id	author	title	date	pages	extension	mime	words	sentences	flesch	summary	cache	txt
cord-325820-tnyzmrm8	Kovacikova, Kristina	6′-β-Fluoro-Homoaristeromycin and 6′-Fluoro-Homoneplanocin A Are Potent Inhibitors of Chikungunya Virus Replication through Their Direct Effect on Viral Nonstructural Protein 1	2020-03-24		.txt	text/plain	9807	519	55	To discover new antiviral agents, we performed a compound screen in cell culture-based infection models and identified two carbocyclic adenosine analogues, 6′-β-fluoro-homoaristeromycin (FHA) and 6′-fluoro-homoneplanocin A (FHNA), that displayed potent activity against CHIKV and Semliki Forest virus (SFV) with 50% effective concentrations in the nanomolar range at nontoxic concentrations. Enzymatic assays with purified wild-type (wt) SFV nsP1 suggested that an oxidized (3′-keto) form, rather than FHNA itself, directly inhibited the MTase activity, while a mutant protein with the K231R and K299E substitutions was insensitive to the compound. Our combined data suggest that FHA and FHNA inhibit CHIKV and SFV replication by directly targeting the MTase activity of nsP1, rather than through an indirect effect on host SAH hydrolase. Since we also identified FHNA analogues that efficiently inhibit host SAH hydrolase in vitro without being active against CHIKV in cell-based assays (31), we reconsidered the possibility of a direct effect of the compound on nsP1 activity.	./cache/cord-325820-tnyzmrm8.txt	./txt/cord-325820-tnyzmrm8.txt