Tivon, Yaniv
(2022)
Chemical Tools to Covalently Modify Proteins and Cells.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41971 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[img]](http://d-scholarship.pitt.edu/style/images/fileicons/application_pdf.png)
![[feed]](/images/feed-icon-32x32.png){kind=icon}