Discovery of a Highly Potent and Selective Small-Molecule Inhibitor of In Vivo Anaerobic Choline Metabolism by Human Gut Bacteria PMID: 41614677

ADC Targets in Oncology

2026-04-10

Discovery of a Highly Potent and Selective Small-Molecule Inhibitor of In Vivo Anaerobic Choline Metabolism by Human Gut Bacteria

J Med Chem. 2026 Feb 12;69(3):2115-2129. doi: 10.1021/acs.jmedchem.5c01451.

Mariell Pettersson ¹ , Giuseppina La Sala ¹ , Anders Gunnarsson ² , Anna Vildhede ³ , Ben Sparklin ⁴ , Björn Holm ¹ , Dušan Petrović ⁵ , Ginger Lasky ⁶ , Scott Turick ⁷ , Marta Szydlowska ⁸ , Vancheswaran Gopalakrishnan ⁴ , Tina Bake ⁹ , Jens Petersen ² , Jonas Brånalt ¹ , Kristina Westerlund ¹ , Marcel Taillefer ¹⁰ , Marcus Henricsson ¹¹ , Margareta Ek ² , Paul Warrener ¹² , Robert Roth ¹³ , Taylor Cohen ¹² , Tove Sjögren ² , Ulf Fahlander ¹ , Ulrik Jurva ³ , Yannick Morias ⁹ , John Liddle ¹

Affiliations

1. Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.
2. Protein, Structure and Biophysics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.
3. Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.
4. Bioinformatics, Research and Early Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland 20878, United States.
5. Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.
6. Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland 20878, United States.
7. Bacterial Vaccine Discovery, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland 20878, United States.
8. Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland 20878, United States.
9. Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.
10. Assays, Profiling, and Cell Sciences, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.
11. Translational Science & Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.
12. Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland 20878, United States.
13. Reagents and Assays Sweden, Assays, Profiling, and Cell Sciences, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 83, Sweden.

Abstract

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 7, a previously unreported highly potent and selective inhibitor of TMA Lyase. When dosed orally to rats, 7 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.