A novel class of meso-tetrakis-porphyrin derivatives exhibits potent activities against hepatitis C virus genotype 1b replicons in vitro.
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.
Cheng
Yao
Y
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Tsou
Lun K
LK
Cai
Jianfeng
J
Aya
Toshihiro
T
Dutschman
Ginger E
GE
Gullen
Elizabeth A
EA
Grill
Susan P
SP
Chen
Annie Pei-Chun
AP
Lindenbach
Brett D
BD
Hamilton
Andrew D
AD
Cheng
Yung-Chi
YC
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008652:Mesoporphyrins / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D012367:RNA, Viral / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins; D012093:Replicon; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000187:drug effects / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D002219:Carbamates; D004272:DNA, Mitochondrial; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047028:Macrocyclic Compounds; D008652:Mesoporphyrins; D011804:Quinolines; D012367:RNA, Viral; D011994:Recombinant Proteins; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C479555:BILN 2061; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase