Small molecule inhibition of hepatitis C virus E2 binding to CD81.
The hepatitis C virus (HCV) is a causal agent of chronic liver infection, cirrhosis, and hepatocellular carcinoma infecting more than 170 million people. CD81 is a receptor for HCV envelope glycoprotein E2. Although the binding of HCV-E2 with CD81 is well documented the role of this interaction in the viral life cycle remains unclear. Host specificity and mutagenesis studies suggest that the helix D region of CD81 mediates binding to HCV-E2. Structural analysis of CD81 has enabled the synthesis of small molecules designed to mimic the space and hydrophobic features of the solvent-exposed face on helix D. Utilizing a novel bis-imidazole scaffold a series of over 100 compounds has been synthesized. Seven related, imidazole-based compounds were identified that inhibit binding of HCV-E2 to CD81. The inhibitory compounds have no short-term effect on cellular expression of CD81 or other tetraspanins, do not disrupt CD81 associations with other cell surface proteins, and bind reversibly to HCV-E2. These results provide an important proof of concept that CD81-based mimics can disrupt binding of HCV-E2 to CD81.
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D018716:Molecular Mimicry; D011485:Protein Binding / Q000187:drug effects; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C554798:CD81 protein, human; D008565:Membrane Proteins; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D000620:Aminoimidazole Carboxamide