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Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase
dc.contributor.author | Gabr, Moustafa | |
dc.contributor.author | Świderek, Katarzyna | |
dc.date.accessioned | 2020-11-25T08:11:28Z | |
dc.date.available | 2020-11-25T08:11:28Z | |
dc.date.issued | 2020-08-22 | |
dc.identifier.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.202000571 | ca_CA |
dc.identifier.issn | 1860-7179 | |
dc.identifier.issn | 1860-7187 | |
dc.identifier.uri | http://hdl.handle.net/10234/190474 | |
dc.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://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. | |
dc.description.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 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. | ca_CA |
dc.format.extent | 8 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | Wiley | ca_CA |
dc.relation.isPartOf | ChemMedChem, 2020 | ca_CA |
dc.rights | Copyright © John Wiley & Sons, Inc. | ca_CA |
dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | * |
dc.subject | choline | ca_CA |
dc.subject | enzyme inhibitors | ca_CA |
dc.subject | gut microbiota | ca_CA |
dc.subject | histidine | ca_CA |
dc.subject | small molecules | ca_CA |
dc.title | Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | https://doi.org/10.1002/cmdc.202000571 | |
dc.relation.projectID | 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-2016-27503 | ca_CA |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.relation.publisherVersion | https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cmdc.202000571?af=R | ca_CA |
dc.date.embargoEndDate | 2021-08-22 | |
dc.type.version | info:eu-repo/semantics/acceptedVersion | ca_CA |
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