Dataset Information

Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.

ABSTRACT: A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC₅₀ values ?10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.

SUBMITTER: Velazquez F

PROVIDER: S-EPMC5150670 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.

Velázquez Francisco F Chelliah Mariappan M Clasby Martin M Guo Zhuyan Z Howe John J Miller Randy R Neelamkavil Santhosh S Shah Unmesh U Soriano Aileen A Xia Yan Y Venkatraman Srikanth S Chackalamannil Samuel S Davies Ian W IW

ACS medicinal chemistry letters 20161017 12

A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC<sub>50</sub> values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic ...[more]

PMID: 27994759

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Project description:BackgroundHepatitis C is a treatment-resistant disease affecting millions of people worldwide. The hepatitis C virus (HCV) genome is a single-stranded RNA molecule. After infection of the host cell, viral RNA is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. Cleavage of the polyprotein involves the viral NS3/4A proteinase, a proven drug target. HCV mutates as it replicates and, as a result, multiple emerging quasispecies become rapidly resistant to anti-virals, including NS3/4A inhibitors.Methodology/principal findingsTo circumvent drug resistance and complement the existing anti-virals, NS3/4A inhibitors, which are additional and distinct from the FDA-approved telaprevir and boceprevir α-ketoamide inhibitors, are required. To test potential new avenues for inhibitor development, we have probed several distinct exosites of NS3/4A which are either outside of or partially overlapping with the active site groove of the proteinase. For this purpose, we employed virtual ligand screening using the 275,000 compound library of the Developmental Therapeutics Program (NCI/NIH) and the X-ray crystal structure of NS3/4A as a ligand source and a target, respectively. As a result, we identified several novel, previously uncharacterized, nanomolar range inhibitory scaffolds, which suppressed of the NS3/4A activity in vitro and replication of a sub-genomic HCV RNA replicon with a luciferase reporter in human hepatocarcinoma cells. The binding sites of these novel inhibitors do not significantly overlap with those of α-ketoamides. As a result, the most common resistant mutations, including V36M, R155K, A156T, D168A and V170A, did not considerably diminish the inhibitory potency of certain novel inhibitor scaffolds we identified.Conclusions/significanceOverall, the further optimization of both the in silico strategy and software platform we developed and lead compounds we identified may lead to advances in novel anti-virals.

Dataset Information

Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.

Publications

Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.

Similar Datasets

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