Towards targeted post-translational modification of endogenous proteins in complex environments

Proteins are commonly thought of as polymers comprising the twenty natural amino acids. However, in actuality, the proteome of a typical cell contains hundreds of different amino acid side chains, brought about by co- and post-translational modifications (PTMs). Depending on the roles of the modified amino acids and the nature of the chemical changes, PTMs can have tremendous influence on protein function. This phenomenon can be exploited pharmacologically, as covalent inhibitors such as aspirin covalently bind, or attach a covalent payload, to the active sites of enzymes. Following this principle, rationally designed targeted covalent inhibitors (TCIs) adapt non-covalent ligands to react with nucleophilic residues adjacent to their binding site. At the moment, most TCIs target cysteine thiols, but advances in bioconjugation chemistries hold the potential to significantly broaden their target range. However, disordered and misfolded proteins, as well as folded targets that lack ligand binding sites, are largely inaccessible to both traditional drugs and TCIs. On the other hand, these proteins are near-ideal candidates for modulation via post-translational modifications. Here, I present new approaches for covalent modification of endogenous proteins in complex environments, at any chosen surface-exposed site. Despite many advances in achieving in vivo PTMs of proteins, no technique or compound exists at this time able to perform this task. Our targeted post-translational modifiers (TPTMs) consist of a rationally designed high affinity specificity moiety and a weak reactive moiety susceptible to catalysis through the proximity effect. Using this design principle, and tailoring the subtle kinetics of in vivo protein chemistry, I anticipate that these approaches will enable to expand the scope of protein covalent modifications well beyond that of TCIs, as far as the realm of currently undruggable targets.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Rimon, Oded

Advisor dc:contributor.advisor

• Vendruscolo, Michele

• PEABS
• targeted post-translational modification
• chemical modification of endogenous proteins
• targeted covalent drugs

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-5848-2968

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/335160