Discovery of a Highly Potent and Selective Small-Molecule Inhibitor of <i>In Vivo</i> Anaerobic Choline Metabolism by Human Gut Bacteria
Trimethylamine (TMA) Lyase is an enzyme expressed in human gut bacteria that plays a pivotal role in the formation of trimethylamine oxide (TMAO), a metabolite implicated in the development of heart failure. Here, we describe a strategy to design covalent inhibitors targeting the active site thiyl radical involved in the catalytic cycle of the enzyme under anaerobic conditions. This strategy led to the discovery of <b>7</b>, a previously unreported highly potent and selective inhibitor of TMA Lyase. When dosed orally to rats, <b>7</b> shows a significant reduction of circulating TMAO levels and, importantly, demonstrates inhibition of TMAO generated from a human microbiome when profiled in a human fecal mouse transplant model.
Authors
- Jonas Brånalt
- Scott Turick (ORCID: https://orcid.org/0000-0003-1472-6745)
- Marcus Henricsson (ORCID: https://orcid.org/0000-0002-4202-0339)
- Giuseppina La Sala (ORCID: https://orcid.org/0000-0001-6565-197X)
- Ginger Lasky
- Marcel Taillefer (ORCID: https://orcid.org/0000-0002-4314-291X)
- Taylor S. Cohen (ORCID: https://orcid.org/0000-0001-9368-0903)
- Tove Sjögren (ORCID: https://orcid.org/0000-0002-6703-4200)
- Marta Szydlowska (ORCID: https://orcid.org/0000-0002-4660-899X)
- Paul Warrener (ORCID: https://orcid.org/0000-0001-8597-7029)
- Dušan Petrović (ORCID: https://orcid.org/0000-0002-1834-7358)
- Anna Vildhede (ORCID: https://orcid.org/0000-0003-4714-7205)
- Ulrik Jurva
- Margareta Ek (ORCID: https://orcid.org/0000-0001-8226-8112)
- Tina Bake (ORCID: https://orcid.org/0000-0003-0500-5129)
- John Liddle (ORCID: https://orcid.org/0000-0003-1805-3728)
- Jens Petersen (ORCID: https://orcid.org/0000-0001-5946-4756)
- Anders Gunnarsson
- Ulf Fahlander
- Mariell Pettersson
- Björn Holm
- Ben Sparklin
- Kristina Westerlund
- Robert Roth
- Yannick Morias
Institutions
- Discovery Centre (CA)
- Bioscience Research (US)
- AstraZeneca (Brazil) (BR)
- Institut thématique Génétique, génomique et bioinformatique (FR)
- Institut de Recherche Vaccinale (FR)
- Generic Assays (Germany) (DE)
- Discovery Laboratories (United States) (US)
- PharmacoGenetics (China) (CN)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
- AstraZeneca (Germany) (DE)
- Global Vaccines (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-01-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01451
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.00