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新型依赖RNA的RNA聚合酶和蛋白酶活性抑制剂对登革病毒复制的抑制作用

Inhibition of dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities.

作者信息

Pelliccia Sveva, Wu Yu-Hsuan, Coluccia Antonio, La Regina Giuseppe, Tseng Chin-Kai, Famiglini Valeria, Masci Domiziana, Hiscott John, Lee Jin-Ching, Silvestri Romano

机构信息

a Department of Drug Chemistry and Technologies , Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti , Roma , Italy.

b Institute of Basic Medical Sciences , College of Medicine, National Cheng Kung University , Tainan , Taiwan.

出版信息

J Enzyme Inhib Med Chem. 2017 Dec;32(1):1091-1101. doi: 10.1080/14756366.2017.1355791.

DOI:10.1080/14756366.2017.1355791
PMID:28776445
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6010079/
Abstract

Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. In the present study, we identified new compounds with anti-DENV replication activity by targeting viral replication enzymes - NS5, RNA-dependent RNA polymerase (RdRp) and NS3 protease, using cell-based reporter assay. Subsequently, we performed an enzyme-based assay to clarify the action of these compounds against DENV RdRp or NS3 protease activity. Moreover, these compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication. These results describe novel prototypical small anti-DENV molecules for further development through compound modification and provide potential antivirals for treating DENV infection and DENV-related diseases.

摘要

登革病毒（DENV）是全球主要的蚊媒传播病毒感染源。每年有超过3.9亿例新感染病例，多达100万例出现严重疾病表现的临床病例，因此持续需要研发针对登革热感染的新型抗病毒药物。此外，目前尚无批准用于治疗登革病毒感染患者的抗登革病毒药物。在本研究中，我们通过基于细胞的报告基因检测，靶向病毒复制酶——NS5、RNA依赖性RNA聚合酶（RdRp）和NS3蛋白酶，鉴定出具有抗登革病毒复制活性的新化合物。随后，我们进行了基于酶的检测，以阐明这些化合物对登革病毒RdRp或NS3蛋白酶活性的作用。此外，这些化合物在ICR乳鼠登革病毒感染模型中表现出体内抗登革病毒活性。联合药物治疗对登革病毒复制具有协同抑制作用。这些结果描述了新型的原型抗登革病毒小分子，可通过化合物修饰进行进一步开发，并为治疗登革病毒感染和登革热相关疾病提供了潜在的抗病毒药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/73a2005c2ed7/IENZ_A_1355791_F0006_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/1e55f3922ff0/IENZ_A_1355791_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/68ea8af6f5a5/IENZ_A_1355791_SCH0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/598294bb30cb/IENZ_A_1355791_SCH0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/5e2c499ec8cf/IENZ_A_1355791_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/039f89f6f91a/IENZ_A_1355791_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/9832ede0cb98/IENZ_A_1355791_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/d9a29fd0d7e7/IENZ_A_1355791_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/73a2005c2ed7/IENZ_A_1355791_F0006_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/1e55f3922ff0/IENZ_A_1355791_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/68ea8af6f5a5/IENZ_A_1355791_SCH0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/598294bb30cb/IENZ_A_1355791_SCH0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/5e2c499ec8cf/IENZ_A_1355791_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/039f89f6f91a/IENZ_A_1355791_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/9832ede0cb98/IENZ_A_1355791_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/d9a29fd0d7e7/IENZ_A_1355791_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/543f/6010079/73a2005c2ed7/IENZ_A_1355791_F0006_B.jpg

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