# Development of a Biocatalytic Toolbox for the Synthesis of Small-Molecule Mimics of cyclic GMPAMP

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $73,828

## Abstract

PROJECT SUMMARY/ABSTRACT
Twenty percent of Americans die of cancer. This alarming statistic reflects a major human health need for novel
cancer therapeutics. Small molecule mimics of cyclic GMP-AMP (cGAMP) represent an emerging new class of
immunotherapeutic cancer drugs, and numerous cGAMP-mimics have been entered into clinical trials in the last
three years. Unfortunately, due to their unusually complex structure, these clinical candidates are exceptionally
difficult to prepare via classic synthetic methodology, which serves as a limitation to their development. Recent
advances in biocatalysis, however, indicate significant opportunity to simplify the synthesis of cGAMP-mimics.
The enzyme that naturally produces cGAMP is called cGAMP synthase (cGAS), and preliminary results suggest
that engineering of cGAS may provide a way to access diverse cGAMP-mimics through a highly direct process.
This proposal aims to develop biocatalytic approaches for the synthesis of cGAMP-mimics using natural and
engineered cGAS variants. As over 500 sequences of cGAS enzymes have been catalogued from nature, there
is already a large protein library from which to develop an expanded biocatalytic lexicon for the synthesis of
cGAMP-mimics. There are three major challenges in the synthesis of unnatural cGAMP-mimics that will be ad-
dressed by this fellowship, which aims to 1) build a panel of cGAS enzymes with non-native nucleobase toler-
ance, 2) create stereocomplementary catalysts for phosphorothioate centers, and 3) engineer cGAS to create
atypical constitutional isomers of cGAMP. It is our hypothesis that novel reactivity and selectivity can be realized
through a two-phase iterative interrogation of cGAS proteins: high-throughput screening of a library of cGAS
enzymes against a reference target followed by engineering of the most successful variants. Insights from this
work will afford an increased knowledge of the specific structural features of cGAS that govern nucleobase tol-
erance, phosphorus-centered stereoselectivity, and site-selectivity in macrocyclization. This work will enable sci-
entists to develop tomorrow’s immunotherapeutic cancer drugs more rapidly.

## Key facts

- **NIH application ID:** 10992596
- **Project number:** 5F32GM151793-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Cole Christian Meyer
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992596

## Citation

> US National Institutes of Health, RePORTER application 10992596, Development of a Biocatalytic Toolbox for the Synthesis of Small-Molecule Mimics of cyclic GMPAMP (5F32GM151793-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10992596. Licensed CC0.

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