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Chemical Tools to Covalently Modify Proteins and Cells

Tivon, Yaniv (2022) Chemical Tools to Covalently Modify Proteins and Cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Conventional small molecule targeted covalent inhibitors, particularly those inhibiting kinases, have dominated the protein covalent inhibition field in the past decade; but sophisticated chemical tools that leverage covalent conjugation to discreetly modify proteins provide complementary avenues to covalent inhibitors by unlocking applications ranging from native protein detection to mediating cell-cell interactions. These approaches are quickly being adopted within academia, while their full potential is under investigation. Herein, contributions towards the development and application of nucleic acid and small molecule-based chemical tools to the fields of native protein modification and immunotherapy are described.
Using aptamers, I have developed a fundamentally new approach to modify endogenous proteins with functional probes that enable their enrichment or sensitive detection in complex environments such as live cell surfaces. These reagents are generated by conjugating aptamers with a cleavable electrophile that transfers a user-chosen molecule to a proximal nucleophilic residue. The aptamer guides the electrophile towards its target protein, and transfers its conjugated probe with exquisite specificity.
I have also contributed to developing an immunotherapy that capitalizes on genetically altered T cells to target tumors by generating small molecule-antibody adducts through chemical synthesis of lysine-reactive probes. Through this system, we targeted several cancer-types using a universal CAR adaptor approach. Precise tuning of T cell activation by conditionally controlling its tumor cell interaction using UV light or with a small molecule trigger, thereby mitigating toxicities was also demonstrated.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Tivon, Yanivyat25@pitt.eduyat250000-0002-1573-4096
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeiters,
Committee MemberLohmueller,
Committee MemberKabirul,
Committee MemberHorne,
Date: 21 July 2022
Date Type: Publication
Defense Date: 15 October 2021
Approval Date: 21 July 2022
Submission Date: 22 November 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 212
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Covalent Aptamer Crosslinking
Date Deposited: 21 Jul 2023 05:00
Last Modified: 21 Jul 2023 05:00


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