The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.
The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.
复制标题
DOI：
10.1016/j.antiviral.2014.12.015
复制
发表时间：
2015-03
影响因子：
7.6
通讯作者：
Mesecar AD
中科院分区：
文献类型：
--
作者：
Báez-Santos YM;St John SE;Mesecar AD
HTS和基于结构的设计产生了基于萘的先导化合物，其对SARS-CoV PLpro的抑制作用在nM范围内。这些基于萘的先导化合物在细胞培养中具有抗SARS-CoV的抗病毒效力。基于萘的SARS-CoV PLpro抑制剂对SARS-CoV PLpro无毒且具有高度选择性。设计的SARS-CoV PLpro抑制剂通过非共价的竞争性抑制机制起作用。SARS-CoV PLpro抑制剂设计的经验教训对疾病过程中涉及的其他USP具有深远的意义。自导致严重急性呼吸综合征（SARS-CoV）的致命人类冠状病毒在中国广东省出现以来，已经过去了10多年。尽管SARS-CoV大流行感染了超过8500人，夺去了800多人的生命，并在全球造成了数十亿美元的经济损失，但仍然没有临床批准的抗病毒药物、疫苗或单克隆抗体疗法来治疗SARS-CoV感染。最近出现的导致中东呼吸综合征（MERS-CoV）的致命人类冠状病毒是一个清醒的提醒，新的和致命的冠状病毒可以随时出现，并有可能成为大流行病。因此，有必要继续开发针对潜在致命冠状病毒的治疗和预防对策。冠状病毒蛋白酶，木瓜蛋白酶样蛋白酶（PLpro）和3C样蛋白酶（3CLpro），是有吸引力的抗病毒药物靶点，因为它们是冠状病毒复制所必需的。虽然PLpro和3CLpro的主要功能是以协调的方式加工病毒多蛋白，但PLpro具有从宿主细胞蛋白质中剥离泛素和ISG 15的额外功能，以帮助冠状病毒逃避宿主先天免疫应答。因此，用抗病毒药物靶向PLpro可能不仅在抑制病毒复制方面具有优势，而且在抑制受感染细胞中可能导致周围未感染细胞中细胞死亡的信号级联反应的失调方面也具有优势。本文综述了SARS-CoV木瓜蛋白酶样蛋白酶的最新研究进展，包括SARS-CoV基因组和复制的简要概述、SARS-CoV PLpro的结构和催化机制、SARS-CoV PLpro的多种细胞功能、小分子抑制剂对SARS-CoV PLpro的抑制作用以及抑制其他冠状病毒木瓜蛋白酶样蛋白酶的前景。这篇论文是《抗病毒研究》系列邀请文章的一部分，题为“从SARS到MERS：对高致病性人类冠状病毒的10年研究”。
HTS and structure-based design produced naphthalene-based lead compounds with inhibition of SARS-CoV PLpro in the nM range. These naphthalene-based lead compounds have antiviral potency against SARS-CoV in cell culture. SARS-CoV PLpro naphthalene-based inhibitors are non-toxic and highly selective for SARS-CoV PLpro. Designed SARS-CoV PLpro inhibitors act through a non-covalent, competitive mechanism of inhibition. Lessons from design of SARS-CoV PLpro inhibitors have profound implications for other USPs implicated in disease processes. Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small molecule inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on “From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.”
登录
查看更多内容
影响因子：
5
作者：
Imbert I;Snijder EJ;Dimitrova M;Guillemot JC;Lécine P;Canard B
通讯作者：
Canard B
影响因子：
7.3
作者：
Ghosh AK;Takayama J;Aubin Y;Ratia K;Chaudhuri R;Baez Y;Sleeman K;Coughlin M;Nichols DB;Mulhearn DC;Prabhakar BS;Baker SC;Johnson ME;Mesecar AD
通讯作者：
Mesecar AD
影响因子：
3.7
作者：
Kanjanahaluethai, Amornrat;Chen, Zhongbin;Jukneliene, Dalla;Baker, Susan C.
通讯作者：
Baker, Susan C.
影响因子：
5.6
作者：
Johnson MA;Chatterjee A;Neuman BW;Wüthrich K
通讯作者：
Wüthrich K
影响因子：
--
作者：
Ghosh, Arun K.;Xi, Kai;Johnson, Michael E.;Baker, Susan C.;Mesecar, Andrew D.
通讯作者：
Mesecar, Andrew D.