Sofosbuvir as treatment against dengue?. (13th September 2017)

• Record Type: Journal Article
• Authors: Gan, Chye Sheng; Lim, See Khai; Chee, Chin Fei; Yusof, Rohana; Heh, Choon Han
• Is Part Of: Chemical biology & drug design. Volume 91:Number 2(2018)
• Page Start: 448
• Page End: 455
• Publication Date: 2017-09-13
• Subjects: antiviral -- dengue -- GS‐461203 -- nucleoside inhibitor -- sofosbuvir; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13091
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : Dengvaxia ® (CTD‐TDV), the only licensed tetravalent dengue vaccine by Sanofi Pasteur, was made available since 2015. However, administration of CTD‐TDV, in general, has not received the prequalification recommendation from the World Health Organization. Having a universal antidengue agent for treatment will therefore beneficial. Accordingly, the development of nucleoside inhibitors specific to dengue viral polymerase that perturb dengue infection has been studied by many. Alternatively, we have used a marketed anti‐HCV prodrug sofosbuvir to study its in silico and in vitro effects against dengue. As a result, the active metabolite of sofosbuvir (GS‐461203) was predicted to bind to the catalytic motif (Gly‐Asp‐Asp) of dengue viral polymerase with binding affinity of −6.9 kcal/mol. Furthermore, sofosbuvir demonstrated excellent in vitro viral inhibition with an EC90 of 0.4 μm . In addition, this study demonstrated the requirement of specific liver enzymes to activate the prodrug into GS‐461203 to exert its antidengue potential. All in all, sofosbuvir should be subjected to in‐depth studies to provide information of its efficacy toward dengue and its lead potential as DENV polymerase inhibitor in human subjects. In conclusion, we have expended the potential of the clinically available drug sofosbuvir as treatment for dengue. Abstract : Molecular docking of the activated structure of sofosbuvir, GS‐461203, was performed on dengue virus polymerase. The findings were then validated using in vitro model of dengue virus infection. This study revealed the potential antidengue activity of sofosbuvir, and GS‐461203 could serve as a lead compound in the development of novel antiviral agents against dengue virus.