 00:34:56,402
SIGLEC RECEPTOR 7 ON THE HUMAN

820
00:34:56,402 --> 00:34:56,736
CELLS.

821
00:34:56,736 --> 00:35:01,608
THIS IS A INHIBITOR SIGNAL TO

822
00:35:01,608 --> 00:35:02,675
TAXONOMY DOWN THE ABILITY TO

823
00:35:02,675 --> 00:35:06,279
KILL THE CANCER CELLS.

824
00:35:06,279 --> 00:35:10,783
WE ENVISIONED IF WE THROW IN AN

825
00:35:10,783 --> 00:35:13,753
IRREVERSIBLE BINDER THIS SIGLEC

826
00:35:13,753 --> 00:35:15,889
7 V, SFY, WHEN IT BIEBDS TO THE

827
00:35:15,889 --> 00:35:18,925
CANCER CELL SURFACE CELL,

828
00:35:18,925 --> 00:35:20,426
GLYCAN, THIS WILL RELEASE THE

829
00:35:20,426 --> 00:35:22,228
CELL FROM THE INHIBITORY

830
00:35:22,228 --> 00:35:24,063
SIGNALING ACCESS AND THEREFORE

831
00:35:24,063 --> 00:35:25,231
ENHANCED NK CELLS ABILITY TO

832
00:35:25,231 --> 00:35:27,934
KILL THE CANCER CELL.

833
00:35:27,934 --> 00:35:30,770
TO TEST THIS HYPOTHESIS, WE ARE

834
00:35:30,770 --> 00:35:32,005
TREATED 3 DIFFERENT CANCER CELL

835
00:35:32,005 --> 00:35:35,375
LINES, THAT HAS HIGH LEVEL

836
00:35:35,375 --> 00:35:39,712
[INDISCERNIBLE] WITH EITHER

837
00:35:39,712 --> 00:35:42,782
WILD-TYPE SIGLEC 7 OR ANOTHER

838
00:35:42,782 --> 00:35:45,218
VERSION OF SIGLEC7 SFY, AND WE

839
00:35:45,218 --> 00:35:46,853
THEN WASH THE CELLS AND ADD THEM

840
00:35:46,853 --> 00:35:48,388
BACK IN AND MEASURE THE CANCER

841
00:35:48,388 --> 00:35:49,322
CELL DEATH.

842
00:35:49,322 --> 00:35:51,591
AS YOU CAN SEE HERE IN THIS

843
00:35:51,591 --> 00:35:54,327
GRAPH, SHOWN IN RED IS OUR

844
00:35:54,327 --> 00:35:56,529
COVALENTERTION OF THE SIERK GLEC

845
00:35:56,529 --> 00:35:58,064
7 V, AND THEY ENHANCE THE

846
00:35:58,064 --> 00:35:59,499
ABILITY TO KILL CANCER CELLS

847
00:35:59,499 --> 00:36:05,738
COMPARED TO THE WILD-TYPE IN

848
00:36:05,738 --> 00:36:06,339
BLACK HERE.

849
00:36:06,339 --> 00:36:09,642
AND THIS FINDING SUGGESTS THAT

850
00:36:09,642 --> 00:36:11,978
COVALENT TARGETED THE GLYCANOT

851
00:36:11,978 --> 00:36:13,246
CANCER CELL SURFACE, MIGHT IT BE

852
00:36:13,246 --> 00:36:20,520
A NEW APPROACH FOR CANCER

853
00:36:20,520 --> 00:36:20,853
IMMUNOTHERAPY.

854
00:36:20,853 --> 00:36:24,357
IN THE FINAL PART OF MY TALK, I

855
00:36:24,357 --> 00:36:27,560
WILL DISCUSS THAT THE CO

856
00:36:27,560 --> 00:36:29,729
VALENTINEDENT PROTEIN DRUGS

857
00:36:29,729 --> 00:36:33,166
USING PRACTICALS MALLY ENABLED

858
00:36:33,166 --> 00:36:37,337
THERAPEUTICS OR PERX FOR SHORT.

859
00:36:37,337 --> 00:36:39,639
COVALENT SMALL MOLECULES CAN

860
00:36:39,639 --> 00:36:41,040
FORM A COVALENT BOND WITH THEIR

861
00:36:41,040 --> 00:36:42,709
TARGET AFTER THE BINDING, AND

862
00:36:42,709 --> 00:36:44,310
THIS LINK CANCER CENTER OFFERS

863
00:36:44,310 --> 00:36:46,746
SEVERAL ADVANTAGE OVER THE

864
00:36:46,746 --> 00:36:50,183
NONCOVALENT DRUGS SUCH AS

865
00:36:50,183 --> 00:36:51,217
INCREASED POTENCY, PROLONGED

866
00:36:51,217 --> 00:36:53,152
DURATION OF ACTION, LESS

867
00:36:53,152 --> 00:36:56,589
PREQUENT AND DOSING AND THE ABLE

868
00:36:56,589 --> 00:36:58,424
TO TARGET THE PREVIOUSLY

869
00:36:58,424 --> 00:36:59,692
UNDRUGGABLE PROTEINS.

870
00:36:59,692 --> 00:37:02,161
ALTHOUGH THE PHARMACEUTICAL

871
00:37:02,161 --> 00:37:03,129
INDUSTRY, IS TOTALLY AVOIDED

872
00:37:03,129 --> 00:37:06,966
THEM DUE TO CONCERN OF OFF

873
00:37:06,966 --> 00:37:08,134
TARGETED REACTION, COVALENT

874
00:37:08,134 --> 00:37:09,535
SMALL MOLECULE DRUGS HAVE

875
00:37:09,535 --> 00:37:11,170
RESURGED WITH GREAT SUCCESS IN

876
00:37:11,170 --> 00:37:12,372
THE RECENT YEARS.

877
00:37:12,372 --> 00:37:15,575
IN CONTRAST THE POTENTIAL OF

878
00:37:15,575 --> 00:37:18,745
COVALENT PROTEIN DRUGS REMAINS

879
00:37:18,745 --> 00:37:20,380
LARGELY UNEXPLORED DUE TO

880
00:37:20,380 --> 00:37:22,081
PROTEINS TYPICALLY LACK THE

881
00:37:22,081 --> 00:37:26,619
ABILITY TO FORM COVALENT BOUNDS

882
00:37:26,619 --> 00:37:28,821
WITH THEIR TARGETS.

883
00:37:28,821 --> 00:37:31,891
TO ENABLE COVALENT PROTEIN DRUGS

884
00:37:31,891 --> 00:37:33,793
WE DEVELOP THE TECHNOLOGY

885
00:37:33,793 --> 00:37:35,628
RECORDED APPROXIMATELILY ENABLED

886
00:37:35,628 --> 00:37:39,299
THERAPEUTICS, IN THIS APPROACH,

887
00:37:39,299 --> 00:37:40,867
SIMILARLY, WE INCORPORATE LATE

888
00:37:40,867 --> 00:37:42,702
IN THE BIOTERM NASAA.COMITY,

889
00:37:42,702 --> 00:37:44,871
INTO THE PROTEIN DRUG NEAR THE

890
00:37:44,871 --> 00:37:45,838
BINDING INTERFACE.

891
00:37:45,838 --> 00:37:47,607
ONCE THE PROTEIN DRUG BINDS WITH

892
00:37:47,607 --> 00:37:50,777
THE TARGET, THEN THE END

893
00:37:50,777 --> 00:37:53,546
TERMINAL REACT WITH THE RESIDUE

894
00:37:53,546 --> 00:37:54,681
IRREVERSIBLY CROSS LINK THE

895
00:37:54,681 --> 00:37:56,916
PROTEIN DRUG TO ITS TARGET

896
00:37:56,916 --> 00:38:03,656
ESSENTIALLY SERVING AS COVALENT

897
00:38:03,656 --> 00:38:04,657
PROTEIN DRUG.

898
00:38:04,657 --> 00:38:09,929
DURING THE COVID PANDEMIC, WE

899
00:38:09,929 --> 00:38:12,398
DEVELOPED A COVALENT NANO BODIES

900
00:38:12,398 --> 00:38:14,967
TRYING TO INHIBIT CROSS

901
00:38:14,967 --> 00:38:16,336
INFECTION USING THIS PERX

902
00:38:16,336 --> 00:38:16,602
MECHANISM.

903
00:38:16,602 --> 00:38:20,473
AS WE ALL KNOW NOW, THE VIRUS

904
00:38:20,473 --> 00:38:22,342
ENTERS THE CELLS WITH THE SPIKE

905
00:38:22,342 --> 00:38:26,546
PROTEIN WITH THE HUMAN AEC2

906
00:38:26,546 --> 00:38:27,947
RECEPTOR, THE CONVENTIONAL NANO

907
00:38:27,947 --> 00:38:28,648
BODIES AND ANTIBODIES CAN BIND

908
00:38:28,648 --> 00:38:30,650
TO THE SITE TO INHIBIT THIS

909
00:38:30,650 --> 00:38:33,720
PROCESS BUT SUCH BIND SUGGEST

910
00:38:33,720 --> 00:38:34,420
NONCOVALENT AND THEREFORE IT'S

911
00:38:34,420 --> 00:38:37,757
REVERSIBLE AND THIS MAKES

912
00:38:37,757 --> 00:38:38,758
COMPLETE INHIBITION QUITE

913
00:38:38,758 --> 00:38:39,058
CHALLENGING.

914
00:38:39,058 --> 00:38:42,628
WE THOUGHT IF WE USE THE

915
00:38:42,628 --> 00:38:44,497
COVALENT NANO BODY TO

916
00:38:44,497 --> 00:38:45,832
IRREVERSIBLY BIND IT TO THE

917
00:38:45,832 --> 00:38:49,302
SPIKE PROTEIN OF THE VIRUS, THIS

918
00:38:49,302 --> 00:38:51,637
MAY REDUCE THE LIKELIHOOD OF A

919
00:38:51,637 --> 00:38:54,073
VIRAL ESCAPE AND SIGNIFICANTLY

920
00:38:54,073 --> 00:39:00,213
IMPROVE TO ACHIEVE A MORE POTENT

921
00:39:00,213 --> 00:39:00,780
INHIBITION.

922
00:39:00,780 --> 00:39:04,984
WE THEN WORK WITH NANO BODY MMB6

923
00:39:04,984 --> 00:39:07,487
TO FIND OUT A SITE THAT IT CAN

924
00:39:07,487 --> 00:39:09,989
DO THE CROSS LINKING.

925
00:39:09,989 --> 00:39:14,327
WE ACTUALLY KREENED ALL SITES IN

926
00:39:14,327 --> 00:39:17,063
THE REGIONS OF THIS NANO BODY

927
00:39:17,063 --> 00:39:17,563
USING FSY.

928
00:39:17,563 --> 00:39:20,700
AS YOU CAN SEE IN THIS CROSS

929
00:39:20,700 --> 00:39:22,835
LINKING ANALYSIS WE FOUND A

930
00:39:22,835 --> 00:39:24,370
MULTIPLE SIZE ENABLING CROSS

931
00:39:24,370 --> 00:39:26,205
LINKING OF THE VIRAL SPEAK OF

932
00:39:26,205 --> 00:39:29,409
THE PROTEIN IN CDR1 REGION HERE

933
00:39:29,409 --> 00:39:32,612
AND IN CDR3 REGION WE FOUND

934
00:39:32,612 --> 00:39:34,147
MULTIPLE SITES THAT ENABLE CROSS

935
00:39:34,147 --> 00:39:34,480
LINKING.

936
00:39:34,480 --> 00:39:36,649
BECAUSE THIS VIRUS INFECTION IS

937
00:39:36,649 --> 00:39:37,817
A VERY ACUTE PROCESS.

938
00:39:37,817 --> 00:39:41,454
QUEE WOULD LIKE TO ACCELERATE

939
00:39:41,454 --> 00:39:43,423
THE REACTION, TO INTRODUCE THIS

940
00:39:43,423 --> 00:39:45,124
WE INTRODUCED FLUORINE GROUP ON

941
00:39:45,124 --> 00:39:47,226
INTO THE FSY CREATING NEW END

942
00:39:47,226 --> 00:39:50,229
TERMINAL TO THE FFY, AND THIS

943
00:39:50,229 --> 00:39:54,867
INCREASED THE REACTION RATE BY

944
00:39:54,867 --> 00:39:55,034
2.4.

945
00:39:55,034 --> 00:39:57,804
IN BEST CASES WHEN WE

946
00:39:57,804 --> 00:40:00,239
INCORPORATE FFY OF THIS SITE OF

947
00:40:00,239 --> 00:40:02,675
THE MMB6, IT CAN CROSS LINK THE

948
00:40:02,675 --> 00:40:12,218
SPIKE PROTEIN INVITRO WITHIN 10

949
00:40:12,218 --> 00:40:13,419
MINUTES.

950
00:40:13,419 --> 00:40:14,387
TO EVALUATE THE NEUTRALIZATION

951
00:40:14,387 --> 00:40:17,557
EFFICIENCY, WE TREATED THIS

952
00:40:17,557 --> 00:40:20,159
PSEUDOVIRUS OF A SARS-COV-2 WITH

953
00:40:20,159 --> 00:40:22,795
EITHER WILD-TYPE NANO BODY OR

954
00:40:22,795 --> 00:40:25,398
COVALENT NANO BODY AND THENEE

955
00:40:25,398 --> 00:40:30,002
WIEWS THIS MEX TOUR TO EFFECT

956
00:40:30,002 --> 00:40:31,404
THE CELLS, AND THE EFFECTOR

957
00:40:31,404 --> 00:40:32,572
CELLS WERE MEASURED AND PLOTTED

958
00:40:32,572 --> 00:40:34,574
AGAINST THE CONCENTRATION OF THE

959
00:40:34,574 --> 00:40:35,041
NANO BODIED ADDED.

960
00:40:35,041 --> 00:40:37,009
AS YOU CAN SEE IN THIS PLOT, IN

961
00:40:37,009 --> 00:40:41,080
GRAY IS THE WILD-TYPE NANO BODY

962
00:40:41,080 --> 00:40:45,418
WHICH HAS 36 NANO MOLAR.

963
00:40:45,418 --> 00:40:47,153
IN CONTRASTURE COVALENT NANO

964
00:40:47,153 --> 00:40:49,222
BODY WITH THE 1 NANO MOLAR,

965
00:40:49,222 --> 00:40:54,093
SUGGESTING 36 FOLD IMPROVEMENT,

966
00:40:54,093 --> 00:40:56,562
WE FURTHER TESTED THESE NANO

967
00:40:56,562 --> 00:40:58,364
BODIES AGAINST THE AUTHENTIC

968
00:40:58,364 --> 00:40:59,165
SARS-COV-2 VIRUS, AGAIN AS CAN

969
00:40:59,165 --> 00:41:00,800
YOU SEE HERE, THE CO VALENTINED

970
00:41:00,800 --> 00:41:03,269
END NANO BODY ACHIEVED A 40 FOLD

971
00:41:03,269 --> 00:41:07,206
IMPROVEMENT, COMPARED TO THE

972
00:41:07,206 --> 00:41:10,510
WILD-TYPE NANO BODY.

973
00:41:10,510 --> 00:41:12,111
REPRESENTING, SO THIS RESULT

974
00:41:12,111 --> 00:41:14,113
INDICATED THAT A SIGNIFICANT

975
00:41:14,113 --> 00:41:17,450
INCREASE IN POTENCY WHEN YOU

976
00:41:17,450 --> 00:41:20,419
HAVE A COVALENT BOUNDING ABILITY

977
00:41:20,419 --> 00:41:24,690
IN NEUTRALIZING THIS WILD-TYPE

978
00:41:24,690 --> 00:41:25,358
SARS-COV-2.

979
00:41:25,358 --> 00:41:27,793
IN ADDITION TO THE WILD-TYPE

980
00:41:27,793 --> 00:41:29,228
VIRUS, MMB6 WAS ALSO ABLE TO

981
00:41:29,228 --> 00:41:31,130
BIND DIFFERENT VALID AND

982
00:41:31,130 --> 00:41:34,934
RELIABLE YABTS INCLUDING ALPHA,

983
00:41:34,934 --> 00:41:36,569
DELTA, EPISILLSON, AND LAMDA,

984
00:41:36,569 --> 00:41:38,571
AND OF COURSE WE TESTED THE

985
00:41:38,571 --> 00:41:40,306
CROSS LINKING WE FOUND OUR

986
00:41:40,306 --> 00:41:42,441
COVALENT NANO BODY WAS ABLE TO

987
00:41:42,441 --> 00:41:43,809
CROSS LINK THIS CO VALENCE AS

988
00:41:43,809 --> 00:41:44,010
WELL.

989
00:41:44,010 --> 00:41:45,378
IN ADDITION THEY SHOW THAT

990
00:41:45,378 --> 00:41:49,415
DRASTIC INCREASE IN THE POTENCY

991
00:41:49,415 --> 00:41:53,553
IN NEUTRALIZING THIS SARS-COV-2

992
00:41:53,553 --> 00:41:54,587
VARIANTS.

993
00:41:54,587 --> 00:41:56,022
BUT THE MMB6 NANO BODY WAS

994
00:41:56,022 --> 00:42:00,359
UNABLE TO BIND THE LATEST

995
00:42:00,359 --> 00:42:02,061
OMICRON VERYIANT SO WE THEN

996
00:42:02,061 --> 00:42:03,696
ENGINEERED A NANO BODY CALLED

997
00:42:03,696 --> 00:42:09,402
MD70 WHICH WAS ABLE TO BIND TO

998
00:42:09,402 --> 00:42:11,203
THE OMINOCRON VARIANT AND IT

999
00:42:11,203 --> 00:42:13,806
CROSS LINKED THE VARIANT IN HIGH

1000
00:42:13,806 --> 00:42:15,374
EFFICIENCY, THIS ACTUALLY CAN

1001
00:42:15,374 --> 00:42:17,476
ACHIEVE A SIGNIFICANT CROSS

1002
00:42:17,476 --> 00:42:21,514
LINKING WITHIN 5 MINUTES.

1003
00:42:21,514 --> 00:42:24,216
AND AS YOU CAN SEE HERE, IT NANO

1004
00:42:24,216 --> 00:42:25,518
BODY SHOWED 8-10 FOLD INCREASE

1005
00:42:25,518 --> 00:42:27,353
IMPROVEMENT IN THE WILD-TYPE

1006
00:42:27,353 --> 00:42:32,758
NANO BODY IN NEUTRALIZING THIS

1007
00:42:32,758 --> 00:42:33,125
OMICRON VARIANT.

1008
00:42:33,125 --> 00:42:35,461
SO IN SUMMARY WE FOUND THE CO

1009
00:42:35,461 --> 00:42:38,264
VALENTINED EPT NANO BODY ARE

1010
00:42:38,264 --> 00:42:40,666
SIGNIFICANTLY MORE POTENT THAN

1011
00:42:40,666 --> 00:42:43,336
THE WILD-TYPE, IN NEUTRALIZING

1012
00:42:43,336 --> 00:42:47,974
WILD-TYPE SARS-COV-2 AND ITS

1013
00:42:47,974 --> 00:42:48,407
VARIANTS.

1014
00:42:48,407 --> 00:42:50,610
IN A SECOND EXAMPLE, I WOULD

1015
00:42:50,610 --> 00:42:53,679
LIKE TO DEMONSTRATE HOW PERX CAN

1016
00:42:53,679 --> 00:42:54,880
ADDRESS A LONG STANDING

1017
00:42:54,880 --> 00:42:59,418
CHALLENGE IN THE TARGETED RADIO

1018
00:42:59,418 --> 00:43:02,922
AND NUCLEI, TRT, TRT BASICALLY

1019
00:43:02,922 --> 00:43:04,991
AIMS TO THEREFORE RADIO ACTIVITY

1020
00:43:04,991 --> 00:43:09,295
INTO TUMORS VIA MINIMIZING THE

1021
00:43:09,295 --> 00:43:10,796
EXPOSURE TO NORMAL TISSUE.

1022
00:43:10,796 --> 00:43:13,199
AND THE RADIATION HAS A VERY

1023
00:43:13,199 --> 00:43:15,668
UNIQUE ABILITY TO KILL CELLS

1024
00:43:15,668 --> 00:43:16,636
REGARDLESS OF THE DEC MECHANISM

1025
00:43:16,636 --> 00:43:20,840
AND THEREFORE IS CURRENTLY

1026
00:43:20,840 --> 00:43:21,641
EXPERIENCE CLINICAL RESURGENCE,

1027
00:43:21,641 --> 00:43:24,377
HOWEVER A MAJOR CHALLENGE IN THE

1028
00:43:24,377 --> 00:43:28,614
FIELD HAS BEEN HOW TO BALANCE

1029
00:43:28,614 --> 00:43:29,081
EFFICACY WITH SAFETY.

1030
00:43:29,081 --> 00:43:32,184
AS CAN YOU SEE HERE, YOU CAN USE

1031
00:43:32,184 --> 00:43:33,185
CONVENTIONAL ANTIBODY TO

1032
00:43:33,185 --> 00:43:34,520
THEREFORE THE RADIO ISOTOPE, CAN

1033
00:43:34,520 --> 00:43:39,558
YOU ACHIEVE A VERY EFFECTIVE

1034
00:43:39,558 --> 00:43:40,826
TUMOR ACCUMULATION BUT BECAUSE

1035
00:43:40,826 --> 00:43:41,794
ANTIBODIES CAN AT A IN THE BLOOD

1036
00:43:41,794 --> 00:43:43,729
STREAM FOR A LONG TIME, THIS

1037
00:43:43,729 --> 00:43:47,433
INCREASE THE DAMAGE TO NORMAL

1038
00:43:47,433 --> 00:43:48,000
TISSUES.

1039
00:43:48,000 --> 00:43:50,703
IN CONTRAST, YOU CAN USE LO

1040
00:43:50,703 --> 00:43:52,905
MOLECULAR RATE FOR THE RADIO

1041
00:43:52,905 --> 00:43:54,173
ISOTOPE, THIS CAN BE CLEARED

1042
00:43:54,173 --> 00:43:56,976
FROM OUR BLOOD VERY QUICKLY,

1043
00:43:56,976 --> 00:43:58,978
PROVIDING A SAFER PROFILE, BUT

1044
00:43:58,978 --> 00:44:01,714
IN THE MEAN TIME REDUCE TUMOR

1045
00:44:01,714 --> 00:44:04,250
UPTAKE AND REDUCE EFFICACY.

1046
00:44:04,250 --> 00:44:05,885
AND IDEAL RADIO PHARMACEUTICAL

1047
00:44:05,885 --> 00:44:07,186
WOULD BE COMBINING THIS, TOO,

1048
00:44:07,186 --> 00:44:09,789
WHAT IF WE HAVE A FAST PLOOT OF

1049
00:44:09,789 --> 00:44:10,990
CLEARANCE AND HIGHER TUMOR

1050
00:44:10,990 --> 00:44:15,261
UPTAKE, THAT WOULD BE PERFECT.

1051
00:44:15,261 --> 00:44:18,531
SO WE THOUGHT THAT A SMALL

1052
00:44:18,531 --> 00:44:20,933
COVALENT PROTEIN WILL BE--COULD

1053
00:44:20,933 --> 00:44:24,570
SERVE AS AN IDEAL VEHICLE FOR

1054
00:44:24,570 --> 00:44:25,404
RADIO PHARMACEUTICAL, BECAUSE

1055
00:44:25,404 --> 00:44:27,306
IT'S LOW, WE ALLOW IT TO RAPIDLY

1056
00:44:27,306 --> 00:44:28,474
BE CLEARED FROM THE BLOOD

1057
00:44:28,474 --> 00:44:33,245
STREAM, BUT IN THE MEAN TIME,

1058
00:44:33,245 --> 00:44:34,914
ONCE IT'S IRREVERSIBLE TO THE

1059
00:44:34,914 --> 00:44:37,116
BINDING OF THE CANCER ANDROGEN

1060
00:44:37,116 --> 00:44:39,085
GEN, YOU SAY AT A THERE FOR A

1061
00:44:39,085 --> 00:44:43,189
LONGER TIME TO ACHIEVE A MORE

1062
00:44:43,189 --> 00:44:43,489
THERAPEUTIC.

1063
00:44:43,489 --> 00:44:46,025
SO TO TEST THIS CONCEPT WE BEGAN

1064
00:44:46,025 --> 00:44:48,027
WITH COVALENT NANO BODY SPECIFIC

1065
00:44:48,027 --> 00:44:58,404
TO THE HER2 RECEPTOR.

1066
00:45:00,272 --> 00:45:01,474
SIMILARLY WE INCORPORATED FSY

1067
00:45:01,474 --> 00:45:06,278
INTO  THE NANO BODY OF THIS P54

1068
00:45:06,278 --> 00:45:11,851
SITE TO TARGET THE HER2 BY

1069
00:45:11,851 --> 00:45:13,652
TARGETING LYSINE 150 SITE AND WE

1070
00:45:13,652 --> 00:45:16,455
SHOWED THIS COVID AND NANO BODY

1071
00:45:16,455 --> 00:45:21,627
FSY COULD CROSS LINK THE HER2

1072
00:45:21,627 --> 00:45:22,261
EXTRA CELLULAR DOMAIN VERY

1073
00:45:22,261 --> 00:45:24,363
EASILY AND IT COULD BE DETECTED

1074
00:45:24,363 --> 00:45:24,964
WITHIN 10 MINUTES.

1075
00:45:24,964 --> 00:45:26,565
WE THEN SHOWED THAT THIS NANO

1076
00:45:26,565 --> 00:45:29,435
BODY WAS ALSO ABLE TO CROSS LINK

1077
00:45:29,435 --> 00:45:31,437
AT THE ENDOGENOUS HER2 RECEPTOR

1078
00:45:31,437 --> 00:45:33,072
ON CELL SURFACE ON DIFFERENT

1079
00:45:33,072 --> 00:45:33,973
CANCER CELL LINES.

1080
00:45:33,973 --> 00:45:37,943
IN THIS 2 CELL LINES THAT LACK

1081
00:45:37,943 --> 00:45:40,613
HER2 EXPRESSION AND THEREFORE WE

1082
00:45:40,613 --> 00:45:42,448
DIDN'T DETECT CROSS LINKING

1083
00:45:42,448 --> 00:45:43,849
SUGGEST THANKSGIVING CROSS LINK

1084
00:45:43,849 --> 00:45:44,850
XG HIGHLY SPECIFIC.

1085
00:45:44,850 --> 00:45:47,286
WE FURTHER SHOWED THAT THIS MB

1086
00:45:47,286 --> 00:45:50,055
NANO BODY FSY WAS ABLE TO CROSS

1087
00:45:50,055 --> 00:45:51,223
LISTENING THE HEERROR 2 RECEPTOR

1088
00:45:51,223 --> 00:45:59,932
TO THE TUMOR DIRECTLY IN MICE AS

1089
00:45:59,932 --> 00:46:00,299
WELL.

1090
00:46:00,299 --> 00:46:03,369
WE NEXT LABELED THIS NANO BODIES

1091
00:46:03,369 --> 00:46:05,905
WITH RDON 124 AND INYECT THEM

1092
00:46:05,905 --> 00:46:08,774
INTO MICE XENO GRAPHED WITH THE

1093
00:46:08,774 --> 00:46:09,975
HER2 EXPRESSING TUMORS FOLLOWED

1094
00:46:09,975 --> 00:46:12,912
BY THE PET IMAGING.

1095
00:46:12,912 --> 00:46:17,316
TO YOUR RIGHT SIDE FROM THE 3210

1096
00:46:17,316 --> 00:46:19,185
POST INYEKS, AS YOU CAN SEE

1097
00:46:19,185 --> 00:46:20,586
THERE WAS NO SIGNIFICANT

1098
00:46:20,586 --> 00:46:22,454
DIFFERENCE BETWEEN THE WILD-TYPE

1099
00:46:22,454 --> 00:46:25,724
NANO BODY, THE TOP HERE, AND THE

1100
00:46:25,724 --> 00:46:29,161
COVALENT NANO BODY IN TERMS OF A

1101
00:46:29,161 --> 00:46:29,995
TOMB'RE TUMOR SIGNATURES NOX

1102
00:46:29,995 --> 00:46:30,396
FAMILY ACTIVATOR.

1103
00:46:30,396 --> 00:46:31,897
HOWEVER A DRAMATIC REDUCTION

1104
00:46:31,897 --> 00:46:33,399
THETIC DEFENSE CAN BE FOUND

1105
00:46:33,399 --> 00:46:36,535
AROUND 24 HOURS TO 72 HOURS.

1106
00:46:36,535 --> 00:46:38,037
WILD THE NANO BODY, THE

1107
00:46:38,037 --> 00:46:41,674
WILD-TYPE NANO BODY WAS NO

1108
00:46:41,674 --> 00:46:42,842
LONGER DETECTABLE, THE

1109
00:46:42,842 --> 00:46:47,146
COLVALENTINEDDENT NANO BODY

1110
00:46:47,146 --> 00:46:47,947
REMAINS CLEARLY SEEN.

1111
00:46:47,947 --> 00:46:50,482
FURTHER MORE IF WE DO 3D IMAGING

1112
00:46:50,482 --> 00:46:54,153
AS YOU SEE HERE FROM 2472 HOURS,

1113
00:46:54,153 --> 00:46:56,222
THE TUMOR SIGNAL WAS DISTINCTLY

1114
00:46:56,222 --> 00:46:57,756
VISIBLE USING THE NANO BODY BUT

1115
00:46:57,756 --> 00:47:01,627
NOT VISIBLE IN THE WILD-TYPE

1116
00:47:01,627 --> 00:47:05,397
NANO BODY.

1117
00:47:05,397 --> 00:47:09,668
AND THE--ANOTHER EXCEPTIONAL

1118
00:47:09,668 --> 00:47:11,270
OBSERVATION IS THAT WE SEE VERY

1119
00:47:11,270 --> 00:47:11,871
CLEAR BACKGROUND AUTONATIONAL

1120
00:47:11,871 --> 00:47:12,805
LIBRARY OF MEDICINAL TISSUES

1121
00:47:12,805 --> 00:47:13,739
EXCEPT THE TIARAS ROADWAY

1122
00:47:13,739 --> 00:47:18,944
BECAUSE IT IS THE NATURAL SIDE

1123
00:47:18,944 --> 00:47:19,845
FOR R-DINE METABOLISM.

1124
00:47:19,845 --> 00:47:21,213
AND THE TOTAL RADIATION

1125
00:47:21,213 --> 00:47:24,416
ACCUMULATED IN THE TUMOR SHOW ON

1126
00:47:24,416 --> 00:47:28,187
LEFT HERE IS 81% MORE WITH THE

1127
00:47:28,187 --> 00:47:29,488
COVALENT NANO BODY, SO THIS

1128
00:47:29,488 --> 00:47:32,091
RESULTS TELL US THAT THE

1129
00:47:32,091 --> 00:47:34,293
COVALENT NANO BODY SIGNIFICANTLY

1130
00:47:34,293 --> 00:47:35,327
PROLONGED TUMOR RETENTION AS

1131
00:47:35,327 --> 00:47:37,096
WELL AS INCREASE THE TUMOR

1132
00:47:37,096 --> 00:47:45,004
ACCUMULATION OF THE RADIO

1133
00:47:45,004 --> 00:47:45,371
ISOTOPE.

1134
00:47:45,371 --> 00:47:47,206
WELL, WOULD THIS BE SUFFICIENT

1135
00:47:47,206 --> 00:47:48,807
TO IMPACT ANTITUMOR EFFECT.

1136
00:47:48,807 --> 00:47:51,243
SO TO TEST THIS WE THEN LABELED

1137
00:47:51,243 --> 00:47:55,481
THE NANO BODY WITH THE 225,

1138
00:47:55,481 --> 00:47:55,981
POTENT [INDISCERNIBLE].

1139
00:47:55,981 --> 00:47:58,384
AND THEN INJECT THIS NANO BODY

1140
00:47:58,384 --> 00:48:01,153
INTO THE MICE XENOGRAFTICALLY TO

1141
00:48:01,153 --> 00:48:02,321
HER2 TO EXPRESS IN TUMORS.

1142
00:48:02,321 --> 00:48:05,391
AS CAN YOU SEE IN THIS GRAPH

1143
00:48:05,391 --> 00:48:14,133
HERE, COMPARED TO THE SALINE IN

1144
00:48:14,133 --> 00:48:16,835
PLAQUE, IT SHOWED NOW DIFFERENCE

1145
00:48:16,835 --> 00:48:19,238
IN TUMOR INHIBITION, IT

1146
00:48:19,238 --> 00:48:22,875
CONTRAST, IN ORANGE HERE THE

1147
00:48:22,875 --> 00:48:24,176
COVALENT ANTIBODY LABELED

1148
00:48:24,176 --> 00:48:26,912
[INDISCERNIBLE] 25, SHOWS A

1149
00:48:26,912 --> 00:48:28,781
SIGNIFICANT TUMOR INHIBITION.

1150
00:48:28,781 --> 00:48:30,582
AND END POINT ANALYSIS OF THE

1151
00:48:30,582 --> 00:48:33,585
TUMOR WEIGHT ALSO INDICATE THE

1152
00:48:33,585 --> 00:48:35,621
COVALENT NANO BODY REDUCED TUMOR

1153
00:48:35,621 --> 00:48:36,855
WEIGHT SIGNIFICANTLY BUT NOT

1154
00:48:36,855 --> 00:48:38,023
WITH THE WILD-TYPE NANO BODY,

1155
00:48:38,023 --> 00:48:41,093
AND THE BODY WEIGHT OF THE MICE

1156
00:48:41,093 --> 00:48:42,494
DID NOT CHANGE SIGNIFICANTLY

1157
00:48:42,494 --> 00:48:44,797
ACROSS ALL THRESHOLD GROUPS,

1158
00:48:44,797 --> 00:48:49,201
SUGGESTING THERE'S NO SYSTEMATIC

1159
00:48:49,201 --> 00:48:49,468
TOXICITY.

1160
00:48:49,468 --> 00:48:52,171
WE FURTHER DID A TISSUE ANALYSIS

1161
00:48:52,171 --> 00:48:55,808
OF LIVER, THE KIDNEY THE HEART

1162
00:48:55,808 --> 00:49:00,980
AND THE BONE HERE, AND WE DIDN'T

1163
00:49:00,980 --> 00:49:03,482
FIND ANY ANOMALIES SUGGESTING

1164
00:49:03,482 --> 00:49:08,854
THERE'S NO TOXICITIES EITHER,

1165
00:49:08,854 --> 00:49:09,321
HERE.

1166
00:49:09,321 --> 00:49:11,724
SO IN SUMMARY THE RADIO

1167
00:49:11,724 --> 00:49:12,558
PHARMACEUTICAL USING THIS COVID

1168
00:49:12,558 --> 00:49:15,427
NANO BODY OF THE DELIVERY

1169
00:49:15,427 --> 00:49:17,596
VEHICLE SHOWS POTENTIAL FOR

1170
00:49:17,596 --> 00:49:18,197
EFFECTING TUMOR INHIBITION

1171
00:49:18,197 --> 00:49:23,369
WITHOUT A COURSE IN TISSUE

1172
00:49:23,369 --> 00:49:23,635
TOXICITY.

1173
00:49:23,635 --> 00:49:26,705
TO CONCLUDE MY TALK, BY

1174
00:49:26,705 --> 00:49:28,374
DEVELOPING LATENT BIOREACTIVE

1175
00:49:28,374 --> 00:49:30,142
UNNATURAL TERMINAL AMINO ARK

1176
00:49:30,142 --> 00:49:32,277
SIDS THROUGH THE APPROXIMATE

1177
00:49:32,277 --> 00:49:33,078
ENABLED BIOREACTIVE MECHANISM,

1178
00:49:33,078 --> 00:49:37,016
WE CAN NOW GENETICALLY INTRODUCE

1179
00:49:37,016 --> 00:49:38,684
COVID LINKAGES BETWEEN PROTEINS

1180
00:49:38,684 --> 00:49:41,854
AS WELL AS TEEN PROTEINS AND

1181
00:49:41,854 --> 00:49:43,455
OTHER BIOMOLECULES INCLUDING

1182
00:49:43,455 --> 00:49:48,127
RNA, AND THE CARBOHYDRATES.

1183
00:49:48,127 --> 00:49:49,762
THIS COVALENT CONNECKS ARE

1184
00:49:49,762 --> 00:49:50,596
SELECTIVELY STABLE AND

1185
00:49:50,596 --> 00:49:52,765
IRREVERSIBLE AND HOPING UP NEW

1186
00:49:52,765 --> 00:49:56,468
POSSIBILITIES FOR CREATING NOVEL

1187
00:49:56,468 --> 00:50:01,940
PROTEIN PROPERTIES WHICH

1188
00:50:01,940 --> 00:50:02,708
I--DON'T COVER TODAY.

1189
00:50:02,708 --> 00:50:05,310
AND WE CAN USELESS USE THESE

1190
00:50:05,310 --> 00:50:08,981
COVALENT LINKAGES TO STUDY CELLS

1191
00:50:08,981 --> 00:50:10,349
IN VIVO.

1192
00:50:10,349 --> 00:50:13,318
ADDITIONAL WE DEVELOPED THIS

1193
00:50:13,318 --> 00:50:15,387
PLATFORM TECHNOLOGY PERX FOR

1194
00:50:15,387 --> 00:50:16,789
COVALENT PROTEIN DRUGS WHICH HAS

1195
00:50:16,789 --> 00:50:20,392
SHOWN PROMISE IN CANCER'MUNE O

1196
00:50:20,392 --> 00:50:20,826
THERAPY, SARS-COV-2

1197
00:50:20,826 --> 00:50:24,563
NEUTRALIZATION AND A TARGETED

1198
00:50:24,563 --> 00:50:25,431
RADIO NUCLEIDE THERAPY.

1199
00:50:25,431 --> 00:50:27,666
WE ANTICIPATE THAT SHIFTING THE

1200
00:50:27,666 --> 00:50:30,302
PARADIGM FROM NONCOVALENT TO

1201
00:50:30,302 --> 00:50:35,007
COVALENT INTERACTIONS IN PROTEIN

1202
00:50:35,007 --> 00:50:36,942
MOLECULAR ADVANCE AMS CAN HELP

1203
00:50:36,942 --> 00:50:42,181
BASIC BIOLOGICAL RESEARCH AND I

1204
00:50:42,181 --> 00:50:42,548
BIOTHERAPEUTICS.

1205
00:50:42,548 --> 00:50:44,817
FINALLY, I WOULD LIKE TO THANK

1206
00:50:44,817 --> 00:50:46,518
MY GROP MEMBERS BOTH PAST AND

1207
00:50:46,518 --> 00:50:47,252
PRESENT FOR MAKE THANKSGIVING

1208
00:50:47,252 --> 00:50:49,621
POSSIBLE AND I'M ALSO DEEPLY

1209
00:50:49,621 --> 00:50:51,056
GRATEFUL FOR THE GENEROUS

1210
00:50:51,056 --> 00:50:52,624
SUPPORT OF MANY WONDERFUL

1211
00:50:52,624 --> 00:50:53,892
COLLABORATORS THAT ARE LISTED

1212
00:50:53,892 --> 00:50:55,761
HERE AND VARIOUS FOUNDING

1213
00:50:55,761 --> 00:50:57,096
ORGANIZATIONS WITH A SPECIAL

1214
00:50:57,096 --> 00:50:59,731
THANKS TO NIH FOR YOUR

1215
00:50:59,731 --> 00:51:00,766
CONTINUOUS SUPPORT AND THANK YOU

1216
00:51:00,766 --> 00:51:02,000
VERY MUCH FOR YOUR ATTENTION.

1217
00:51:02,000 --> 00:51:07,773
I WILL BE HAPPY TO TAKE

1218
00:51:07,773 --> 00:51:08,040
QUESTIONS.

1219
00:51:08,040 --> 00:51:09,942
[ APPLAUSE ]

1220
00:51:09,942 --> 00:51:12,244
SO THERE ARE MICs ON EITHER

1221
00:51:12,244 --> 00:51:19,651
SIDE, NO QUESTIONS YET COMING ON

1222
00:51:19,651 --> 00:51:19,852
LINE.

1223
00:51:19,852 --> 00:51:20,719
>> HI, LEI, GREAT TALK.

1224
00:51:20,719 --> 00:51:23,489
SO I HAVE SORT OF A CONCEPTUAL

1225
00:51:23,489 --> 00:51:25,591
LEVEL QUESTION. 

1226
00:51:25,591 --> 00:51:28,060
SO YOU HAVE DIFFERENT LATENT

1227
00:51:28,060 --> 00:51:33,765
BIOREACTIVE AMINO ACIDS AND THEY

1228
00:51:33,765 --> 00:51:35,767
HAVE SORT OF DIFFERENT LEVELS OF

1229
00:51:35,767 --> 00:51:38,170
REACTIVITY, DO YOU THINK YOU

1230
00:51:38,170 --> 00:51:40,272
PUSHED REACAS FAR AS CAN YOU

1231
00:51:40,272 --> 00:51:41,807
WITHOUT ENCOUNTERING SOME SORT

1232
00:51:41,807 --> 00:51:42,508
OF AUTOREACTIVITY OR DO YOU

1233
00:51:42,508 --> 00:51:44,143
THINK IT WILL BE POSSIBLE TO

1234
00:51:44,143 --> 00:51:46,778
MAKE AMINO ACIDS THAT HAVE

1235
00:51:46,778 --> 00:51:48,547
HIGHER RATES OF REACTIVITY IN

1236
00:51:48,547 --> 00:51:58,123
THE CONTEXT OF FULL SIZE

1237
00:51:58,123 --> 00:51:59,124
PROTEINS?

1238
00:51:59,124 --> 00:52:05,764
WOO HAVE A WIDE RANGE OF OF

1239
00:52:05,764 --> 00:52:06,064
REACTIVITY.

1240
00:52:06,064 --> 00:52:08,534
WE STUDIED THIS SYSTEM WITH

1241
00:52:08,534 --> 00:52:09,168
DIFFERENT BYPASSING AFFINITYS,

1242
00:52:09,168 --> 00:52:10,402
ET CETERA WE FOUND THAT THE

1243
00:52:10,402 --> 00:52:13,539
REACTION DEPENDS ON MULTIPLE

1244
00:52:13,539 --> 00:52:13,772
FACTORS.

1245
00:52:13,772 --> 00:52:15,240
THE INTRINSIC REACTIVITY OF THE

1246
00:52:15,240 --> 00:52:18,143
WAR HEAD IS 1 ASPECT OF IT, THE

1247
00:52:18,143 --> 00:52:19,845
AFFINITY IS ANOTHER PART AND THE

1248
00:52:19,845 --> 00:52:22,481
ORIENTATION IN THE DISTANCE,

1249
00:52:22,481 --> 00:52:23,749
EVERYTHING ENCLOUDED CONTRIBUTES

1250
00:52:23,749 --> 00:52:25,184
TO THE FINAL REACTIVITY, TO GIVE

1251
00:52:25,184 --> 00:52:27,819
YOU EXAMPLE, SOME OF THE

1252
00:52:27,819 --> 00:52:29,588
REACTIONS MAY TAKE MULTIPLE

1253
00:52:29,588 --> 00:52:34,293
HOURS, 6 HOURS, 8 HOURS, TO

1254
00:52:34,293 --> 00:52:35,928
ACHIEVE 80% AND SOME ASSISTANCE

1255
00:52:35,928 --> 00:52:38,030
WE FOUND THAT THIS CROSS LINKING

1256
00:52:38,030 --> 00:52:39,631
CAN OCCUR WITHIN 5 MINUTE ANDS

1257
00:52:39,631 --> 00:52:41,333
IN SOME SYSTEMS WE FOUND THE

1258
00:52:41,333 --> 00:52:44,736
CROSS LINKING CAN REACH 99%

1259
00:52:44,736 --> 00:52:46,171
COMPLETION WHEREAS MANY OTHER

1260
00:52:46,171 --> 00:52:51,877
SYSTEMS, AS YOU SUGGESTED WE DO

1261
00:52:51,877 --> 00:52:57,816
SEE INTRA MOLECULAR CROSS LINK.

1262
00:52:57,816 --> 00:52:59,985
AND GENERALLY AS YOU SUGGESTED

1263
00:52:59,985 --> 00:53:03,055
THIS LINK IS CORRELATED WITH THE

1264
00:53:03,055 --> 00:53:04,723
REACTIVITY OF THE WAR HEAD, SO

1265
00:53:04,723 --> 00:53:06,625
I'M HOPING THAT WITH THE

1266
00:53:06,625 --> 00:53:07,659
ADVANCEMENT OF NEW CHEMISTRY, WE

1267
00:53:07,659 --> 00:53:12,197
MAY BE ABLE TO FIND AN EVEN

1268
00:53:12,197 --> 00:53:13,665
BETTER [INDISCERNIBLE] THAN WHAT

1269
00:53:13,665 --> 00:53:16,535
WE CURRENTLY HAVE TO MINIMIZE

1270
00:53:16,535 --> 00:53:18,170
CROSS LINKING WHILE

1271
00:53:18,170 --> 00:53:18,837
SIGNIFICANTLY EXPAND, ACCELERATE

1272
00:53:18,837 --> 00:53:20,872
THE FINAL REACTION FOR EXAMPLE,

1273
00:53:20,872 --> 00:53:27,112
BETWEEN 2 PROTEINS INSTEAD OF

1274
00:53:27,112 --> 00:53:29,648
HAVING BY INTERNAL MOLECULAR

1275
00:53:29,648 --> 00:53:32,384
REACTIONS. 

1276
00:53:32,384 --> 00:53:33,018
GREAT, THANK YOU!

1277
00:53:33,018 --> 00:53:35,153
>> HI THIS, IS AN AMAZING,

1278
00:53:35,153 --> 00:53:37,723
CREATIVE AND THOUGHT PROVOKING

1279
00:53:37,723 --> 00:53:40,826
PRESENTATION EMPLOY

1280
00:53:40,826 --> 00:53:41,326
CONGRATULATIONS.

1281
00:53:41,326 --> 00:53:43,161
I'M JUST WONDERING ABOUT THE

1282
00:53:43,161 --> 00:53:45,264
PATH TO COMMERCIALIZATION, AND

1283
00:53:45,264 --> 00:53:48,200
WE KNOW HOW DIFFICULT IT IS HERE

1284
00:53:48,200 --> 00:53:50,569
TO PUT OUR SMALL MOLECULES ON TO

1285
00:53:50,569 --> 00:53:51,336
A TRANSLATIONAL PATH.

1286
00:53:51,336 --> 00:53:55,240
I IMAGINE THAT IF YOU PROPOSE TO

1287
00:53:55,240 --> 00:53:56,975
ACCOMPANY THAT HAVE YOU SOME

1288
00:53:56,975 --> 00:53:58,777
COVALENT WAR HEAD ON YOUR

1289
00:53:58,777 --> 00:54:00,712
PROTEIN OR ON YOUR SMALL

1290
00:54:00,712 --> 00:54:03,548
MOLECULE, THE PATH WOULD BE EVEN

1291
00:54:03,548 --> 00:54:04,516
HARDER.

1292
00:54:04,516 --> 00:54:10,722
WHAT CAN YOU SAY ABOUT THE

1293
00:54:10,722 --> 00:54:11,456
DERISKING OR POTENTIAL TOXICITY

1294
00:54:11,456 --> 00:54:12,457
OF THE WAR HEAD.

1295
00:54:12,457 --> 00:54:14,559
YOU MEKSED IN 1 CASE YOU DIDN'T

1296
00:54:14,559 --> 00:54:15,794
HAVE ANY REACTIVITY WITH GLUTEA

1297
00:54:15,794 --> 00:54:17,329
THE IPAD OWN, BUT WHAT EVERYONE

1298
00:54:17,329 --> 00:54:19,965
DO YOU HAVE THAT THERE'S NOT

1299
00:54:19,965 --> 00:54:27,739
OTHER TOXICITY FOR INSTANCE THE

1300
00:54:27,739 --> 00:54:31,310
TYROSEEN DERIVATIVES WITH THE

1301
00:54:31,310 --> 00:54:32,277
DISCIPLINARY SULFER

1302
00:54:32,277 --> 00:54:32,611
NEOFLUORIDES.

1303
00:54:32,611 --> 00:54:33,045
>> GREAT QUESTION.

1304
00:54:33,045 --> 00:54:38,617
THANK YOU VERY MUCH FOR POINTING

1305
00:54:38,617 --> 00:54:39,751
THAT OUT.

1306
00:54:39,751 --> 00:54:42,621
O MY THINKING IS COVALENT SMALL

1307
00:54:42,621 --> 00:54:44,289
MOLECULE DRUG VS BEEN SO

1308
00:54:44,289 --> 00:54:47,092
SUCCESSFUL AND INITIALLY PEOPLE

1309
00:54:47,092 --> 00:54:53,432
ALSO WERE AFRAID OF MANY OFF

1310
00:54:53,432 --> 00:54:55,000
TARGET AND TOXICITIES THE REASON

1311
00:54:55,000 --> 00:54:59,805
WE STARTED THIS PROGRAM ALMOST

1312
00:54:59,805 --> 00:55:02,074
10 YEARS AGO IS WE THINK

1313
00:55:02,074 --> 00:55:03,542
PROTEINS COMPARED TO SMALL

1314
00:55:03,542 --> 00:55:05,377
MOLECULES, I THINK CO VERSION, I

1315
00:55:05,377 --> 00:55:08,380
IT SHOULD HAVE ADVANTAGES OVER

1316
00:55:08,380 --> 00:55:10,649
SMALL MOLECULES BECAUSE 1,

1317
00:55:10,649 --> 00:55:12,117
PROTEINS HAVE LARGER INTERACTION

1318
00:55:12,117 --> 00:55:19,891
AND INTERPHASE WHICH CAN ACHIEVE

1319
00:55:19,891 --> 00:55:21,259
A BETTER SPECIFICITY, AND

1320
00:55:21,259 --> 00:55:23,562
PROTEINS ALSO HAVE A LOT OF

1321
00:55:23,562 --> 00:55:25,397
LOCAL MICROVIERM, IDEALLY YOU

1322
00:55:25,397 --> 00:55:27,165
CAN MANIPULATE BUT MANY TIMES

1323
00:55:27,165 --> 00:55:32,671
YOU COULD HAVE A CHANCE TO FOR

1324
00:55:32,671 --> 00:55:38,610
EXAMPLE, BLOCK AMINO REACTION TO

1325
00:55:38,610 --> 00:55:39,244
TRIGGER THE REACTIVITY AND

1326
00:55:39,244 --> 00:55:40,145
ANOTHER THING I WANT TO POINT

1327
00:55:40,145 --> 00:55:43,181
OUT IN OUR CASE, WHEN THE

1328
00:55:43,181 --> 00:55:44,783
COVALENT--IN ORDER FOR THE

1329
00:55:44,783 --> 00:55:45,617
COVALENT BOND TO FOR THE

1330
00:55:45,617 --> 00:55:47,018
PURPOSE, THERE ARE 2 STEPS

1331
00:55:47,018 --> 00:55:49,788
INVOLVED, 1 IS PROTEIN A, NEEDS

1332
00:55:49,788 --> 00:55:51,289
TO BIND WITH PROTEIN B,

1333
00:55:51,289 --> 00:55:52,858
REQUIREMENT 1.

1334
00:55:52,858 --> 00:55:53,792
THIS REQUIRES SOME SPECIFICITY,

1335
00:55:53,792 --> 00:55:57,162
AND THE REQUIREMENT OF B, IS

1336
00:55:57,162 --> 00:56:00,031
THIS END TERM NOWS EXCITAIEN IS

1337
00:56:00,031 --> 00:56:01,533
CORRECT IN THE ORIENTATION IS

1338
00:56:01,533 --> 00:56:04,035
DISTANCE TOWARDS ITS TARGET OF

1339
00:56:04,035 --> 00:56:06,104
NATURAL RESIDUE, THEREFORE THESE

1340
00:56:06,104 --> 00:56:13,645
2 GAUGE, THE SPECIFICITY I THINK

1341
00:56:13,645 --> 00:56:13,979
IS VERY HIGH.

1342
00:56:13,979 --> 00:56:18,083
IN ADDITION WE DID SOME

1343
00:56:18,083 --> 00:56:21,920
OFF-TARGETED REACTIONS BOTH IN

1344
00:56:21,920 --> 00:56:25,624
MICE AND IN HUMAN SERUM, AND

1345
00:56:25,624 --> 00:56:28,160
USING WESTERN BLOT WE HAVEN'T

1346
00:56:28,160 --> 00:56:29,761
DETECTED ANY OFFTARGET CROSS

1347
00:56:29,761 --> 00:56:30,228
LINKING YET.

1348
00:56:30,228 --> 00:56:35,801
OF COURSE I UNDERSTAND THIS IS

1349
00:56:35,801 --> 00:56:37,536
NOT SUFFICIENT AND FOR EXAMPLE

1350
00:56:37,536 --> 00:56:40,105
IN OUR RADIO TRT EXPERIMENT, WE

1351
00:56:40,105 --> 00:56:42,541
ALSO MONITORED THE SECRETION OF

1352
00:56:42,541 --> 00:56:44,609
THE COVALENT NANO BODY VERSUS

1353
00:56:44,609 --> 00:56:46,778
WILD-TYPE NANO BODY RADIO

1354
00:56:46,778 --> 00:56:50,348
LABELED AND WE DIDN'T SEE ANY

1355
00:56:50,348 --> 00:56:51,950
SIGNIFICANCE EITHER, SUGGESTING

1356
00:56:51,950 --> 00:56:53,819
THERE'S NO SIGNIFICANT MUTATION

1357
00:56:53,819 --> 00:56:55,220
OR OFF TARGET REACTIVITY,

1358
00:56:55,220 --> 00:56:55,487
EITHER.

1359
00:56:55,487 --> 00:56:57,622
BUT YOU HAVE A IMRIT POINT.

1360
00:56:57,622 --> 00:57:04,362
IT'S REALLY IMPORTANT TO ADDRESS

1361
00:57:04,362 --> 00:57:06,898
THIS AND I THINK AS THIS

1362
00:57:06,898 --> 00:57:08,066
COVALENT PROTEIN DRUG, AT EARLY

1363
00:57:08,066 --> 00:57:09,367
STAGE, THERE'S A LOT OF WORK TO

1364
00:57:09,367 --> 00:57:12,604
BE DONE AND WE THINK THIS' A

1365
00:57:12,604 --> 00:57:14,005
GREAT POTENTIAL BUT WE NEED TO

1366
00:57:14,005 --> 00:57:16,074
ARE VERY CAREFUL TO EVALUATE ALL

1367
00:57:16,074 --> 00:57:17,976
THIS ASPECTS AS YOU SUGGESTED.

1368
00:57:17,976 --> 00:57:20,579
THANK YOU.

1369
00:57:20,579 --> 00:57:21,746
NTHANK YOU.

1370
00:57:21,746 --> 00:57:23,415
>> HI, LEI, THAT WAS
BEAUTIFUL.

1371
00:57:23,415 --> 00:57:24,850
I HAVE 2 QUESTIONS.

1372
00:57:24,850 --> 00:57:27,385
THE FIRST QUESTION ACTUALLY SORT

1373
00:57:27,385 --> 00:57:30,422
OF RELATES TO THE RATE

1374
00:57:30,422 --> 00:57:33,124
ENHANCEMENT OF THE SULFINATE

1375
00:57:33,124 --> 00:57:33,625
FLUORIDE REACTION.

1376
00:57:33,625 --> 00:57:38,063
SO HAVE YOU DONE ANY SORT OF

1377
00:57:38,063 --> 00:57:38,997
INVITRO MEASUREMENTS THAT GIVE

1378
00:57:38,997 --> 00:57:42,100
YOU AN IDEA OF WHAT YOU HAVE A

1379
00:57:42,100 --> 00:57:43,902
PROTEIN-PROTEIN BYPASSING

1380
00:57:43,902 --> 00:57:45,871
FOLLOWED BY THEN THE REACTION

1381
00:57:45,871 --> 00:57:47,906
WITH THE HYDROXYL WITH THE

1382
00:57:47,906 --> 00:57:50,408
SULFINE OLDER PEOPLE FLUORIDE,

1383
00:57:50,408 --> 00:57:51,576
WHAT ENHANCEMENT ARE YOU

1384
00:57:51,576 --> 00:57:53,912
ACHIEVING COMPARED TO LET'S SAY

1385
00:57:53,912 --> 00:57:55,347
JUST IN SOLUTION REACTION, AND

1386
00:57:55,347 --> 00:57:57,148
COUPLED TO THAT I HAVE ANOTHER

1387
00:57:57,148 --> 00:58:00,318
QUESTION WHICH IS THAT WHEN YOU

1388
00:58:00,318 --> 00:58:04,356
THINK ABOUT JUST THE FEN

1389
00:58:04,356 --> 00:58:05,056
ILLEGALS SULFIN FLUORIDE AND

1390
00:58:05,056 --> 00:58:08,760
THEN THAT ON A PROTEIN, ARE YOU

1391
00:58:08,760 --> 00:58:11,062
ACTUALLY RETARDING ITS REACTION

1392
00:58:11,062 --> 00:58:15,400
BY ESSENTIALLY PUTTING ON A

1393
00:58:15,400 --> 00:58:17,469
BULKY SUBSTITUTE WHICH IS THE

1394
00:58:17,469 --> 00:58:17,736
PROTEIN?

1395
00:58:17,736 --> 00:58:19,004
SO IN OTHER WORDS IS THE

1396
00:58:19,004 --> 00:58:23,008
REACTION ON SUCH ON A NONENGAGED

1397
00:58:23,008 --> 00:58:26,211
SURFACE RETARDED BECAUSE IT HAD

1398
00:58:26,211 --> 00:58:28,713
STATIC INHIBITION BY HAVING

1399
00:58:28,713 --> 00:58:30,382
BULKY PROTEIN, CAN YOU COMMENT

1400
00:58:30,382 --> 00:58:31,616
ON THAT?

1401
00:58:31,616 --> 00:58:32,450
>> REALLY INTERESTING
COMMENT.

1402
00:58:32,450 --> 00:58:34,953
THE FIRST 1 IS HOW MANY PHOTO

1403
00:58:34,953 --> 00:58:36,488
IMPROVEMENT WE HAVE WITH THIS

1404
00:58:36,488 --> 00:58:36,721
EFFECT.

1405
00:58:36,721 --> 00:58:38,557
SO WHEN THE COMEMMISTRY WAS

1406
00:58:38,557 --> 00:58:40,725
DEVELOPED BY BARRY SHARPLESS ON

1407
00:58:40,725 --> 00:58:42,027
THE SMALL MOLECULE LEVEL, THEY

1408
00:58:42,027 --> 00:58:43,228
NEED CATALYST TO ALLOW THE

1409
00:58:43,228 --> 00:58:44,863
REACTION TO OCCUR, BUT LATER

1410
00:58:44,863 --> 00:58:48,133
FURTHER DEVELOPMENT SHOWS CAN

1411
00:58:48,133 --> 00:58:50,402
YOU ALSO HAVE SOME

1412
00:58:50,402 --> 00:58:53,271
[INDISCERNIBLE] IN THE CATALYST.

1413
00:58:53,271 --> 00:58:55,206
IN OUR CASE, BARRY AND JEFF

1414
00:58:55,206 --> 00:58:56,374
[INDISCERNIBLE] AT SCRIPTS THEY

1415
00:58:56,374 --> 00:58:59,744
DID BEAUTIFUL SPRMS TO TEST THE

1416
00:58:59,744 --> 00:59:01,279
REACTION OF THIS ON THE SMALL

1417
00:59:01,279 --> 00:59:09,087
MOLECULE LEVEL, YOU CAN

1418
00:59:09,087 --> 00:59:11,489
BASICALLY BOIL UPON FLOWERRAL

1419
00:59:11,489 --> 00:59:12,490
SULFONATE WITH [INDISCERNIBLE]

1420
00:59:12,490 --> 00:59:14,259
AND THEN BOIL, MANY, MANY HOUR

1421
00:59:14,259 --> 00:59:16,661
ANDS THERE'S NO REACTION, IF WE

1422
00:59:16,661 --> 00:59:19,965
LET THIS REACTION TO OCCUR AS

1423
00:59:19,965 --> 00:59:21,600
YOU SUGGIESTED WITHOUT THIS

1424
00:59:21,600 --> 00:59:22,734
PROXIMITY EFFECT, THEY ACTUALLY

1425
00:59:22,734 --> 00:59:23,835
DON'T REACT.

1426
00:59:23,835 --> 00:59:25,870
>> I SEE.

1427
00:59:25,870 --> 00:59:28,406
NTHAT'S WHAT--THEY HAVE MULTIPLE

1428
00:59:28,406 --> 00:59:30,008
PAPERS TO DEMONSTRATE THAT.

1429
00:59:30,008 --> 00:59:31,977
SO I ACTUALLY CANNOT MEASURE

1430
00:59:31,977 --> 00:59:33,511
ENHANCEMENT BUT WHAT WE DID IS

1431
00:59:33,511 --> 00:59:35,480
WE MEASURED THE KINETETTIC ON

1432
00:59:35,480 --> 00:59:37,349
THE PROTEIN LEVEL WHERE WE HAVE

1433
00:59:37,349 --> 00:59:42,520
2 PROTEINS BINDED TOGETHER, WE

1434
00:59:42,520 --> 00:59:43,955
MEASURED THE K22nd WAY OF THIS

1435
00:59:43,955 --> 00:59:47,425
REACTION AND OUR RESULT WAS IN

1436
00:59:47,425 --> 00:59:51,863
THE RANGE OF 5-50 PER MOLE PER

1437
00:59:51,863 --> 00:59:52,230
SECOND.

1438
00:59:52,230 --> 00:59:54,833
SO THIS IS NOT GREAT BECAUSE

1439
00:59:54,833 --> 00:59:57,268
QUICK CHEMISTRY ARE IN THE RANGE

1440
00:59:57,268 --> 00:59:58,670
OF 1-210 TO THE FIFTHS.

1441
00:59:58,670 --> 01:00:00,772
IN THE RAW IT HAS GREATER

1442
01:00:00,772 --> 01:00:02,540
REACTION, SHE SHOWED ME, REACH

1443
01:00:02,540 --> 01:00:05,644
TO THE HIGHEST LEVEL OF

1444
01:00:05,644 --> 01:00:06,845
[INDISCERNIBLE] TO 10 TO THE

1445
01:00:06,845 --> 01:00:08,847
FIFTH EMPLOY FOR US THE

1446
01:00:08,847 --> 01:00:12,984
[INDISCERNIBLE] IS 5 TO 50, BUT

1447
01:00:12,984 --> 01:00:20,759
WE RECENTLY FOUND R-GENINE, AND

1448
01:00:20,759 --> 01:00:24,062
AND SLOWER THAN THE CLICK

1449
01:00:24,062 --> 01:00:25,130
CHEMISTRY LEVEL, AND THIS IS

1450
01:00:25,130 --> 01:00:29,401
MANY REACTIONS AND THAT'S

1451
01:00:29,401 --> 01:00:30,669
QUESTION 1 QUESTION 2 IS VERY

1452
01:00:30,669 --> 01:00:31,970
INTERESTING SO YOU'RE THINKING

1453
01:00:31,970 --> 01:00:34,639
THIS REACTION IS TABLE IN OUR

1454
01:00:34,639 --> 01:00:38,877
PROTEIN COMPLEX BECAUSE PROTEINS

1455
01:00:38,877 --> 01:00:42,313
ARE DIFFICULT TO--AS IN 2 LIVING

1456
01:00:42,313 --> 01:00:43,948
GREEP IS DIFFICULT TO LEAVE

1457
01:00:43,948 --> 01:00:46,818
BECAUSE HAVE YOU THIS BINDING

1458
01:00:46,818 --> 01:00:47,085
AFFINITY.

1459
01:00:47,085 --> 01:00:48,019
>> SO ESSENTIALLY LIKE IF
YOU

1460
01:00:48,019 --> 01:00:50,689
HAVE A BULKY PROTEIN, DOES THAT

1461
01:00:50,689 --> 01:00:52,057
DISCOURAGE REACTION THE SULFA

1462
01:00:52,057 --> 01:00:54,325
NEAL UNLESS HAVE YOU A

1463
01:00:54,325 --> 01:00:57,028
PROTEIN-PROTEIN BINDING BECAUSE

1464
01:00:57,028 --> 01:00:59,898
THE PROTEIN ACTS AS ESSENTIALLY

1465
01:00:59,898 --> 01:01:03,835
SORT OF--DOESN'T SORT OF

1466
01:01:03,835 --> 01:01:05,403
ENCOURAGE,--THAT'S--LOSE WORD.

1467
01:01:05,403 --> 01:01:06,671
>> THIS IS GREAT QUESTION.

1468
01:01:06,671 --> 01:01:08,640
SO, THAT'S I THINK THAT'S 1

1469
01:01:08,640 --> 01:01:10,742
ADVANTAGE OF USING PROTEINS AS

1470
01:01:10,742 --> 01:01:11,009
COVALENT.

1471
01:01:11,009 --> 01:01:13,011
YOU CAN PUT A WAR HEAD INTO THE

1472
01:01:13,011 --> 01:01:16,848
PROTEINS AND PROTEINS HAVE THIS

1473
01:01:16,848 --> 01:01:21,019
BULKY EFFECT TO PREVENT OR AT

1474
01:01:21,019 --> 01:01:22,220
LEAST MINIMIZE REACTIONS TO

1475
01:01:22,220 --> 01:01:22,587
[INDISCERNIBLE].

1476
01:01:22,587 --> 01:01:23,855
>> SO I HAVE ANOTHER
QUESTION IF

1477
01:01:23,855 --> 01:01:26,257
THAT'S OKAY, FOR YOUR 2 NANO

1478
01:01:26,257 --> 01:01:27,592
BODIES AGAINST THE SPIKE

1479
01:01:27,592 --> 01:01:28,960
PROTEIN, THERE ARE I THINK A

1480
01:01:28,960 --> 01:01:31,930
NUMBER OF NANO BODIES, DID

1481
01:01:31,930 --> 01:01:35,600
YOU--HOW DID YOU SELECT THE NANO

1482
01:01:35,600 --> 01:01:36,134
BODY?

1483
01:01:36,134 --> 01:01:37,802
DID YOU CHOOSE THE MOST TIGHT OR

1484
01:01:37,802 --> 01:01:41,272
THE 1 AVAILABLE AT THE TIME?

1485
01:01:41,272 --> 01:01:41,973
>> WE ACTUALLY DIDN'T
CHOOSE

1486
01:01:41,973 --> 01:01:43,908
THAT TIME IS DURING THE PANDEMIC

1487
01:01:43,908 --> 01:01:45,744
IT WAS ALL IN A MESS.

1488
01:01:45,744 --> 01:01:47,979
SO WE USE WHATEVER IN THE

1489
01:01:47,979 --> 01:01:48,279
LITERATURE.

1490
01:01:48,279 --> 01:01:54,419
THE MMB6 WAS DEVELOPED BY PETER

1491
01:01:54,419 --> 01:01:58,523
WRIGHT GROUP AT UCSF, AND MD7

1492
01:01:58,523 --> 01:02:00,358
WAS DEVELOPED BY SOMEONE AT

1493
01:02:00,358 --> 01:02:00,925
[INDISCERNIBLE] UNIVERSITY.

1494
01:02:00,925 --> 01:02:03,228
SO WE DIDN'T PICK WHICH NANO

1495
01:02:03,228 --> 01:02:05,964
BODY TO USE, OUR STRATEGIES,

1496
01:02:05,964 --> 01:02:07,265
THAT SPEAKS SOMETHING OF OUR

1497
01:02:07,265 --> 01:02:08,833
STRATEGY THAT WORKS INTO--SO

1498
01:02:08,833 --> 01:02:10,401
FAR, IN OUR HANDS IT WORKS ON

1499
01:02:10,401 --> 01:02:12,937
ANY NANO BODY WE USE IT ALL.

1500
01:02:12,937 --> 01:02:13,404
>> I SEE.

1501
01:02:13,404 --> 01:02:15,940
>> AND MANY OTHER PROTEINS

1502
01:02:15,940 --> 01:02:17,942
BECAUSE THE TYROSEEN, LYSINE AND

1503
01:02:17,942 --> 01:02:19,611
HISTODEANS IS JUST EVERYWHERE,

1504
01:02:19,611 --> 01:02:20,945
SO WE NEVER FAILED SO FAR TO

1505
01:02:20,945 --> 01:02:23,248
CROSS LINK THE TARGETED PROTEIN

1506
01:02:23,248 --> 01:02:27,952
INTEREST IN THE EFFECTS

1507
01:02:27,952 --> 01:02:28,887
APPROXIMATELILY ENABLED

1508
01:02:28,887 --> 01:02:29,187
REACTIVITY.

1509
01:02:29,187 --> 01:02:30,455
AND THESE 2 HAVE 10 FOLD

1510
01:02:30,455 --> 01:02:33,625
DIFFERENCE, 1 NANO BODY HAS 1

1511
01:02:33,625 --> 01:02:36,294
NANO MOLE OAR BIENING AFFINITY,

1512
01:02:36,294 --> 01:02:38,963
THE OTHER HAN .1 NANO MOLAR.

1513
01:02:38,963 --> 01:02:39,397
MD70 AS .1.

1514
01:02:39,397 --> 01:02:41,299
THEREFORE YOU SEE THE

1515
01:02:41,299 --> 01:02:43,401
IMPROVEMENT IS 8 TO 10.

1516
01:02:43,401 --> 01:02:45,170
THE OTHER HAS 1 NANO MOLAR IS

1517
01:02:45,170 --> 01:02:46,671
LIKE 44 EMPLOY NTHANK YOU.

1518
01:02:46,671 --> 01:02:49,440
>> OKAY, WE'RE AT THE TOP
OF THE

1519
01:02:49,440 --> 01:02:50,975
HOUR THERE'S A RECEPTION RIGHT

1520
01:02:50,975 --> 01:02:51,309
OUTSIDE.

1521
01:02:51,309 --> 01:02:53,745
PLEASE AT A, 1 MORE TIME, THANK

1522
01:02:53,745 --> 01:02:54,345
THE SPEAKER.

1523
01:02:54,345 --> 01:02:55,413
[ APPLAUSE ]

1524
01:02:55,413 --> 01:03:05,690
>> THANK YOU.