# Protein Chemistry

> **NIH NIH R35** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $474,861

## Abstract

PROJECT SUMMARY/ABSTRACT
The majority of drugs in the extant pharmacopeia are small molecules. Half of those small molecules act
on extracellular targets, and half act on intracellular targets. A minority of drugs are proteins, and
virtually all of those proteins are antibodies, hormones, or enzymes that act on extracellular targets. The
proposed research program will endow proteins with the ability to enter cells and act on intracellular
targets. The program takes advantage of new chemical reactivity that uses tuned diazo compounds to
esterify protein carboxyl groups in water. The resulting esterified proteins are analogous to small-
molecule prodrugs in enabling traversal of the plasma membrane of human cells. Ester hydrolysis
catalyzed by intracellular esterases makes the modifications traceless, avoiding any compromise to proper
function. “Protein esterification” has an uncharted landscape. Accordingly, the work will begin by
exploring fundamental attributes of esterified proteins, including their mechanism of cellular uptake and
the enzymology of ester hydrolysis by cellular esterases. Specific systems will be enlisted to assess the
generality of this delivery method and provide opportunities for discovery. In particular, esterification
will be used to deliver particular proteins that elicit cytotoxicity or tumor suppression, or control genome
editing. The delivery strategy will also be used to anchor oligonucleotides and other beneficial moieties
on the cell surface and generalize the selective degradation of cellular proteins. These broad and far-
reaching efforts will provide high-impact advances in biomedicine, chemical biology, and allied fields.

## Key facts

- **NIH application ID:** 10767808
- **Project number:** 5R35GM148220-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Ronald T Raines
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,861
- **Award type:** 5
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767808

## Citation

> US National Institutes of Health, RePORTER application 10767808, Protein Chemistry (5R35GM148220-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10767808. Licensed CC0.

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