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

Yao Cheng, Lun K. Tsou, Jianfeng Cai, Toshihiro Aya, Ginger E. Dutschman, Elizabeth A. Gullen, Susan P. Grill, Annie Pei Chun Chen, Brett D. Lindenbach, Andrew D. Hamilton, Yung Chi Cheng

Research output: Contribution to journalArticle

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-α-2a. Our results demonstrate the potential use of tetracarboxyphenylporphyrins as potent anti-HCV agents.

Original languageEnglish (US)
Pages (from-to)197-206
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume54
Issue number1
DOIs
StatePublished - Jan 1 2010

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Cheng, Y., Tsou, L. K., Cai, J., Aya, T., Dutschman, G. E., Gullen, E. A., Grill, S. P., Chen, A. P. C., Lindenbach, B. D., Hamilton, A. D., & Cheng, Y. C. (2010). A novel class of meso-tetrakis-porphyrin derivatives exhibits potent activities against hepatitis C virus genotype 1b replicons in vitro. Antimicrobial agents and chemotherapy, 54(1), 197-206. https://doi.org/10.1128/AAC.01206-09