# Bioorthogonal methods for unveiling chemical reactivity

> **NIH NIH R01** · GEORGIA INSTITUTE OF TECHNOLOGY · 2024 · $317,623

## Abstract

Project Summary
The long-term goal of our research program is to develop chemistry that can facilitate the synergetic interaction
between biomolecules and small molecules to achieve site-selective transformations in a biological context. The
objective of this application is to develop the chemistry of N-oxides and integrate them into biological systems
that stand to benefit from reversible covalent modifications by prosthetic agents. N-oxides are versatile reagents
with a minimalist design that encapsulate both ligation and release properties. They are synthesized through a
rapid bioorthogonal hydroamination reaction and disassembled under similarly bioorthogonal conditions through
reduction. This chemistry allows the transient, yet controlled, attachment of small molecules to proteins or
proteins to small molecules and enables the temporary use of functional modules that are not normally present
in the active form of a protein or small molecule effector. The specific aims of the project are: 1) Development of
reactive species for target identification applications; 2) Development of proximity labeling tools for interactome
studies; 3) Development of biologically compatible directing group chemistry. In the first aim, we will develop
reactive chemical species that can functional proteins and use them to identify the molecular target of a bioactive
small molecule. In the second aim, we will develop new catalysts for proximity labeling. In the third aim, we will
develop chemical methods and reagents for the reversible covalent functionalization of proteins. We use the
chemistry to introduce small molecules or enzymes that can site-specifically modify proteins of interest with
native post-translational modifications. The approach we take is innovative because we make use of a unique
pair of chemical reactions that enables the rapid and complete bioorthogonal ligation and cleavage of two
components in either a single step or in two discrete and independent steps. This contrasts with existing
bioorthogonal tools designed either to ligate or to cleave but not to do both separately. The research we propose
is significant because it provides a new method for discovering proteins that interact in either an on-target or off-
target manner with a lead drug candidate, for studying the interactome of a protein complex, and for accessing
homogeneous preparations of native post-translationally modified proteins for biochemical and biophysical
studies. Most importantly, the fundamental chemistry we explore and the tools that we create will expand the
functional repertoire of chemistry that can be performed on biological systems and pave the way to new
discoveries.

## Key facts

- **NIH application ID:** 10800059
- **Project number:** 1R01GM149693-01A1
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Justin Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $317,623
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800059

## Citation

> US National Institutes of Health, RePORTER application 10800059, Bioorthogonal methods for unveiling chemical reactivity (1R01GM149693-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10800059. Licensed CC0.

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