Kadam Rameshwar U, Juraszek Jarek, Brandenburg Boerries, Buyck Christophe, Schepens Wim B G, Kesteleyn Bart, Stoops Bart, Vreeken Rob J, Vermond Jan, Goutier Wouter, Tang Chan, Vogels Ronald, Friesen Robert H E, Goudsmit Jaap, van Dongen Maria J P, Wilson Ian A
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Janssen Prevention Center, Leiden, Netherlands.
Science. 2017 Oct 27;358(6362):496-502. doi: 10.1126/science.aan0516. Epub 2017 Sep 28.
Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH-induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule- and peptide-based therapeutics against influenza virus.
为应对潜在的大流行、新出现的病毒以及正在传播的不断变异的毒株，迫切需要具有新靶点和作用机制的流感治疗药物。我们在此报告流感血凝素强效肽抑制剂的设计和结构表征。肽的设计基于针对血凝素的人广谱中和抗体（FI6v3和CR9114）的互补决定区环。优化后的肽对甲型流感病毒1组病毒表现出纳摩尔亲和力和中和作用，包括2009年H1N1大流行毒株和禽源H5N1毒株。肽抑制剂与高度保守的茎部表位结合，并阻断与膜融合相关的低pH诱导的构象重排。这些肽类化合物及其有利的生物学特性应能加速新型小分子和肽类流感病毒治疗药物的开发。
