小分子流感病毒融合抑制剂在小鼠体内具有口服活性。
A small-molecule fusion inhibitor of influenza virus is orally active in mice.
机构信息
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.
Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium.
出版信息
Science. 2019 Mar 8;363(6431). doi: 10.1126/science.aar6221.
Abstract
Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.
摘要
最近对流感病毒的广谱中和抗体（bnAb）的特性分析表明，保守的血凝素（HA）茎是开发通用疫苗和治疗方法的靶点。尽管有几种茎 bnAb 正在临床试验中进行评估，但抗体通常不适合口服给药。受抗茎 bnAb CR6261 相互作用和作用机制的结构知识的指导，我们选择并优化了模拟 bnAb 功能的小分子。我们的先导化合物通过抑制体外 HA 介导的融合来中和甲型流感病毒 1 组病毒，经口服给药后可保护小鼠免受致死性和亚致死性流感病毒的攻击，并且还可以有效地中和重建的完全分化的人支气管上皮细胞的三维细胞培养物中的病毒感染。与 H1 和 H5 HAs 的共晶结构表明，先导化合物再现了 bnAb 的热点相互作用。
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