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In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542

The SARS-CoV-2 pandemic requires a new therapeutic target for viral infection, and papain-like protease (Plpro) has been suggested as a druggable target. This in-vitro study was conducted to examine the drug metabolism of the GRL0617 and HY-17542, Plpro inhibitors. Metabolism of these inhibitors was...

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Autores principales: Cho, Hyunki, Kim, Young Jun, Chae, Jung-Woo, Meyer, Markus R., Kim, Sang Kyum, Ryu, Chang Seon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975351/
https://www.ncbi.nlm.nih.gov/pubmed/36874001
http://dx.doi.org/10.3389/fphar.2023.1067408
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author Cho, Hyunki
Kim, Young Jun
Chae, Jung-Woo
Meyer, Markus R.
Kim, Sang Kyum
Ryu, Chang Seon
author_facet Cho, Hyunki
Kim, Young Jun
Chae, Jung-Woo
Meyer, Markus R.
Kim, Sang Kyum
Ryu, Chang Seon
author_sort Cho, Hyunki
collection PubMed
description The SARS-CoV-2 pandemic requires a new therapeutic target for viral infection, and papain-like protease (Plpro) has been suggested as a druggable target. This in-vitro study was conducted to examine the drug metabolism of the GRL0617 and HY-17542, Plpro inhibitors. Metabolism of these inhibitors was studied to predict the pharmacokinetics in human liver microsomes. The hepatic cytochrome P450 (CYP) isoforms responsible for their metabolism were identified using recombinant enzymes. The drug–drug interaction potential mediated by cytochrome P450 inhibition was estimated. In human liver microsomes, the Plpro inhibitors had phase I and phase I + II metabolism with half-lives of 26.35 and 29.53 min, respectively. Hydroxylation (M1) and desaturation (-H2, M3) of the para-amino toluene side chain were the predominant reactions mediated with CYP3A4 and CYP3A5. CYP2D6 is responsible for the hydroxylation of the naphthalene side ring. GRL0617 inhibits major drug-metabolizing enzymes, including CYP2C9 and CYP3A4. HY-17542 is structural analog of GRL0617 and it is metabolized to GRL0617 through non-cytochrome P450 reactions in human liver microsomes without NADPH. Like GRL0617 and HY-17542 undergoes additional hepatic metabolism. The in-vitro hepatic metabolism of the Plpro inhibitors featured short half-lives; preclinical metabolism studies are needed to determine therapeutic doses for these inhibitors.
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spelling pubmed-99753512023-03-02 In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542 Cho, Hyunki Kim, Young Jun Chae, Jung-Woo Meyer, Markus R. Kim, Sang Kyum Ryu, Chang Seon Front Pharmacol Pharmacology The SARS-CoV-2 pandemic requires a new therapeutic target for viral infection, and papain-like protease (Plpro) has been suggested as a druggable target. This in-vitro study was conducted to examine the drug metabolism of the GRL0617 and HY-17542, Plpro inhibitors. Metabolism of these inhibitors was studied to predict the pharmacokinetics in human liver microsomes. The hepatic cytochrome P450 (CYP) isoforms responsible for their metabolism were identified using recombinant enzymes. The drug–drug interaction potential mediated by cytochrome P450 inhibition was estimated. In human liver microsomes, the Plpro inhibitors had phase I and phase I + II metabolism with half-lives of 26.35 and 29.53 min, respectively. Hydroxylation (M1) and desaturation (-H2, M3) of the para-amino toluene side chain were the predominant reactions mediated with CYP3A4 and CYP3A5. CYP2D6 is responsible for the hydroxylation of the naphthalene side ring. GRL0617 inhibits major drug-metabolizing enzymes, including CYP2C9 and CYP3A4. HY-17542 is structural analog of GRL0617 and it is metabolized to GRL0617 through non-cytochrome P450 reactions in human liver microsomes without NADPH. Like GRL0617 and HY-17542 undergoes additional hepatic metabolism. The in-vitro hepatic metabolism of the Plpro inhibitors featured short half-lives; preclinical metabolism studies are needed to determine therapeutic doses for these inhibitors. Frontiers Media S.A. 2023-02-15 /pmc/articles/PMC9975351/ /pubmed/36874001 http://dx.doi.org/10.3389/fphar.2023.1067408 Text en Copyright © 2023 Cho, Kim, Chae, Meyer, Kim and Ryu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Cho, Hyunki
Kim, Young Jun
Chae, Jung-Woo
Meyer, Markus R.
Kim, Sang Kyum
Ryu, Chang Seon
In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542
title In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542
title_full In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542
title_fullStr In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542
title_full_unstemmed In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542
title_short In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542
title_sort in vitro metabolic characterization of the sars-cov-2 papain-like protease inhibitors grl0617 and hy-17542
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975351/
https://www.ncbi.nlm.nih.gov/pubmed/36874001
http://dx.doi.org/10.3389/fphar.2023.1067408
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