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

Antimicrob Agents Chemother. 2010 Jan;54(1):197-206. doi: 10.1128/AAC.01206-09. Epub 2009 Nov 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Carbamates / pharmacology
  • Cell Line
  • DNA, Mitochondrial / drug effects
  • DNA, Mitochondrial / genetics
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Resistance, Viral
  • Drug Synergism
  • Genotype
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics*
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / pharmacology
  • Macrocyclic Compounds / pharmacology
  • Mesoporphyrins / chemistry*
  • Mesoporphyrins / pharmacology*
  • Quinolines / pharmacology
  • RNA, Viral / drug effects
  • RNA, Viral / genetics
  • Recombinant Proteins
  • Replicon
  • Structure-Activity Relationship
  • Thiazoles / pharmacology
  • Viral Nonstructural Proteins / drug effects
  • Viral Nonstructural Proteins / genetics

Substances

  • Antiviral Agents
  • BILN 2061
  • Carbamates
  • DNA, Mitochondrial
  • Interferon alpha-2
  • Interferon-alpha
  • Macrocyclic Compounds
  • Mesoporphyrins
  • Quinolines
  • RNA, Viral
  • Recombinant Proteins
  • Thiazoles
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus