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

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

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.
PMID: 41614677 DOI: 10.1021/acs.jmedchem.5c01451
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.

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