# Site-Selective Modification of Peptides and Proteins through Noncovalent Interactions

> **NIH NIH F32** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $64,926

## Abstract

PROJECT SUMMARY/ABSTRACT
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 i...

## Key facts

- **NIH application ID:** 9937522
- **Project number:** 5F32GM133073-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Christopher Ryan Shugrue
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937522

## Citation

> US National Institutes of Health, RePORTER application 9937522, Site-Selective Modification of Peptides and Proteins through Noncovalent Interactions (5F32GM133073-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9937522. Licensed CC0.

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