Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Rue du Bugnon 48, 1011, Switzerland.
Viruses. 2012 Oct 17;4(10):2162-81. doi: 10.3390/v4102162.
Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and therapeutic options are limited, making the identification of novel drug targets for the development of efficacious therapeutics an urgent need. Arenaviruses are comprised of two RNA genome segments and four proteins, the polymerase L, the envelope glycoprotein GP, the matrix protein Z, and the nucleoprotein NP. A crucial step in the arenavirus life-cycle is the biosynthesis and maturation of the GP precursor (GPC) by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) yielding a tripartite mature GP complex formed by GP1/GP2 and a stable signal peptide (SSP). GPC cleavage by SKI-1/S1P is crucial for fusion competence and incorporation of mature GP into nascent budding virion particles. In a first part of our review, we cover basic aspects and newer developments in the biosynthesis of arenavirus GP and its molecular interaction with SKI-1/S1P. A second part will then highlight the potential of SKI-1/S1P-mediated processing of arenavirus GPC as a novel target for therapeutic intervention to combat human pathogenic arenaviruses.
沙粒病毒包括致命的人类病原体,对公共健康构成严重威胁。迄今为止,尚无获得 FDA 批准的针对沙粒病毒感染的疫苗,治疗选择也有限,因此迫切需要确定新的药物靶点,以开发有效的治疗方法。沙粒病毒由两个 RNA 基因组片段和四种蛋白组成,即聚合酶 L、包膜糖蛋白 GP、基质蛋白 Z 和核蛋白 NP。沙粒病毒生命周期中的一个关键步骤是细胞信号肽酶和细胞酶枯草杆菌蛋白酶 Kexin 同工酶-1(SKI-1)/位点 1 蛋白酶(S1P)对 GP 前体(GPC)的生物合成和成熟,产生由 GP1/GP2 和稳定信号肽(SSP)组成的三分体成熟 GP 复合物。SKI-1/S1P 对 GPC 的切割对于融合能力和成熟 GP 掺入新生出芽病毒颗粒至关重要。在我们综述的第一部分中,我们涵盖了沙粒病毒 GP 生物合成的基本方面和较新的发展及其与 SKI-1/S1P 的分子相互作用。然后,第二部分将强调 SKI-1/S1P 介导的沙粒病毒 GPC 加工作为针对治疗人类致病性沙粒病毒的新型治疗靶点的潜力。