Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun, Jilin, China.
Chem Biol Drug Des. 2011 Nov;78(5):835-43. doi: 10.1111/j.1747-0285.2011.01201.x. Epub 2011 Sep 26.
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.
缺乏 HCV 和 HIV 的疫苗使得抗病毒药物的开发变得迫切需要。最近发现的 HCV NS5A 衍生的病毒杀伤肽 (C5A) 对多种病毒表现出广泛的活性。在这项研究中，利用 C5A 序列 SWLRDIWDWICEVLSDFK 作为框架，研究了调节肽螺旋性和疏水性对其抗 HCV 和抗 HIV 活性的影响。通过改变 C5A 非极性面上的不同氨基酸来改变肽的螺旋性和疏水性。已经证明肽疏水性在肽抗 HCV 或抗 HIV 活性中起着至关重要的作用。肽螺旋性与抗病毒活性相对独立。然而，在水介质中具有二聚化结构的肽类似物同时保持在疏水环境中诱导形成更螺旋结构的能力，可能倾向于表现出与 C5A 相当或改善的抗病毒活性和特异性。通过调节肽的螺旋性和疏水性，我们将 C5A 对 HCV 和 HIV 的特异性分别提高了 23 倍和 69 倍，这是溶血活性与抗病毒活性之比。我们证明，通过从头设计方法获得的肽 I6L/I10L/V13L 可能是一种有前途的抗 HCV 和抗 HIV 治疗候选药物。
