Date of Award
Fall 2024
Language
English
Embargo Period
11-19-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College/School/Department
Department of Chemistry
Program
Chemistry
First Advisor
Qiang Zhang
Committee Members
Jeremy Feldblyum, Maksim Royzen, Ting Wang, Pan Li
Abstract
Synthesis of small-molecule conjugates capable of selective attachment to a peptide/protein backbone paves way for new therapeutic applications of protein modification. Sufficient inhibition or installation of function requires extensive design so the compound may identify and attach to the intended site. The utility of such an approach has prompted a number of applicable strategies and has rendered the development of new modification scaffolds less necessary. On the other hand, covalent modification to the biologics with ability to remove the conjugate via stimulus is underdeveloped, amplifying a current need to investigate the reversible potential for conjugation and deconjugation techniques in regard to molecular scaffolds.
The investigation reported therein involves a small molecule design capable of conjugation and facile deconjugation from peptide/protein structure. Taking advantage of special reactivity between aldehyde and thiol, we utilize a number of readily available mercapto-benzaldehyde derivatives that have been synthesized by simple procedure and characterized by NMR. These compounds chemoselectively bind to backbone amino by institution of distinctive [3.3.1] and [2.2.1] bicyclic scaffolds. This protocol enables amino modification in a multi-component fashion in aqueous buffer and mild conditions, characterized by combination of HPLC and LC-MS methods.
The various bicyclic modification derivatives were investigated for progression of the reversed reaction under mild condition, utilizing a commercially available amine reagent. In restoring the original protein motif, a full investigation of a heterocyclic derivative for reversible attachment to several linear peptides was subsequently performed. Upon completion, the effectiveness of this approach was demonstrated in the modification and quantifiable regeneration of insulin protein.
License
This work is licensed under the University at Albany Standard Author Agreement.
Recommended Citation
Bartlett, Ryan, "STUDIES IN THREE-COMPONENT MODIFICATION OF LYSINE, INVESTIGATING REVERSIBLE POTENTIAL OF AN INTRICATE BICYCLO [3.3.1] NONANE SCAFFOLD" (2024). Electronic Theses & Dissertations (2024 - present). 69.
https://scholarsarchive.library.albany.edu/etd/69