Kennelly Samantha A, Sawyer Jacob M, Payne Anne F, Ciota Alexander T, Harki Daniel A
Department of Medicinal Chemistry, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
ACS Med Chem Lett. 2024 Jul 15;15(8):1334-1339. doi: 10.1021/acsmedchemlett.4c00225. eCollection 2024 Aug 8.
The antiviral enzyme viperin catalyzes the formation of 3'-deoxy-3',4'-didehydro-cytidine-5'-triphosphate (ddhCTP). ddhCTP is incorporated into viral genomes and terminates genomic replication to confer broad-spectrum antiviral effects. We have previously utilized phosphoramidate pronucleotide (ProTide) technology to enable metabolic production of ddhCTP in cells from an exogenously dosed 3'-deoxy-3',4'-didehydro-cytidine ProTide, which confers inhibitory activity against West Nile virus (WNV) and Zika virus (ZIKV). Herein, we synthesized 3'-deoxy-3',4'-didehydro-nucleosides containing all native nucleobases (thymine, uracil, adenine, guanine, and hypoxanthine), elaborated each to a ProTide, and measured their activity for controlling WNV and ZIKV infection. In comparison to the ddhC ProTide, we found that the ProTides of 3'-deoxy-3',4'-didehydro-guanosine and 3'-deoxy-3',4'-didehydro-adenosine possess 2- and 4-fold greater antiviral effects against ZIKV, respectively. Collectively, this work advances the development of 3'-deoxy-3',4'-didehydro nucleosides as promising compounds for further development into broad-spectrum antiviral agents.
抗病毒酶蝰蛇毒蛋白催化形成3'-脱氧-3',4'-二脱氢胞苷-5'-三磷酸（ddhCTP）。ddhCTP被掺入病毒基因组并终止基因组复制，从而产生广谱抗病毒作用。我们之前利用氨基磷酸前体核苷酸（ProTide）技术，使外源性给药的3'-脱氧-3',4'-二脱氢胞苷ProTide在细胞中代谢产生ddhCTP，该ProTide对西尼罗河病毒（WNV）和寨卡病毒（ZIKV）具有抑制活性。在此，我们合成了包含所有天然核苷酸碱基（胸腺嘧啶、尿嘧啶、腺嘌呤、鸟嘌呤和次黄嘌呤）的3'-脱氧-3',4'-二脱氢核苷，将每种核苷制备成ProTide，并测定它们控制WNV和ZIKV感染的活性。与ddhC ProTide相比，我们发现3'-脱氧-3',4'-二脱氢鸟苷和3'-脱氧-3',4'-二脱氢腺苷的ProTide对ZIKV的抗病毒作用分别强2倍和4倍。总的来说，这项工作推动了3'-脱氧-3',4'-二脱氢核苷作为有前景的化合物进一步开发成广谱抗病毒药物的进程。
