Peptidomimetic-based approach toward inhibitors of microbial trimethylamine lyases

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The development of gut microbiota-targeted small molecules represents a promising platform for the identification of new therapeutics based on the implication of human gut bacteria with different diseases. Bacterial trimethylamine (TMA)-lyase (CutC) is expressed in gut bacteria and catalyzes the conversion of choline to TMA. The association of elevated TMA production with various disorders has directed research efforts toward identification of CutC inhibitors. Herein, we introduce peptidomimetics as a promising toolbox for the discovery of CutC inhibitors. Our approach starts with screening a library of peptidomimetics for intestinal metabolic stability followed by in vitro CutC inhibition. Compound 5 was identified from this screening platform with IC50 value of 5.9 ± 0.6 μM for CutC inhibition. Unlike previously reported CutC inhibitors, compound 5 possessed universal CutC inhibitory activity in different bacterial strains. Molecular dynamics simulations suggested a plausible binding site and inhibition mechanism for compound 5. Therefore, compound 5 is a promising lead for further structural optimization in the search for CutC-targeted small molecules.

    Original languageEnglish
    Pages (from-to)231-236
    Number of pages6
    JournalChemical Biology and Drug Design
    Volume97
    Issue number2
    Early online date9 Aug 2020
    DOIs
    Publication statusPublished - Feb 2021

    Keywords

    • choline metabolism
    • gut microbiota
    • peptidomimetics
    • trimethylamine lyase

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Pharmacology
    • Drug Discovery
    • Organic Chemistry

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