Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

O'Meara, Jeff A.; Lemke, Christopher T.; Godbout, Cédrickx; Kukolj, George; Lagacé, Lisette; Moreau, Benoît; Thibeault, Diane; White, Peter W.; Llinàs‐Brunet, Montse

doi:10.1074/jbc.m112.439455

Cited by 18 publications

(31 citation statements)

References 39 publications

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“…45 For carbamate-linked P4 capping groups, generally bulky hydrophobic moieties are preferred but the size of the group appears to be dependent on the heterocyclic moiety present at the P2 position. 35 …”

Section: Resultsmentioning

confidence: 99%

“…Disruption of electrostatic interactions between Arg155 and Asp168 due to mutations underlies drug resistance against NS3/4A PIs. 31–33,35 Moreover, we have shown that structural differences at the P2 moiety largely determine the resistance profile of these inhibitors. 36 …”

Section: Introductionmentioning

confidence: 99%

“…39–41 Another approach applied to design PIs with improved resistant profiles involves incorporation of conformational flexibility that can allow the inhibitor to adapt to structural changes in the protease active site due to mutations. 35 Here, we describe a structure-guided strategy that combines these two approaches and, together with our understanding of the mechanisms of drug resistance, led to the design of NS3/4A PIs with exceptional potency profiles against major drug resistant HCV variants. Based on the lead compound 2 , a series of analogues were designed and synthesized with diverse substituents at the 3-position of P2 quinoxaline moiety.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

et al. 2017

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A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156 and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values ≤ 5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

et al. 2017

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“…This hypothesis is supported by a recent report detailing a P 4 capping SAR in a faldaprevir derivative. 52 …”

Section: Discussionmentioning

confidence: 99%

Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease

et al. 2016

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Hepatitis C virus (HCV), affecting an estimated 150 million people worldwide, is the leading cause of viral hepatitis, cirrhosis and hepatocellular carcinoma. HCV is genetically diverse with six genotypes (GTs) and multiple subtypes of different global distribution and prevalence. Recent development of direct-acting antivirals against HCV including NS3/4A protease inhibitors (PIs) has greatly improved treatment outcomes for GT-1. However, all current PIs exhibit significantly lower potency against GT-3. Lack of structural data on GT-3 protease has limited our ability to understand PI failure in GT-3. In this study the molecular basis for reduced potency of current inhibitors against GT-3 NS3/4A protease is elucidated with structure determination, molecular dynamics simulations and inhibition assays. A chimeric GT-1a3a NS3/4A protease amenable to crystallization was engineered to recapitulate decreased sensitivity of GT-3 protease to PIs. High-resolution crystal structures of this GT-1a3a bound to 3 PIs, asunaprevir, danoprevir and vaniprevir, had only subtle differences relative to GT-1 despite orders of magnitude loss in affinity. In contrast, hydrogen-bonding interactions within and with the protease active site and dynamic fluctuations of the PIs were drastically altered. The correlation between loss of intermolecular dynamics and inhibitor potency suggests a mechanism where polymorphisms between genotypes (or selected mutations) in the drug target confer resistance through altering the intermolecular dynamics of the protein–inhibitor complex.

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“…This may be due to the P2 moiety constraint reducing the inhibitor's ability to adapt to changes resulting from HCV protease mutations. In addition, the recently published crystal structures of several inhibitors in complex with the major drug resistant mutants have revealed the molecular basis underlying the unique resistance profiles of these inhibitors, [34][35][36] and will provide useful information for further designing macrocyclic PIs against a wider spectrum of HCV PI-resistant mutants. Tremendous progress has been made in the discovery and development of macrocyclic HCV PIs over the past decade.…”

Section: Resultsmentioning

confidence: 99%

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

Kazmierski

Jarvest

Plattner³

et al. 2014

Macrocycles in Drug Discovery

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Enormous progress has been made towards an all-oral, very highly sustained viral response (considered a cure) treatment of hepatitis C. Key ingredients of these therapies are hepatitis C virus (HCV) protease inhibitors (PIs). The first generation linear and covalent PIs, telaprevir and boceprevir, were discovered through the enzyme substrate-based approach and are being followed by a second generation of non-covalent PIs. Many of these are macrocycles, as exemplified by the recently FDA-approved simeprevir. This chapter will detail the science successfully employed in both the substrate-based and inhibitor macrocyclization approaches. Additionally, as HCV PI C-terminal motifs develop critical contacts with the enzyme catalytic Ser139 and adjacent sites, this chapter discusses the mechanistic and structural details of such interactions for both the reversible covalent ketoamide as well as non-covalent sulfonamide and carboxylic acid moieties. Efforts to explore a cyclic boronate motif in various linear and cyclic HCV PIs in search of both Ser139-specific and opportunistic enzyme–inhibitor interactions are also summarized herein. In addition, key clinical and marketed PIs are described, including extensive references to primary literature. Finally, this chapter briefly covers key macrocyclic inhibitors of HCV RNA-dependent RNA polymerase NS5B and selected non-HCV macrocyclic protease inhibitors in order to provide additional insights into the successful design of macrocyclic drugs.

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Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

Cited by 18 publications

References 39 publications

Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

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