KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
PLoS Pathog. 2019 May 9;15(5):e1007760. doi: 10.1371/journal.ppat.1007760. eCollection 2019 May.
Enterovirus A71 (EV-A71) is a non-polio neurotropic enterovirus with pandemic potential. There are no antiviral agents approved to prevent or treat EV-A71 infections. We here report on the molecular mechanism by which a novel class of tryptophan dendrimers inhibits (at low nanomolar to high picomolar concentration) EV-A71 replication in vitro. A lead compound in the series (MADAL385) prevents binding and internalization of the virus but does not, unlike classical capsid binders, stabilize the particle. By means of resistance selection, reverse genetics and cryo-EM, we map the binding region of MADAL385 to the 5-fold vertex of the viral capsid and demonstrate that a single molecule binds to each vertex. By interacting with this region, MADAL385 prevents the interaction of the virus with its cellular receptors PSGL1 and heparan sulfate, thereby blocking the attachment of EV-A71 to the host cells.
肠道病毒 A71（EV-A71）是一种具有流行潜力的非脊髓灰质炎嗜神经肠道病毒。目前尚无批准的抗病毒药物用于预防或治疗 EV-A71 感染。我们在此报告了一类新型色氨酸树状聚合物抑制（在低纳摩尔至高皮摩尔浓度下）EV-A71 体外复制的分子机制。该系列的一种先导化合物（MADAL385）可阻止病毒的结合和内化，但与经典衣壳结合物不同，它不会稳定颗粒。通过耐药性选择、反向遗传学和 cryo-EM，我们将 MADAL385 的结合区域定位到病毒衣壳的 5 倍顶点，并证明每个顶点都结合了一个分子。通过与该区域相互作用，MADAL385 阻止了病毒与其细胞受体 PSGL1 和肝素硫酸的相互作用，从而阻止了 EV-A71 与宿主细胞的附着。
