Category Ranking

98%

Total Visits

921

Avg Visit Duration

2 minutes

Citations

20

Article Abstract

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.6b01310DOI Listing

Publication Analysis

Top Keywords

ns5a inhibitor
12
ruzasvir mk-8408
8
discovery ruzasvir
4
mk-8408 potent
4
potent pan-genotype
4
pan-genotype hcv
4
ns5a
4
hcv ns5a
4
inhibitor optimized
4
optimized activity
4

Similar Publications

Hepatitis C virus (HCV) exhibits a narrow species tropism, causing robust infections only in humans and experimentally inoculated chimpanzees. While many host factors and restriction factors are known, many more likely remain unknown, which has limited the development of mouse or other small animal models for HCV. One putative restriction factor, the black flying fox orthologue of receptor transporter protein 4 (RTP4), was previously shown to potently inhibit viral genome replication of several ER-replicating RNA viruses.

View Article and Find Full Text PDF

This study employs structural bioinformatics approaches to identify and evaluate potential drug targets within the Hepatitis C virus (HCV) proteome. Through integration of homology modeling, molecular docking, and molecular dynamics simulations, we analyzed the structural features and druggability of key HCV proteins. The research focused on predicting binding sites, evaluating protein-ligand interactions, and assessing the therapeutic potential of identified targets.

View Article and Find Full Text PDF

Background: The National Viral Hepatitis Control Program (NVHCP) has a cure rate of 91.6% when using direct-acting antivirals (DAAs)-sofosbuvir with an NS5A inhibitor (ledipasvir, daclatasvir or velpatasvir) ± ribavirin in the Punjab hub-and-spoke model of hepatitis C virus (HCV) elimination.

Methods: We collected the clinical and virological data for the ∼8.

View Article and Find Full Text PDF

A combination of nucleotide hepatitis C virus (HCV) nonstructural protein (NS) 5B and 5A inhibitors is a preferred standard of care for treating chronic HCV. Bemnifosbuvir is a novel oral guanosine nucleotide prodrug with potent pan-genotypic inhibitory activity against HCV NS5B. Ruzasvir, a small-molecule NS5A inhibitor, has demonstrated improved anti-HCV activity compared with first-generation NS5A inhibitors.

View Article and Find Full Text PDF

Chronic viral infections like HIV, HBV, and HCV establish persistent interactions with the host immune system, resulting in immune evasion and long-term immune dysfunction. These viruses use a range of strategies to limit host defenses, such as downregulating MHC class I, disrupting interferon signaling, altering apoptosis pathways, and suppressing cytotoxic T-cell activity. Key viral proteins, including HIV Nef, HBV X protein, and HCV NS5A, interfere with antigen presentation and JAK/STAT signaling, thereby reducing antiviral immune responses.

View Article and Find Full Text PDF