更新于：2024-11-01

3Cpro

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 3Cpro 相关的药物

DC07090

靶点

3Cpro

作用机制

EV71 3Cpro 抑制剂

在研机构

中国科学院上海药物研究所

原研机构

中国科学院上海药物研究所

在研适应症

手足口病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

GC-373

靶点

3Cpro x SARS-CoV-2 3CLpro

作用机制

3Cpro 抑制剂 [+1]

在研机构

Wichita State University

原研机构

Wichita State University [+2]

在研适应症

诺如病毒感染

非在研适应症

新型冠状病毒感染

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 3Cpro 相关的临床结果

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100 项与 3Cpro 相关的转化医学

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0 项与 3Cpro 相关的专利（医药）

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项与 3Cpro 相关的文献（医药）

2024-09-01·eBioMedicine

Tanomastat exerts multi-targeted inhibitory effects on viral capsid dissociation and RNA replication in human enteroviruses

Article

作者: Jaladanki, Chaitanya K. ; Fan, Hao ; Wong, Yi Hao ; Jaladanki, Chaitanya K ; Yogarajah, Thinesshwary ; Chu, Justin Jang Hann ; Lim, Therese Yien May

BACKGROUNDGlobal cyclical outbreaks of human enterovirus infections has positioned human enterovirus A71 (EV-A71) as a neurotropic virus of clinical importance. However, there remains a scarcity of internationally approved antivirals and vaccines.METHODSIn pursuit of repurposing drugs for combating human enteroviruses, we employed a comprehensive pharmacophore- and molecular docking-based virtual screen targeting EV-A71 capsid protein VP1-4, 3C protease, and 3D polymerase proteins. Among 15 shortlisted ligand candidates, we dissected the inhibitory mechanism of Tanomastat in cell-based studies and evaluated its in vivo efficacy in an EV-A71-infected murine model.FINDINGSWe demonstrated that Tanomastat exerts dose-dependent inhibition on EV-A71 replication, with comparable efficacy profiles in enterovirus species A, B, C, and D in vitro. Time-course studies suggested that Tanomastat predominantly disrupts early process(es) of the EV-A71 replication cycle. Mechanistically, live virus particle tracking and docking predictions revealed that Tanomastat specifically impedes viral capsid dissociation, potentially via VP1 hydrophobic pocket binding. Bypassing its inhibition on entry stages, we utilized EV-A71 replication-competent, 3D^pol replication-defective, and bicistronic IRES reporter replicons to show that Tanomastat also inhibits viral RNA replication, but not viral IRES translation. We further showed that orally administered Tanomastat achieved 85% protective therapeutic effect and alleviated clinical symptoms in EV-A71-infected neonatal mice.INTERPRETATIONOur study establishes Tanomastat as a broad-spectrum anti-enterovirus candidate with promising pre-clinical efficacy, warranting further testing for potential therapeutic application.FUNDINGMOE Tier 2 grants (MOE-T2EP30221-0005, R571-000-068-592, R571-000-076-515, R571-000-074-733) and A∗STARBiomedical Research Council (BMRC).

2024-09-01·Protein Science

Profiling of coronaviral M^pro and enteroviral 3C^pro specificity provides a framework for the development of broad‐spectrum antiviral compounds

Article

作者: Groborz, Katarzyna ; Drag, Marcin ; Rut, Wioletta ; Sun, Xinyuanyuan ; Hilgenfeld, Rolf

AbstractThe main protease from coronaviruses and the 3C protease from enteroviruses play a crucial role in processing viral polyproteins, making them attractive targets for the development of antiviral agents. In this study, we employed a combinatorial chemistry approach—HyCoSuL—to compare the substrate specificity profiles of the main and 3C proteases from alphacoronaviruses, betacoronaviruses, and enteroviruses. The obtained data demonstrate that coronavirus Mpros exhibit overlapping substrate specificity in all binding pockets, whereas the 3Cpro from enterovirus displays slightly different preferences toward natural and unnatural amino acids at the P4‐P2 positions. However, chemical tools such as substrates, inhibitors, and activity‐based probes developed for SARS‐CoV‐2 Mpro can be successfully applied to investigate the activity of the Mpro from other coronaviruses as well as the 3Cpro from enteroviruses. Our study provides a structural framework for the development of broad‐spectrum antiviral compounds.

2024-08-01·Acta Crystallographica Section F Structural Biology Communications

Crystal structures of the 3C proteases from Coxsackievirus B3 and B4

Article

作者: Chang, Jingyi ; Li, Jian ; Zou, Xiaofang ; Zhang, Jin ; Jiang, Haihai ; Lin, Cheng

Enteroviruses cause a wide range of disorders with varying presentations and severities, and some enteroviruses have emerged as serious public health concerns. These include Coxsackievirus B3 (CVB3), an active causative agent of viral myocarditis, and Coxsackievirus B4 (CVB4), which may accelerate the progression of type 1 diabetes. The 3C proteases from CVB3 and CVB4 play important roles in the propagation of these viruses. In this study, the 3C proteases from CVB3 and CVB4 were expressed in Escherichia coli and purified by affinity chromatography and gel-filtration chromatography. The crystals of the CVB3 and CVB4 3C proteases diffracted to 2.10 and 2.01 Å resolution, respectively. The crystal structures were solved by the molecular-replacement method and contained a typical chymotrypsin-like fold and a conserved His40–Glu71–Cys147 catalytic triad. Comparison with the structures of 3C proteases from other enteroviruses revealed high similarity with minor differences, which will guide the design of 3C-targeting inhibitors with broad-spectrum properties.