This proposed research is centered on the development of new techniques for the site-selective modification of peptide-based drugs. Peptides have emerged as promising, alternative therapeutic agents, yet a number of drawbacks preclude their widespread use. These limitations can be resolved through the late-stage modification of peptide primary sequences, such as through bioconjugation or stapling, yet methods for selectively functionalizing these chemically complex, unprotected peptides is challenging. This proposal focuses on harnessing this functional group richness of peptides for noncovalent interactions between reagents and residues near sites of desired nucleophilic aromatic substitution (SNAr) reactions. First, electrophilic arenes for SNAr will be appended with directing groups to interact with matched sequences on peptides, directing reactivity toward adjacent Cys residues for functionalization Second, Lewis acidic catalysts that are able to further activate arenes for SNAr will be designed to likewise interact with certain peptide residues, enabling the achievement of catalyst- and ligand-control over sites of modification. Both of these strategies will allow for the pairing of particular directing groups or catalysts with specific sequences of residues adjacent to targeted nucleophilic residues, such as Cys. Orthogonal derivatization of peptides containing many reactive residues with a toolbox of reagents, each designed to target a nucleophilic residue in a different environment, could be imagined. This proposal will facilitate the rapid bioconjugation of a variety of relevant molecules to peptide therapeutics to enhance their efficacies, such as small molecule receptors or drugs, fluorophores, other peptides, or even proteins such as antibodies. Multiple functionalizations, such as through stapling, could also be utilized to enhance the peptides? structural stabilities and their resistance to proteolytic cleavage in vivo. Since few methods for site-selective modification exist, this research would facilitate studies of how alterations to different locations on peptide medicines alter their structure and function, allowing for wider access to more diverse drug analogs. The paradigm of directed reactivity for site-selective peptide modifications would not only be useful for SNAr reactions, but represents a general approach amenable to a multitude of other tagging reagents or metal- mediated processes. These discoveries would serve to accomplish the overarching goal of this project, which is the further development of peptide-based medicines into a powerful, and highly sought-out approach to solve the many challenges to human health today. The Pentelute group at MIT will be an ideal location to conduct this research, given their expertise in peptide synthesis and modification and in the development of peptide therapeutics. Their highly collaborative and team-based laboratory environment will promote exchange of ideas, creativity, and problem solving in tackling the incredibly important topic of modern therapeutics.

Public Health Relevance

The overarching goal of this project is to develop new methods for site-selective nucleophilic aromatic substitution reactions on Cys residues of therapeutically-relevant peptides. These selectivities will be achieved by reliance on noncovalent interactions between peptides and both (1) directing groups on arene electrophiles and (2) added Lewis acid catalyst/ligand complexes. High levels of control over sites of peptide modification will enable the rapid synthesis and optimization of a myriad of analogs of peptide medicines.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Lees, Robert G
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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