Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia.
Experiments division, Synchrotron SOLEIL, Gif-sur-Yvette, France.
Sci Rep. 2017 Jul 3;7(1):4507. doi: 10.1038/s41598-017-04656-y.
Human parainfluenza viruses represent a leading cause of lower respiratory tract disease in children, with currently no available approved drug or vaccine. The viral surface glycoprotein haemagglutinin-neuraminidase (HN) represents an ideal antiviral target. Herein, we describe the first structure-based study on the rearrangement of key active site amino acid residues by an induced opening of the 216-loop, through the accommodation of appropriately functionalised neuraminic acid-based inhibitors. We discovered that the rearrangement is influenced by the degree of loop opening and is controlled by the neuraminic acid's C-4 substituent's size (large or small). In this study, we found that these rearrangements induce a butterfly effect of paramount importance in HN inhibitor design and define criteria for the ideal substituent size in two different categories of HN inhibitors and provide novel structural insight into the druggable viral HN protein.
人类副流感病毒是导致儿童下呼吸道疾病的主要原因，目前尚无获得批准的药物或疫苗。病毒表面糖蛋白血凝素-神经氨酸酶（HN）是一个理想的抗病毒靶点。本文首次描述了通过 216 环的诱导开放，使关键活性位点氨基酸残基重新排列，从而容纳适当功能化的神经氨酸基抑制剂，这是一项基于结构的研究。我们发现，这种重排受环开口程度的影响，并由神经氨酸 C-4 取代基的大小（大或小）控制。在本研究中，我们发现这些重排诱导 HN 抑制剂设计中至关重要的蝴蝶效应，并为两种不同类别 HN 抑制剂中理想取代基大小定义标准，为可药用病毒 HN 蛋白提供新的结构见解。
