# Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $254,250

## Abstract

Project summary: The development of therapies inspired by the human microbiome is at least in part limited
by our lack of understanding of how human associated (HA-) bacteria communicate with their human host and
affect pathogens. Human microbiome sequencing studies show strong correlations between changes in
bacterial populations and human health. Despite these correlations and the evidence linking HA-bacteria to
disease in mice, the mechanistic details of how HA-bacteria specifically affect mammalian physiology remain
largely unknown. In other environments, bacteria are known to rely heavily on low molecular weight
compounds (small molecules or natural products) to interact with other organisms. Similarly, we expect that
HA-bacteria are likely to use small molecules to interact with their human hosts and pathogens. Mounting
evidence suggests that, although each human microbiome is composed of a complex collection of bacteria, a
much smaller number of species is highly prevalent across the majority of individuals. While we don’t know
exactly which HA-bacteria are responsible for maintaining human health or causing disease, we hypothesize
that small molecules produced by these commonly encountered HA-bacteria are likely to play an important role
in these processes. The central aim of this proposal is to screen metabolites produced by the most commonly
observed HA-bacteria in high-throughput bioactivity screening to identify GPCR and SARS-CoV-2-active small
molecules and their producing biosynthetic gene clusters (BGCs). GPCRs constitute the largest family of
eukaryotic trans-membrane receptors. They are known to play diverse and profound roles in human biology
and are prone to regulation by small molecules. Based on the fact that GPCRs play such an extensive role in
transforming chemical information from the environment into biological signals in eukaryotic cells, I believe that
HA-bacteria likely affect host physiology through the production of small molecules that interact with GPCRs.
The emergence of the SARS-CoV-2 virus represents a worldwide pandemic with no therapeutic drug
treatments. The two Aims of this proposal will result in (1) the identification, isolation, and structure elucidation
of HA-bacteria-encoded metabolites that either interact with diverse GPCRs or inhibit SARS-CoV-2, (2) the
characterization of the gene clusters for these metabolites, and (3) the validation of their production by
colonizing bacteria. These studies will help to illuminate the mechanistic details of how HA-bacteria shape
human health. The human microbiome is reported to influence complex pathophysiological processes ranging
from the regulation of the immune system to the development of the brain and the central nervous system.
Changes in HA-bacterial populations are associated with diseases that affect over 200 million Americans
including obesity, diabetes, inflammatory bowel disease, autism, irritable bowel syndrome, and cirrhosis among
many others. Therap...

## Key facts

- **NIH application ID:** 10229230
- **Project number:** 3R01AT009562-04S1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** SEAN F BRADY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,250
- **Award type:** 3
- **Project period:** 2017-07-14 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229230

## Citation

> US National Institutes of Health, RePORTER application 10229230, Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria (3R01AT009562-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10229230. Licensed CC0.

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