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

ABSTRACT 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 remarkab...

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Autores principales:	Ashley N. Matthew, Jacqueto Zephyr, Desaboini Nageswara Rao, Mina Henes, Wasih Kamran, Klajdi Kosovrasti, Adam K. Hedger, Gordon J. Lockbaum, Jennifer Timm, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	X-ray crystallography drug design drug resistance mechanisms hepatitis C virus structural biology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c55fb866934b41dabb2b47c634a8609a
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spelling	oai:doaj.org-article:c55fb866934b41dabb2b47c634a8609a2021-11-15T15:57:02ZAvoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors10.1128/mBio.00172-202150-7511https://doaj.org/article/c55fb866934b41dabb2b47c634a8609a2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00172-20https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.Ashley N. MatthewJacqueto ZephyrDesaboini Nageswara RaoMina HenesWasih KamranKlajdi KosovrastiAdam K. HedgerGordon J. LockbaumJennifer TimmAkbar AliNese Kurt YilmazCelia A. SchifferAmerican Society for MicrobiologyarticleX-ray crystallographydrug designdrug resistance mechanismshepatitis C virusstructural biologyMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	X-ray crystallography drug design drug resistance mechanisms hepatitis C virus structural biology Microbiology QR1-502
spellingShingle	X-ray crystallography drug design drug resistance mechanisms hepatitis C virus structural biology Microbiology QR1-502 Ashley N. Matthew Jacqueto Zephyr Desaboini Nageswara Rao Mina Henes Wasih Kamran Klajdi Kosovrasti Adam K. Hedger Gordon J. Lockbaum Jennifer Timm Akbar Ali Nese Kurt Yilmaz Celia A. Schiffer Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors
description	ABSTRACT 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. IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.
format	article
author	Ashley N. Matthew Jacqueto Zephyr Desaboini Nageswara Rao Mina Henes Wasih Kamran Klajdi Kosovrasti Adam K. Hedger Gordon J. Lockbaum Jennifer Timm Akbar Ali Nese Kurt Yilmaz Celia A. Schiffer
author_facet	Ashley N. Matthew Jacqueto Zephyr Desaboini Nageswara Rao Mina Henes Wasih Kamran Klajdi Kosovrasti Adam K. Hedger Gordon J. Lockbaum Jennifer Timm Akbar Ali Nese Kurt Yilmaz Celia A. Schiffer
author_sort	Ashley N. Matthew
title	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_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_sort	avoiding drug resistance by substrate envelope-guided design: toward potent and robust hcv ns3/4a protease inhibitors
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c55fb866934b41dabb2b47c634a8609a
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Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

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