Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

Maynard, Andy; Crosby, Renae M.; Ellis, Byron; Hamatake, Robert; Hong, Zhi; Johns, Brian A.; Kahler, Kirsten M.; Koble, Cecilia S.; Leivers, Anna L.; Leivers, Martin; Mathis, Amanda; Peat, Andrew J.; Pouliot, Jeffrey J.; Roberts, Christopher D.; Sámano, Vicente; Schmidt, Rachel; Smith, Gary K.; Spaltenstein, Andrew; Stewart, Eugene L.; Thömmes, Pia; Turner, Elizabeth M.; Voitenleitner, Christian; Walker, Jill; Waitt, Greg; Weaver, K.; Williams, Shawn P.; Wright, Laura; Xiong, Zhiping; Haigh, David; Shotwell, J. Brad

doi:10.1021/jm400317w

Cited by 49 publications

(49 citation statements)

References 36 publications

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“…1). The mechanism of action was confirmed to be inhibition of NS5B by inhibition of its enzymatic activity and cocrystallization with NS5B (30). The antiviral activity of GSK5852 was evaluated on subgenomic replicons derived from the genotype 1a H77, genotype 1b Con1, and genotype 2a JFH-1 strains in replicon assays using the luciferase reporter as a readout as well as the genotype 2a chimeric virus.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to HCV-796, GSK5852 is still active against C316Y replicons as well as several other mutations that severely impacted HCV-796 activity (Table 3). GSK5852 was found to form a direct hydrogen bond between the boronic acid residue and the tyrosine hydroxyl group in genotype 1b crystal structures, potentially accounting for the retention of activity against C316Y (30). For genotype 1b, most of the single amino acid changes did not result in significant loss of potency except for some changes at position 365.…”

Section: Discussionmentioning

confidence: 98%

“…GSK5852 inhibits HCV replication by targeting the RDRP activity of NS5B (30). It binds to the NNI allosteric palm site 2 of NS5B as shown by single amino acid changes at positions 316, 365, and 368 of NS5B identified during selection of resistance to GSK5852.…”

Section: Discussionmentioning

confidence: 99%

“…Substantial decreases in potency were also observed for amino acid variants at position 316 (29). We have developed NNI palm site 2 inhibitors with improvements in activity against HCV-796-resistant mutations (30). We describe here the characterization of GSK2485852 (referred to here as GSK5852) as an NNI palm site 2 inhibitor that has a high genetic barrier to resistance and has the potential to be a pangenotypic HCV inhibitor.…”

mentioning

confidence: 99%

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In Vitro Characterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor

Voitenleitner

Crosby

Walker

et al. 2013

Antimicrob Agents Chemother

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; GlaxoSmithKline, Collegeville, Pennsylvania, USA c GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC 50 s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H. Testing of a diverse mutant panel also revealed a lack of cross-resistance against known resistance mutations in other viral proteins. Data from both the newer 454 sequencing method and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA-dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long-term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes, but its superior resistance profile suggests that it could be an attractive component of an all-oral regimen for treating HCV.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In Vitro Characterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor

Voitenleitner

Crosby

Walker

et al. 2013

Antimicrob Agents Chemother

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“…Voitenleitner et al reported that GSK5852 showed good anti-HCV activity with EC50 values in the nanomolar range against HCV genotypes 1 and 2 and has an excellent resistant profile. This molecule is currently in clinic [147,148]. The Palm II nonnucleoside inhibitors that are currently in different phases of development are given in Table 7.…”

Section: Site IV [Palm Ii]mentioning

confidence: 99%

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Polamreddy

Vishwakarma

Gundla

2016

Int J Pharm Pharm Sci

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Hepatitis C, a chronic disease affecting the global population significantly is caused majorly by Hepatitis C virus [HCV]. Among the several druggable targets explored for Hepatitis C, the viral protein, non-structural protein 5B [NS5B] is the target of choice for researchers as it is the key enzyme in the HCV replication and its active site is conserved among all genotypes. In the recent years the landscape of Hepatitis C therapies, have evolved from Peg-Interferon [PEG-INF]/Ribavirin, to directly acting anti-virus along with PEG-INF and finally, INF free regimens with greater than 90% sustained virological response [SVR]. The launch of Sofosbuvir, a nucleotide inhibitor of NS5B marks the major paradigm in hepatitis C research. Sofosbuvir exhibits, pan-genotypic activity, low barrier to resistance, highly effective and safe. However, the high prices of these medications limit their universal access. This review will focus on progress towards the discovery and development of NS5B inhibitors targeting allosteric sites and active site, covering the chemical class and structure-activity relationships.

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Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

et al. 2018

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The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single‐electron reduction of an α‐boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α‐amino, α‐oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron‐containing molecules of potential biological importance.

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Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

Cited by 49 publications

References 36 publications

In Vitro Characterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor

In Vitro Characterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

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