Institute of Physics of São Carlos, University of São Paulo, Av. Joao Dagnone, 1100-Jardim Santa Angelina, São Carlos 13563-120, Brazil.
Cellco Biotec, R. Alberto Lanzoni, 993-Parque Santa Felicia, São Carlos 13562-390, Brazil.
Nat Commun. 2017 Mar 27;8:14764. doi: 10.1038/ncomms14764.
The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 Å resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution.
目前的 Zika 病毒（ZIKV）疫情已成为具有复杂流行病学和严重神经影响的全球健康威胁，因此需要紧急努力开发新型有效且安全的抗病毒药物。由于其在 RNA 病毒复制中的核心作用，非结构蛋白 5（NS5）RNA 依赖性 RNA 聚合酶（RdRp）是药物发现的主要靶标。在这里，我们描述了重组 ZIKV NS5 RdRp 结构域的晶体结构，分辨率为 1.9Å，作为基于结构的药物设计策略的平台。整体结构与其他黄病毒类似物相似。然而，与登革热病毒结构相比，引物环靶位更适合非核苷聚合酶抑制剂的设计，包括更紧密的口袋和局部电荷分布的改变。
