De Novo Design of α-Helical Lipopeptides Targeting Viral Fusion Proteins: A Promising Strategy for Relatively Broad-Spectrum Antiviral Drug Discovery

作者：Chao Wang, Lei Zhao, Shuai Xia, Tianhong Zhang, Ruiyuan Cao, Guodong Liang, Yue Li, Guangpeng Meng, Weicong Wang, Weiguo Shi, Wu Zhong, Shibo Jiang, Keliang Liu · 发表于：Journal of Medicinal Chemistry · 年份：2018 · DOI：10.1021/acs.jmedchem.8b00890 · 被引用次数：56 · 研究领域：Influenza Virus Research Studies、RNA and protein synthesis mechanisms、Respiratory viral infections research

Class I enveloped viruses share similarities in their apparent use of a hexameric coiled-coil assembly to drive the merging of virus and host cell membranes. Inhibition of coiled coil-mediated interactions using bioactive peptides that replicate an α-helical chain from the viral fusion machinery has significant antiviral potential. Here, we present the construction of a series of lipopeptides composed of a de novo heptad repeat sequence-based α-helical peptide plus a hydrocarbon tail. Promisingly, the constructs adopted stable α-helical conformations and exhibited relatively broad-spectrum antiviral activities against Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A viruses (IAVs). Together, these findings reveal a new strategy for relatively broad-spectrum antiviral drug discovery by relying on the tunability of the α-helical coiled-coil domains present in all class I fusion proteins and the amphiphilic nature of the individual helices from this multihelix motif.