# Adding new covalent bonds to proteins in live cells

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $350,834

## Abstract

Project Summary/Abstract
Proteins perform a variety of biological functions by interacting with different families of bimolecules. These
interactions are largely noncovalent in nature. Although such noncovalent interactions provide diversity and
dynamics for biology, their reversibility and weakness also impose strong limitations on researching and
engineering protein-bimolecule interactions. In this application the natural barrier will be broken by designing
and genetically incorporating bioreactive unnatural amino acids (Uaas) into proteins, which will enable proteins
to bind with ribonucleic acids and carbohydrates in the covalent mode. The underlying innovation is to develop
biocompatible chemistry, so that the Uaa will selectively react with the target ribonucleic acid or carbohydrate
via proximity-enabled reactivity only upon binding, resulting in stable and irreversible linkage between protein
and the target. To achieve these goals, new chemistries suitable for covalently targeting ribonucleic acids and
carbohydrates in cellular and physiological conditions will be developed. The desired chemical functionality will
be synthesized into the side chain of a Uaa, and the Uaa will be site-specifically incorporated into proteins in
live cells via the genetic code expansion technology. This new covalent bonding strategy will be applied in live
cells to understand RNA-protein recognition specificity, to identify substrate glycoproteins for glycosylation
modifying enzymes, and to antagonize cell-cell communication. By harnessing the new covalent linkages
inaccessible to natural proteins, this project will initiate a new dimension for researching and rationally
engineering protein-RNA and protein-carbohydrate interactions. As such interactions are indispensable for
biological functions and their aberrations are extensively implicated in various human diseases, new
technologies resulting from this project will fundamentally impact both basic biological research and therapeutic
applications.

## Key facts

- **NIH application ID:** 10442720
- **Project number:** 5R01GM118384-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Lei Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $350,834
- **Award type:** 5
- **Project period:** 2016-04-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442720

## Citation

> US National Institutes of Health, RePORTER application 10442720, Adding new covalent bonds to proteins in live cells (5R01GM118384-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10442720. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*