Discovery of Dengue Virus NS4B Inhibitors
| العنوان: | Discovery of Dengue Virus NS4B Inhibitors |
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| المؤلفون: | Julien Lescar, Feng Gu, Kah Fei Wan, Francesca Blasco, CongBao Kang, Wai Ling Chan, Wei Liu, Paul W. Smith, Agatha Susila, Bin Zou, Qing Yin Wang, K.L. Yeo, Mei Ding, Chao Shan, Andy M. Yip, Haoying Xu, Hongping Dong, Jing Zou, Suresh B. Lakshminarayana, Ratna Karuna, Pei Yong Shi, Peck Gee Seah |
| المساهمون: | Diamond, M. S., School of Biological Sciences |
| المصدر: | Journal of Virology. 89:8233-8244 |
| بيانات النشر: | American Society for Microbiology, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | viruses, Immunology, Viremia, Viral Nonstructural Proteins, Dengue virus, Biology, medicine.disease_cause, Antiviral Agents, Microbiology, Cell Line, In vivo, Cricetinae, Virology, Vaccines and Antiviral Agents, Drug Discovery, medicine, Animals, Humans, Spiro Compounds, Replicon, chemistry.chemical_classification, Drug discovery, virus diseases, Dengue Virus, biochemical phenomena, metabolism, and nutrition, medicine.disease, In vitro, Amino acid, chemistry, Insect Science, Viral replication complex |
| الوصف: | The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo . The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC 50 ], 10 to 80 nM) but not DENV-1 and -4 (EC 50 , >20 μM). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial “hit” (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients. IMPORTANCE Dengue virus (DENV) threatens up to 2.5 billion people and is now spreading in many regions in the world where it was not previously endemic. While there are several promising vaccine candidates in clinical trials, approved vaccines or antivirals are not yet available. Here we describe the identification and characterization of a spiropyrazolopyridone as a novel inhibitor of DENV by targeting the viral NS4B protein. The compound potently inhibits two of the four serotypes of DENV (DENV-2 and -3) both in vitro and in vivo . Our results validate, for the first time, that NS4B inhibitors could potentially be developed for antiviral therapy for treatment of DENV infection in humans. |
| وصف الملف: | application/pdf |
| تدمد: | 1098-5514 0022-538X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d9c6a3590eab912cf760905f732513b3 https://doi.org/10.1128/jvi.00855-15 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d9c6a3590eab912cf760905f732513b3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10985514 0022538X |
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