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Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improv...

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Autores principales: Matthew, Ashley N., Zephyr, Jacqueto, Nageswara Rao, Desaboini, Henes, Mina, Kamran, Wasih, Kosovrasti, Klajdi, Hedger, Adam K., Lockbaum, Gordon J., Timm, Jennifer, Ali, Akbar, Kurt Yilmaz, Nese, Schiffer, Celia A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157764/
https://www.ncbi.nlm.nih.gov/pubmed/32234812
http://dx.doi.org/10.1128/mBio.00172-20
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author Matthew, Ashley N.
Zephyr, Jacqueto
Nageswara Rao, Desaboini
Henes, Mina
Kamran, Wasih
Kosovrasti, Klajdi
Hedger, Adam K.
Lockbaum, Gordon J.
Timm, Jennifer
Ali, Akbar
Kurt Yilmaz, Nese
Schiffer, Celia A.
author_facet Matthew, Ashley N.
Zephyr, Jacqueto
Nageswara Rao, Desaboini
Henes, Mina
Kamran, Wasih
Kosovrasti, Klajdi
Hedger, Adam K.
Lockbaum, Gordon J.
Timm, Jennifer
Ali, Akbar
Kurt Yilmaz, Nese
Schiffer, Celia A.
author_sort Matthew, Ashley N.
collection PubMed
description Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles.
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spelling pubmed-71577642020-04-15 Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors Matthew, Ashley N. Zephyr, Jacqueto Nageswara Rao, Desaboini Henes, Mina Kamran, Wasih Kosovrasti, Klajdi Hedger, Adam K. Lockbaum, Gordon J. Timm, Jennifer Ali, Akbar Kurt Yilmaz, Nese Schiffer, Celia A. mBio Research Article Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles. American Society for Microbiology 2020-03-31 /pmc/articles/PMC7157764/ /pubmed/32234812 http://dx.doi.org/10.1128/mBio.00172-20 Text en Copyright © 2020 Matthew et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Matthew, Ashley N.
Zephyr, Jacqueto
Nageswara Rao, Desaboini
Henes, Mina
Kamran, Wasih
Kosovrasti, Klajdi
Hedger, Adam K.
Lockbaum, Gordon J.
Timm, Jennifer
Ali, Akbar
Kurt Yilmaz, Nese
Schiffer, Celia A.
Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors
title Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors
title_full Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors
title_fullStr Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors
title_full_unstemmed Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors
title_short Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors
title_sort avoiding drug resistance by substrate envelope-guided design: toward potent and robust hcv ns3/4a protease inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157764/
https://www.ncbi.nlm.nih.gov/pubmed/32234812
http://dx.doi.org/10.1128/mBio.00172-20
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