Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
Zoonosis Science Center, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
J Biomol Struct Dyn. 2020 Nov;38(18):5526-5536. doi: 10.1080/07391102.2019.1704882. Epub 2019 Dec 27.
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as , was identified by screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound formed a stable complex with ZIKV protease. Interaction analysis of compound 's binding pose from the cluster analysis of MD simulations trajectories predicted that mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound was found to inhibit ZIKV serine protease with IC = 143.25 ± 5.45 µM, in line with the results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds and (a known panflavivirus peptide hybrid with IC = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound to be lower than that of , proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.
Zika 病毒（ZIKV）是一种新兴的蚊媒黄病毒，已知感染 ZIKV 亚洲谱系会导致胎儿大脑异常和格林-巴利综合征。世界卫生组织于 2016 年宣布 ZIKV 为全球公共卫生紧急事件。然而，目前既没有疫苗也没有抗病毒预防/治疗方法。在这项研究中，我们报告了一种基于 C2 对称二醇的人类免疫缺陷病毒 1 型（HIV）蛋白酶抑制剂的鉴定，该抑制剂对 ZIKV NS2B-NS3 蛋白酶具有活性。该化合物被称为 ，是通过对 6265 种蛋白酶抑制剂文库进行筛选而发现的。分子动力学（MD）模拟研究表明，化合物 与 ZIKV 蛋白酶形成了稳定的复合物。从 MD 模拟轨迹的聚类分析中对化合物 的结合构象进行相互作用分析预测，化合物 主要与 ZIKV NS3 相互作用。尽管设计为天冬氨酸蛋白酶抑制剂，但发现化合物 以 143.25±5.45µM 的 IC 抑制 ZIKV 丝氨酸蛋白酶 ，与 结果一致。此外，线性相互作用能法（LIE）用于估计化合物 和 的结合亲和力（一种已知的泛黄病毒肽杂种，其对 ZIKV 蛋白酶的 IC = 1.64±0.015µM）。LIE 方法正确预测了化合物 的结合亲和力低于 ，证明在评分和化合物排序方面优于分子对接方法。由于报道的大多数 ZIKV 蛋白酶抑制剂都是带正电荷的肽杂种，具有或不具有亲电弹头，化合物 代表一种极性较低、更具类药性的非肽命中化合物，可用于进一步优化。由 Ramaswamy Sarma 传达。
