Zafferani Martina, Haddad Christina, Luo Le, Davila-Calderon Jesse, Chiu Liang-Yuan, Mugisha Christian Shema, Monaghan Adeline G, Kennedy Andrew A, Yesselman Joseph D, Gifford Robert J, Tai Andrew W, Kutluay Sebla B, Li Mei-Ling, Brewer Gary, Tolbert Blanton S, Hargrove Amanda E
Chemistry Department, Duke University, 124 Science Drive, Durham, NC 27705, USA.
Department of Chemistry, Case Western Reserve University, Cleveland, OH 441106, USA.
Sci Adv. 2021 Nov 26;7(48):eabl6096. doi: 10.1126/sciadv.abl6096.
The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）大流行以及未来冠状病毒大流行的可能性，凸显了开发新型抗病毒药物的迫切需求。小分子化学探针既能揭示病毒复制的各个方面，又能作为抗病毒治疗药物开发的先导。在此，我们报告了基于氨氯地平的小分子的鉴定，这些小分子通过靶向病毒5′端的保守结构元件来有效抑制OC43和SARS-CoV-2的复制。基于核磁共振的结构研究揭示了氨氯地平与含有类似凸起结构的茎环的特定相互作用，并且在回顾性对接研究中预测先导氨氯地平会与之紧密结合。氨氯地平是首个靶向冠状病毒基因组5′非翻译区和近端区域内RNA结构的抗病毒小分子。这些分子将作为化学探针，以进一步了解冠状病毒RNA生物学，并可为开发针对冠状病毒RNA的特异性抗病毒药物铺平道路。
