Understanding the drug resistance mechanism of hepatitis C virus NS3/4A to ITMN-191 due to R155K, A156V, D168A/E mutations: A computational study

Pan, Dabo; Xue, Weiwei; Zhang, Wenqi; Liu, Huanxiang; Yao, Xiaojun

doi:10.1016/j.bbagen.2012.06.001

Cited by 36 publications

(27 citation statements)

References 38 publications

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“…The MD simulations here provided additional insights also into the mechanism of resistance due to R155K mutation, which was previously revealed from crystal structures (Romano, Ali et al 2010, Romano, Ali et al 2012). The destabilization of danoprevir's P2 isoindoline in the presence of R155K both in the crystal structures and MD simulations is consistent with earlier simulation results of Pan et al (Pan, Xue et al 2012), indicating that the severe destabilization of P2 is not a crystallization or force-field dependent artifact. In fact, the P2 moiety samples diverse conformations distinct from the one observed in the crystal structure (Figure 3), with substantial losses in vdW interactions with the active site protease residues.…”

Section: Discussionsupporting

confidence: 89%

“…As a result, the altered charge distribution along the binding surface affects the P2 cyclopentylproline and P4 cyclohexylalanine moieties of telaprevir whereas danoprevir loses a favorable cation-π interaction at the P2 isoindoline (Romano, Ali et al 2012). MD simulations based on these crystal structures suggest that the destruction of the salt bridge between 168 and 155 may cause additional conformational changes in the binding pocket (Pan, Xue et al 2012).…”

Section: Introductionmentioning

confidence: 97%

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Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease

Özen

Lin

Romano

et al. 2018

Preprint

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Hepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 Å away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K/V36M crystal structures differ in the α-2 helix and E2 strand near the active site, with alternative conformations at M36 and side chains of active site residues D168 and R123, revealing an allosteric coupling, which persists dynamically in MD simulations, between the distal mutation and the active site. This allosteric modulation validates the network hypothesis and elucidates how distal mutations confer resistance through propagation of conformational changes to the active site.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 97%

Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease

Özen

Lin

Romano

et al. 2018

Preprint

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“…These results are in agreement with other previous in vitro resistance studies and clinical observations. For example, R155 in GT 1a virus and D168 in GT 1b virus, conferring cross-resistance to other macrocyclic PIs, are also commonly seen in patients treated with vaniprevir, danoprevir, BI 201335, and TMC-435 (7,12,15,26). Clinical studies with telaprevir identified V36A/M, T54A, R155T/K, and A156S/V/T mutations in NS3.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients

Dvory‐Sobol

Wong

et al. 2012

Antimicrob Agents Chemother

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b GS-9451, a novel hepatitis C virus (HCV) nonstructural 3/4a (NS3/4a) protease inhibitor, is highly active in patients infected with HCV genotype 1 (GT 1). The aim of this study is to characterize the clinical resistance profile of GS-9451 in GT 1 HCV-infected patients in a phase 1, 3-day monotherapy study. The full-length NS3/4A gene was population sequenced at baseline, on the final treatment day, and at follow-up time points. NS3 protease domains from patient isolates with emerging mutations were cloned into an NS3 shuttle vector, and their susceptibilities to GS-9451 and other HCV inhibitors were determined using a transient replication assay. No resistance mutations at NS3 position 155, 156, or 168 were detected in any of the baseline samples or in viruses from patients treated with 60 mg of GS-9451 once daily. Among patients who received 200 mg and 400 mg of GS-9451, viruses with mutations at position D168 (D168E/G/V) and R155 (R155K), which confer high-level resistance to GS-9451, were detected in those with GT 1b and GT 1a virus, respectively. Viruses with D168 mutations were no longer detected in any GT 1b patient at day 14 and subsequent time points. In GT 1a patients, R155K mutants were replaced by the wild type in 57% of patients at week 24. These NS3 clinical mutants were sensitive to NS5B and NS5A inhibitors, as well as alpha interferon (IFN-␣) and ribavirin. The lack of cross-resistance between GS-9451 and other classes of HCV inhibitors supports the utility of combination therapy. Hepatitis C virus (HCV) infects an estimated 170 million people around the world (2,19,21). Infection can lead to cirrhosis and, sometimes, to hepatocellular carcinoma (1, 13). Prior to May 2011, when the two protease inhibitors (PIs) telaprevir and boceprevir were approved, treatment of chronic HCV infection included a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) (5,13,21). This treatment is associated with significant side effects, such as fever, fatigue, anemia, leucopenia, thrombocytopenia, and depression (3,14,24), and results in sustained virologic response (SVR) in only 42% to 53% of patients with HCV genotype 1 (GT 1) and GT 4, respectively, and up to 78% to 82% of patients infected with HCV GT 2 or 3 (5, 13).Direct-acting antivirals (DAAs), including the HCV nonstructural (NS) 3/4a serine protease inhibitors (NS3 PIs), have demonstrated antiviral activity in HCV-infected patients (6,8). Among NS3 PIs, telaprevir and boceprevir have recently been approved for genotype 1 infections. There are more than 9 other NS3 PIs in different stages of clinical development (TMC-435, danoprevir, vaniprevir, BI201335, narlaprevir, MK-5172, asunaprevir, BMS-791325, ABT-450, ACH-1625, GS-9451, and GS-9256). The approved NS3 PIs have demonstrated increased SVR rates in patients when combined with PEG-IFN plus RBV. During the phase 2b PROVE2 study, genotype 1 (GT 1)-infected individuals treated with 12 weeks of telaprevir plus PEG-IFN plus RBV followed by 12 additional weeks of PEG-IFN plus RBV had SVR rates ...

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“…It should be noted that earlier studies for HCV protease were not able to reproduce the experimental observations even in a qualitative agreement. 18,19 In these studies, the popular molecular mechanics PB surface area (MM/PBSA) model and the related molecular mechanics-generalized Born surface area (MM/GBSA) were used. These models are apparently an inconsistent adaptation of the earlier PDLD/S-LRA idea of MD generated configurations for implicit solvent calculations, calculating the average over the configurations generated with the charged solute alone.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Drug Resistance of HCV Protease

2017

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Hepatitis C virus (HCV) currently affects several million people across the globe. One of the major classes of drugs against HCV inhibits the NS3/4A protease of the polyprotein chain. Efficacy of these drugs is severely limited due to the high mutation rate that results in several genetically related quasispecies. The molecular mechanism of drug resistance is frequently deduced from structural studies and binding free energies. However, prediction of new mutations requires the evaluation of both binding free energy of the drug as well as the parameters (κcat and KM) for the natural substrate. The vitality values offer a good approach to investigate and predict mutations that render resistance to the inhibitor. A successful mutation should only affect the binding of the drug and not the catalytic activity and binding of the natural substrate. In this article, we have calculated the vitality values for four known drug inhibitors that are either currently in use or in clinical trials, evaluating binding free energies by the relevant PDLD/S-LRA method and activation barriers by the EVB method. The molecular details pertaining to resistance are also discussed. We show that our calculations are able to reproduce the catalytic effects and binding free energies in a good agreement with the corresponding observed values. Importantly, previous computational approaches have not been able to achieve this task. The trend for the vitality values is in accordance with experimental findings. Finally, we calculate the vitality values for mutations that have either not been studied experimentally or reported for some inhibitors.

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Understanding the drug resistance mechanism of hepatitis C virus NS3/4A to ITMN-191 due to R155K, A156V, D168A/E mutations: A computational study

Cited by 36 publications

References 38 publications

Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease

Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease

Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients

Exploring the Drug Resistance of HCV Protease

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