Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors

[Image: see text] Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA(N)) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-bindi...

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Autores principales: Stokes, Ryjul W., Kohlbrand, Alysia J., Seo, Hyeonglim, Sankaran, Banumathi, Karges, Johannes, Cohen, Seth M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9841593/
https://www.ncbi.nlm.nih.gov/pubmed/36655124
http://dx.doi.org/10.1021/acsmedchemlett.2c00434
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author Stokes, Ryjul W.
Kohlbrand, Alysia J.
Seo, Hyeonglim
Sankaran, Banumathi
Karges, Johannes
Cohen, Seth M.
author_facet Stokes, Ryjul W.
Kohlbrand, Alysia J.
Seo, Hyeonglim
Sankaran, Banumathi
Karges, Johannes
Cohen, Seth M.
author_sort Stokes, Ryjul W.
collection PubMed
description [Image: see text] Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA(N)) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn(2+) active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PA(N) using a FRET-based enzymatic assay, and their mode of binding in PA(N) was determined using X-ray crystallography.
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spelling pubmed-98415932023-01-17 Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors Stokes, Ryjul W. Kohlbrand, Alysia J. Seo, Hyeonglim Sankaran, Banumathi Karges, Johannes Cohen, Seth M. ACS Med Chem Lett [Image: see text] Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA(N)) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn(2+) active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PA(N) using a FRET-based enzymatic assay, and their mode of binding in PA(N) was determined using X-ray crystallography. American Chemical Society 2022-12-09 /pmc/articles/PMC9841593/ /pubmed/36655124 http://dx.doi.org/10.1021/acsmedchemlett.2c00434 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Stokes, Ryjul W.
Kohlbrand, Alysia J.
Seo, Hyeonglim
Sankaran, Banumathi
Karges, Johannes
Cohen, Seth M.
Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors
title Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors
title_full Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors
title_fullStr Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors
title_full_unstemmed Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors
title_short Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors
title_sort carboxylic acid isostere derivatives of hydroxypyridinones as core scaffolds for influenza endonuclease inhibitors
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9841593/
https://www.ncbi.nlm.nih.gov/pubmed/36655124
http://dx.doi.org/10.1021/acsmedchemlett.2c00434
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