Department of Biotechnology, Sri Jayachamarajendra College of Engineering, JSS Science and Technology University, JSS TEI Campus, Mysuru 57006, Karnataka, India.
Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Biochem Pharmacol. 2018 Aug;154:54-63. doi: 10.1016/j.bcp.2018.04.008. Epub 2018 Apr 17.
Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A-2K cleavage and NS4A-NS4B association, respectively. In NS4B, the cytoplasmic loop connecting helices α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B-NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their association with membrane lipids. Despite the lack of 3D structural data, recent topological findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design.
尽管登革热在全球的发病率不断上升，但目前尚无针对该病的特异性化学疗法。对登革热病毒（DENV）蛋白的结构研究揭示了一些潜在的药物靶点。包膜蛋白和非结构蛋白（NS）蛋白 3 和 5 等主要 DENV 蛋白已在抗病毒研究中得到广泛研究，但在体外的效果有限。然而，次要 NS 蛋白 NS2 和 NS4 的研究相对较少。新出现的证据表明它们在病毒繁殖和宿主免疫调节方面的不可或缺的作用，应该鼓励我们针对这些蛋白进行药物发现。这篇综述从结构和功能的角度涵盖了 DENV NS2 和 NS4 蛋白的最新知识，并评估了它们作为抗病毒设计的潜在靶标。NS2A 的抗病毒靶标包括参与发病机制的表面暴露的跨膜区，而 NS2B 的靶标包括在保守的亲水域中的蛋白酶结合位点。NS4A 的理想药物靶标包括对于 NS4A-2K 切割和 NS4A-NS4B 关联分别至关重要的螺旋α4 和 PEPEKQR 序列。在 NS4B 中，连接螺旋α5 和α7 的细胞质环是抗病毒设计的有吸引力的靶标，因为它在二聚化和 NS4B-NS3 相互作用中起作用。NS2A、NS2B 和 NS4A 参与膜调节和类病毒孔蛋白活性的研究结果表明，可以通过破坏它们与膜脂质的关联来靶向这些蛋白。尽管缺乏 3D 结构数据，但最近的拓扑发现和结构预测方法的进展应该足以推动针对 NS2 和 NS4 的药物设计。
