# Biochemical Strategy to Avert Microbial Drug Resistance

> **NIH NIH R21** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $264,139

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of the proposed research is to develop a generalizable antimicrobial strategy
that averts the onset of resistance. The proposed antiviral agent has a mechanism of
action that relies on the function of a pathogenic protein rather than its inhibition.
Specifically, the agent is a cytotoxic variant of a human enzyme, ribonuclease 1
(RNase 1), that is cloaked and thus inactive as a catalyst. The cloak is removable only by
a pathogenic protease that is essential for the lifecycle of the pathogen. SARS-CoV-2 will
serve as a model pathogen in the study. The goal will be attained by (1) identifying an
optimal amino acid sequence that is cleaved by the 3CLpro protease of SARS-CoV-2 but
not by endogenous human proteases, (2) using that sequence and intein-mediated cis-
splicing to create a cyclic RNase 1 zymogen, and (3) demonstrating the ability of the
zymogen to kill human lung cells that express 3CLpro and that are infected by
SARS-CoV-2. Because the activated zymogen can also destroy the genome of an RNA
virus like SARS-CoV-2, it could eradicate the viral reservoir in patients. A notable feature
of the strategy is its modularity: the protease-cleavage sequence is a cassette that can be
altered to match the specificity of pathogenic proteases for the treatment of other
infectious diseases.

## Key facts

- **NIH application ID:** 10510991
- **Project number:** 1R21AI171663-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Ronald T Raines
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $264,139
- **Award type:** 1
- **Project period:** 2022-06-14 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10510991

## Citation

> US National Institutes of Health, RePORTER application 10510991, Biochemical Strategy to Avert Microbial Drug Resistance (1R21AI171663-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10510991. Licensed CC0.

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