Rational design of peptides with anti-HCV/HIV activities and enhanced specificity

Lack of vaccines for HCV and HIV makes the antiviral drug development urgently needed. The recently identified HCV NS5A-derived virucidal peptide (C5A) demonstrated a wide spectrum of activities against viruses. In this study, the C5A sequence SWLRDIWDWICEVLSDFK was utilized as the framework to study the effect of the modulation of peptide helicity and hydrophobicity on its anti-HCV and anti-HIV activities. Peptide helicity and hydrophobicity were altered by substitutions of varying amino acids on the non-polar face of C5A. Peptide hydrophobicity has been proved to play a crucial role in peptide anti-HCV or anti-HIV activities. Peptide helicity was relatively independent with antiviral activity. However, peptide analogs with dimerized structure in an aqueous medium while maintaining the ability to be induced into a more helical structure in a hydrophobic environment may tend to show comparable or improved antiviral activity and specificity to C5A. By modulating peptide helicity and hydrophobicity, we improved the specificity of C5A against HCV and HIV by 23- and 69-fold, respectively, in terms of the ratio of hemolytic activity to antiviral activity. We demonstrated that obtained by de novo design approach, peptide I6L/I10L/V13L may be a promising candidate as a new anti-HCV and anti-HIV therapeutic.