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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A target site for template-based design of measles virus entry inhibitors.
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A target site for template-based design of measles virus entry inhibitors.

机译：基于模板的麻疹病毒进入抑制剂设计的目标位点。

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摘要

Measles virus (MV) constitutes a principal cause of worldwide mortality, accounting for almost 1 million deaths annually. Although a live-attenuated vaccine protects against MV, vaccination efficiency of young infants is low because of interference by maternal antibodies. Parental concerns about vaccination safety further contribute to waning herd immunity in developed countries, resulting in recent MV outbreaks. The development of novel antivirals that close the vaccination gap in infants and silence viral outbreaks is thus highly desirable. We previously identified a microdomain in the MV fusion protein (F protein) that is structurally conserved in the paramyxovirus family and constitutes a promising target site for rationally designed antivirals. Here we report the template-based development of a small-molecule MV inhibitor, providing proof-of-concept for our approach. This lead compound specifically inhibits fusion and spread of live MV and MV glycoprotein-induced membrane fusion. The inhibitor induces negligible cytotoxicity and does not interfere with receptor binding or F protein biosynthesis or transport but prevents F protein-induced lipid mixing. Mutations in the postulated target site alter viral sensitivity to inhibition. In silico docking of the compound in this microdomain suggests a binding model that is experimentally corroborated by a structure-activity analysis of the compound and the inhibition profile of mutated F proteins. A second-generation compound designed on the basis of the interaction model shows a 200-fold increase in antiviral activity, creating the basis for novel MV therapeutics. This template-based design approach for MV may be applicable to other clinically relevant members of the paramyxovirus family.
机译：麻疹病毒（MV）构成世界范围内死亡的主要原因，每年约有100万人死亡。尽管减毒活疫苗可以预防MV，但由于母体抗体的干扰，婴儿的疫苗接种效率很低。父母对疫苗接种安全性的担忧进一步加剧了发达国家的牛群免疫力，导致最近爆发了MV。因此，迫切需要开发出新型的抗病毒药物，以缩小婴儿的疫苗接种间隔并抑制病毒爆发。我们之前在MV融合蛋白（F蛋白）中鉴定了一个微结构域，该结构域在副粘病毒家族中结构保守，并构成合理设计的抗病毒药物的有希望的靶位点。在这里，我们报告了基于模板的小分子MV抑制剂的开发，为我们的方法提供了概念验证。该先导化合物特异性抑制活MV和MV糖蛋白诱导的膜融合的融合和扩散。该抑制剂诱导的细胞毒性可忽略不计，并且不干扰受体结合或F蛋白的生物合成或转运，但可以阻止F蛋白诱导的脂质混合。假定靶位点的突变会改变病毒对抑制的敏感性。化合物在该微域中的计算机对接表明，通过化合物的结构活性分析和突变的F蛋白的抑制作用，实验上证实了结合模型。根据相互作用模型设计的第二代化合物显示出200倍的抗病毒活性，为新型MV治疗奠定了基础。这种基于模板的MV设计方法可能适用于副粘病毒家族的其他临床相关成员。

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