Off-campus UMass Amherst users: To download campus access dissertations, please use the following link to log into our proxy server with your UMass Amherst user name and password.
Non-UMass Amherst users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Dissertations that have an embargo placed on them will not be available to anyone until the embargo expires.
Author ORCID Identifier
Open Access Dissertation
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Amino Acids, Peptides, and Proteins | Analytical Chemistry | Bioimaging and Biomedical Optics | Biomaterials | Biomedical Devices and Instrumentation | Materials Chemistry | Organic Chemistry | Other Chemicals and Drugs | Polymer Chemistry | Structural Biology
Reactive chemistries for protein chemical modification play an instrumental role in chemical biology, proteomics, and therapeutics. Depending on the application, the selectivity of these modifications can range from precise modification of an amino acid sequence by genetic manipulation of protein expression machinery to a stochastic modification of lysine residues on the protein surface. Ligand-Directed (LD) chemistry is one of the few methods for targeted modification of endogenous proteins without genetic engineering. However, current LD strategies are limited by stringent amino acid selectivity. To bridge this gap, this thesis focuses on the development of highly reactive LD Triggerable Michael Acceptors (LD-TMAcs) that feature rapid protein labeling.
Unlike previous LD approaches, the unique reactivity of LD-TMAcs enables multiple modifications on a single target protein. This capability is attributed to the tunable reactivity of TMAcs that enable the labeling of several amino acid functionalities via a binding-induced increase in local concentration while remaining fully dormant in the absence of protein binding. We demonstrate the utility of this method by selectively labeling membrane-bound carbonic anhydrase XII in live cells. Then, by using our LD-TMAc platform, we have developed target selective covalent Hydrophobic Tagging (HyT) probes. By target-selectively labeling the membrane CAXII with multiple hydrophobic adamantane tags, we demonstrate ~75% CAXII degradation in MCF7 cells in 30 minutes. We envision that the unique features of LD-TMAcs will find use in a range of applications from target identification, investigation of binding/allosteric sites, studies of membrane proteins, and targeted protein degradation. Finally, this thesis also involves the development of reactive polymers for covalent encapsulation and photo-responsive release of proteins and small molecule therapeutics in hydrogel drug depots. We envision the ability of our polymers to directly conjugate natural proteins without genetic or enzymatic engineering and release the encapsulated cargo in a photo-responsive and traceless manner that will find use in drug-encapsulated hydrogel systems.
Kurbanov, Myrat, "REACTIVE CHEMISTRIES FOR PROTEIN LABELING, DEGRADATION, AND STIMULI RESPONSIVE DELIVERY" (2023). Doctoral Dissertations. 3006.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Amino Acids, Peptides, and Proteins Commons, Analytical Chemistry Commons, Bioimaging and Biomedical Optics Commons, Biomaterials Commons, Biomedical Devices and Instrumentation Commons, Materials Chemistry Commons, Organic Chemistry Commons, Other Chemicals and Drugs Commons, Polymer Chemistry Commons, Structural Biology Commons