A novel class of meso-tetrakis-porphyrin derivatives exhibits potent activities against hepatitis C virus genotype 1b replicons in vitro.

Publication Type:

Journal Article

Source:

Antimicrobial agents and chemotherapy, Volume 54, Issue 1, p.197-206 (2010)

Keywords:

Antiviral Agentsdigestive disease, digestive deseases Carbamatesdigestive disease, digestive deseases Cell Linedigestive disease, digestive deseases DNA, Mitochondrialdigestive disease, digestive deseases Dose-Response Relationship, Drugdigestive disease, digestive deseases Drug Discoverydigestive disease, digestive deseases Drug Resistance, Viraldigestive disease, digestive deseases Drug Synergismdigestive disease, digestive deseases Genotypedigestive disease, digestive deseases Hepacivirusdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Interferon-alphadigestive disease, digestive deseases Macrocyclic Compoundsdigestive disease, digestive deseases Mesoporphyrinsdigestive disease, digestive deseases Quinolinesdigestive disease, digestive deseases Recombinant Proteinsdigestive disease, digestive deseases Replicondigestive disease, digestive deseases RNA, Viraldigestive disease, digestive deseases Structure-Activity Relationshipdigestive disease, digestive deseases Thiazolesdigestive disease, digestive deseases Viral Nonstructural Proteins

Abstract:

Recent years have seen the rapid advancement of new therapeutic agents against hepatitis C virus (HCV) in response to the need for treatment that is unmet by interferon (IFN)-based therapies. Most antiviral drugs discovered to date are small molecules that modulate viral enzyme activities. In the search for highly selective protein-binding molecules capable of disrupting the viral life cycle, we have identified a class of anionic tetraphenylporphyrins as potent and specific inhibitors of the HCV replicons. Based on the structure-activity relationship studies reported herein, meso-tetrakis-(3,5-dicarboxy-4,4'-biphenyl) porphyrin was found to be the most potent inhibitor of HCV genotype 1b (Con1) replicon systems but was less effective against the genotype 2a (JFH-1) replicon. This compound induced a reduction of viral RNA and protein levels when acting in the low nanomolar range. Moreover, the compound could suppress replicon rebound in drug-treated cells and exhibited additive to synergistic effects when combined with protease inhibitor BILN 2061 or with IFN-alpha-2a. Our results demonstrate the potential use of tetracarboxyphenylporphyrins as potent anti-HCV agents.