# Protein Chemistry

> **NIH NIH R35** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $196,980

## Abstract

PROJECT SUMMARY/ABSTRACT
Approximately 80% of drugs in the pharmacopeia are small molecules. Half of those small molecules act
on extracellular targets, and half act on intracellular targets. The remaining 20% of drugs are proteins, and
virtually all of those proteins are antibodies, hormones, or enzymes that act on extracellular targets. The
proposed research will enable proteins to act on intracellular targets. The proposed research program
takes advantage of new chemical reactivity that is applicable in a physiological context. The overall goal
is to develop a facile, general means to endow native proteins with the ability to enter the cytosol of
human cells with desirable consequences. The strategy is to esterify protein carboxyl groups by using
α-aryl-α-diazoamides. The basicity of these diazo compounds are tuned to enable the efficient
esterification of carboxyl groups in water. The resulting esterified proteins are analogous to small-
molecule prodrugs. Intracellular esterases make these modifications traceless, avoiding any compromise
to proper function or potential for immunogenicity. “Protein esterification” has an uncharted landscape.
Accordingly, work will begin by exploring fundamental attributes of esterified proteins, including the
mechanism of cellular uptake and the enzymology of ester hydrolysis by cellular esterases. Esterification
will then be used to deliver proteins for eliciting cytotoxicity, tumor suppression, and genome editing.
The work relies on methods and ideas from chemical biology and allied fields, especially organic
chemistry and enzymology. The research will establish a new paradigm for developing chemotherapeutic
agents that are capable of addressing numerous unmet medical needs.

## Key facts

- **NIH application ID:** 11037216
- **Project number:** 3R35GM148220-02S1
- **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:** $196,980
- **Award type:** 3
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11037216

## Citation

> US National Institutes of Health, RePORTER application 11037216, Protein Chemistry (3R35GM148220-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11037216. Licensed CC0.

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