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

Journal article

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.

Authors: Cheng, Y; Tsou, L; Cai, J; Aya, T; Dutschman, G

• Publication status: Published
• Journal: Antimicrobial agents and chemotherapy
• Volume: 54
• Issue: 1
• Pages: 197-206
• Publication date: 2010-01-01
• DOI: 10.1128/aac.01206-09
• EISSN: 1098-6596
• ISSN: 0066-4804
• Language: English
• Keywords: Cell Line; Hepacivirus; Dose-Response Relationship, Drug; Humans; RNA, Viral; Recombinant Proteins; Viral Nonstructural Proteins; Structure-Activity Relationship; Drug Resistance, Viral; Macrocyclic Compounds; DNA, Mitochondrial; Interferon-alpha; Genotype; Quinolines; Carbamates; Mesoporphyrins; Drug Discovery; Replicon; Antiviral Agents; Thiazoles; Drug Synergism