Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi®

Taylor, James G.; Zipfel, Sheila; Ramey, Kyla; Vivian, Randall W.; Schrier, Adam J.; Karki, Kapil; Katana, Ashley; Kato, Darryl; Kobayashi, Tetsuya; Martinez, Ruben; Sangi, Michael; Siegel, Dustin S.; Tran, Chinh V.; Yang, Zhengyu; Zablocki, Jeff; Yang, Chui‐Ping; Wang, Yujin; Wang, Kelly; Chan, Katie; Barauskas, Ona; Cheng, Guofeng; Jin, Debi; Schultz, Brian E.; Appleby, T.C.; Villaseñor, Armando G.; Link, John O.

doi:10.1016/j.bmcl.2019.03.037

Cited by 62 publications

(38 citation statements)

References 34 publications

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“…Three third-generation macrocyclics, glecaprevir, voxilaprevir and grazoprevir were developed not only to target genotype 3 but to expand drug coverage to genotypes 1-6. 12 All of these drugs showed pangenotypic inhibition of NS3 protease in vitro, [39][40][41] however, grazoprevir was a significantly less effective inhibitor for genotype 3 as compared to genotype 1 (90-fold difference in Ki). 41 Glecaprevir 13,17 and grazoprevir 15,16 are now approved for use in combination with NS5A inhibitors (as Mavyret and Zepatier, respectively), while Voxilaprevir 11,14 is approved for use with NS5A and NS5B inhibitors (as Vosevi).…”

Section: Discussionmentioning

confidence: 99%

<p>Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure–Activity Relationships</p>

Zhu

Mathahs

et al. 2020

DDDT

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Background: Antiviral actions of tetrapyrroles have been described in a number of systems. Our goal was to evaluate antagonism of the HCV NS3-4A protease by a variety of common porphyrins and characterize structure-activity relationships that may be useful for future drug design of HCV and related Flaviviruses. Methods: Using fluorometric assays, common metalloprotoporphyrins (MPP) all inhibited NS3-4A protease with IC 50 values in low micromolar ranges [CoPP (1.4 µM) < ZnPP = MnPP = SnPP < CuPP < FePP (6.5 µM) = protoporphyrin]. Results: Lineweaver-Burk plots confirmed that MPP: NS3 inhibition was basically competitive. All tested MPPs inhibited HCV genotype 1A, 1B, 2A and 3A recombinant proteases with the same fidelity suggesting wide antagonistic capabilities. However, when the MPPs were tested in cellular incubations with HCV replicons only Zn, Fe and free-base protoporphyrin showed comparable EC 50 and IC 50 values suggesting that there may be critical differences in MPP uptake and intracellular availability. Meso, deutero, and isohematoporphyrin derivatives, with or without metal substitution, all showed less anti-protease and antiviral activities as compared to protoporphyrins, suggesting that the planar, vinyl side chains are important for protease active site binding. MPPs were also active against three common protease mutants (T54A, A156T, and V36M) with equivalent or better IC 50 values as compared to wild type enzyme. Conclusion: These findings document the versatility of MPPs as antiviral agents with an expanded sensitivity for HCV genotypes and resistance to some common viral mutations. The results also suggest that further study of MPP structure and function will be useful for the development of new antiviral agents.

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Section: Discussionmentioning

confidence: 99%

<p>Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure–Activity Relationships</p>

Zhu

Mathahs

et al. 2020

DDDT

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“…Since the identification of the first NS3/4A inhibitor, HCV replicon systems have been widely used to identify safe and effective pangenotypic antivirals. Among many effective, not limited to, the most effective DAAs that are recommended for HCV treatment include, NS3/4A protease inhibitors (PIs, names end in -previr): glecaprevir (ABT-493) (Ng et al, 2014 ), grazoprevir (MK-5172) (Summa et al, 2012 ), paritaprevir (ABT-450) (Pilot-Matias et al, 2015 ), and voxilaprevir (GS-9857) (Taylor et al, 2019 ); NS5A inhibitors (names end in -asvir): daclatasvir (BMS-790052) (Gao et al, 2010 ), ledipasvir (GS-9451) (Yang et al, 2014 ), elbasvir (MK-8742) (Coburn et al, 2013 ), velpatasvir (GS-5816) (Cheng et al, 2013 ), ombitasvir (ABT-267) (DeGoey et al, 2014 ), pibrentasvir (ABT-530) (Ng et al, 2014 ) and ruzasvir (MK-8408) (Tong et al, 2017 ); inhibitors of NS5B nucleoside polymerase (NPIs, names end in -buvir): sofosbuvir (GS-7977) and non-nucleoside (NNPIs): dasabuvir (?ABT-333) (Maring et al, 2009 ) ( Figure 1 ). These DAAs exhibited subnanomolar 50% effective concentrations (EC 50 s) toward replicons expressing a wide range of HCV GTs with minimal cytotoxicity.…”

Section: Replicon Systemsmentioning

confidence: 99%

HCV Replicon Systems: Workhorses of Drug Discovery and Resistance

Khan

Soni

Veerapu

2020

Front. Cell. Infect. Microbiol.

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The development of direct-acting antivirals (DAAs) has revolutionized the state-of-the art treatment of HCV infections, with sustained virologic response rates above 90%. However, viral variants harboring substitutions referred to as resistance-associated substitutions (RASs) may be present in baseline levels and confer resistance to DAAs, thereby posing a major challenge for HCV treatment. HCV replicons have been the primary tools for discovering and evaluating the inhibitory activity of DAAs against viral replication. Interest in replicon systems has further grown as they have become indispensable for discovering genotype-specific and cross-genotype RASs. Here, we review functional replicon systems for HCV, how these replicon systems have contributed to the development of DAAs, and the characteristics and distribution of RASs for DAAs.

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“…This cis bond largely depends on the presence of Gly-27` because it allows lessening the steric conflict with the Val-26`side chain. Interestingly, this glycine turn is conserved in all crystal structures of HCV NS3 protease deposited to date in the Protein Data Bank (PDB), regardless of their genotype [33][34][35] or of the sequence constructs used (NS4A fused with NS3 or non-fused) [14,23,35] (See Supplementary Material, Figure S1-A). Accordingly, we postulated that an imidazole nucleus appending two amide groups should mimic this planar region.…”

Section: Rationale and Designmentioning

confidence: 99%

1H-Imidazole-2,5-Dicarboxamides as NS4A Peptidomimetics: Identification of a New Venue to Inhibit HCV-NS3 Protease

Omar¹,

Elfaky²,

Arold³

et al. 2020

Preprint

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The non-structural protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been in consideration in literature, and therefore, we decided to explore this strategy to develop a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25` to Arg-28` at the core of NS4A21`-33` needed to activate the NS3 protease. Some of the synthesized MOC compounds were able to compete with and displace NS4A21`-33` for binding to NS3. For instance, N5-(4-guanidinobutyl)-N2-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A21`-33` with a competition IC50 of 1.9 ± 0.12 µM in a fluorescence anisotropy assay, stabilized the denaturation of NS3 by increasing the aggregation temperature by ΔTagg 0.6 ± 0.140 ℃. MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations rationalized the structure-activity relationship (SAR) differences between the active MOC-24 and the inactive MOC-26. Our data shows that MOC compounds are possibly the first examples of NS4A peptidomimetics that demonstrated promising activities against NS3 proteins.

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Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi®

Cited by 62 publications

References 34 publications

<p>Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure–Activity Relationships</p>

<p>Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure–Activity Relationships</p>

HCV Replicon Systems: Workhorses of Drug Discovery and Resistance

1H-Imidazole-2,5-Dicarboxamides as NS4A Peptidomimetics: Identification of a New Venue to Inhibit HCV-NS3 Protease

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