Conditional Activation of Protein Function

Janosko, Chasity Paige (2024) Conditional Activation of Protein Function. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The ability to demonstrate conditional control over biological processes is fundamental to the field of chemical biology and is thoroughly discussed in Chapter 1.0. In this work, I investigated various methods of conditional activation including the modification of small molecule ligands with light, peroxide, or enzymatically activated caging groups as discussed in Chapter 2.1. Peroxide-cleavable functionalities were also utilized for the selective release of the chemotherapeutics pederin, camptothecin, and phorbol in cancerous cell lines as demonstrated in Chapter 5.0. The
natural product rapamycin was modified to include either a photoswitchable arylazopyrazole or a photoactivatable ROS-generating chromophore, further demonstrating light control of small molecule ligands in Chapter 4.0.
In addition to the use of small molecule ligands, a variety of photoactivatable unnatural amino acids were utilized throughout Chapters 2.2 and 3.0 to directly render proteins conditionally activatable, specifically for the selective control of MAPK signaling and antibody-directed enzyme
prodrug therapies. The unnatural amino acids utilized herein fall under two major categories: 1) photocaging, in which irradiation activates protein function or 2) photoswitchable, in which irradiation with two different wavelengths of light control protein function in a reversible manner. In either case, the unnatural amino acid was typically introduced to the protein via genetic code expansion, a concept which has been widely utilized by the Deiters lab in order to control and
study various biological processes as demonstrated in this work and the work of previous lab members.

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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Janosko, Chasity Paige cph34@pitt.edu CPH34
ETD Committee:	Title Member Email Address Pitt Username ORCID Committee Chair Deiters, Alexander deiters@pitt.edu deiters Committee Member Floreancig, Paul florean@pitt.edu florean Committee Member Weber, Stephen sweber@pitt.edu sweber Committee Member Khare, Sagar khare@chem.rutgers.edu
Date:	10 January 2024
Date Type:	Publication
Defense Date:	3 November 2023
Approval Date:	10 January 2024
Submission Date:	15 November 2023
Access Restriction:	2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages:	357
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:	chemical biology, unnatural amino acid mutagenesis
Date Deposited:	10 Jan 2024 13:37
Last Modified:	10 Jan 2024 13:37
URI:	http://d-scholarship.pitt.edu/id/eprint/45556

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