Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase
![Thumbnail](/xmlui/bitstream/handle/10234/190474/71885.pdf.jpg?sequence=4&isAllowed=y)
View/ Open
Metadata
Show full item recordcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
comunitat-uji-handle4:
INVESTIGACIONMetadata
Title
Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐LyaseDate
2020-08-22Publisher
WileyISSN
1860-7179; 1860-7187Bibliographic citation
Gabr, M. and Świderek, K. (2020), Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase. ChemMedChem. https://doi.org/10.1002/cmdc.202000571Type
info:eu-repo/semantics/articlePublisher version
https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cmdc.202000571?af=RVersion
info:eu-repo/semantics/acceptedVersionSubject
Abstract
Anaerobic choline metabolism by human gut microbiota to produce trimethylamine (TMA) has recently evolved as a potential therapeutic target because of its association with chronic kidney disease and increased cardio ... [+]
Anaerobic choline metabolism by human gut microbiota to produce trimethylamine (TMA) has recently evolved as a potential therapeutic target because of its association with chronic kidney disease and increased cardiovascular risks. Limited examples of choline analogues have been reported as inhibitors of bacterial enzyme choline TMA‐lyase (CutC), a key enzyme regulating choline anaerobic metabolism. We used a new workflow to discover CutC inhibitors based on focused screening of a diversified library of small molecules for intestinal metabolic stability followed by in vitro CutC inhibitory assay. This workflow identified a histidine‐based scaffold as a CutC inhibitor with an IC50 value of 1.9±0.2 μM. Remarkably, the identified CutC inhibitor was able to reduce the production of TMA in whole‐cell assays using various bacterial strains as well as in complex gut microbiota environment. The improved efficiency of the new scaffold identified in this study in comparison to previously reported CutC inhibitors would enable optimization of potential leads for in vivo screening and clinical translation. Finally, docking studies and molecular‐dynamic simulations were used to predict putative interactions created between inhibitor and CutC. [-]
Description
This is the peer reviewed version of the following article: Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase, which has been published in final form at https://do ... [+]
This is the peer reviewed version of the following article: Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase, which has been published in final form at https://doi.org/10.1002/cmdc.202000571. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. [-]
Is part of
ChemMedChem, 2020Investigation project
Spanish Ministerio de Ciencia e Innovación. Grant Numbers: PGC2018-094852-B-C21, PID2019-107098RJ-I00; Generalitat Valenciana. Grant Number: SEJI/2020/007; Universitat Jaume. Grant Number: UJI-A2019-04; MINECO. Grant Number: IJCI-2016-27503Rights
Copyright © John Wiley & Sons, Inc.
http://rightsstatements.org/vocab/InC/1.0/
info:eu-repo/semantics/openAccess
http://rightsstatements.org/vocab/InC/1.0/
info:eu-repo/semantics/openAccess
This item appears in the folowing collection(s)
- QFA_Articles [825]