Nemanja Milisavljevic, Eva Konkolová, Jaroslav Kozák, Jan Hodek, Lucia Veselovská, Veronika Sýkorová, Karel Čížek, Radek Pohl, Luděk Eyer, Pavel Svoboda, Daniel Růžek, Jan Weber, Radim Nencka, Evžen Bouřa, Michal Hocek
ACS infectious diseases 2021 Feb 12A series of 7-deazaadenine ribonucleosides bearing alkyl, alkenyl, alkynyl, aryl, or hetaryl groups at position 7 as well as their 5'-O-triphosphates and two types of monophosphate prodrugs (phosphoramidates and S-acylthioethanol esters) were prepared and tested for antiviral activity against selected RNA viruses (Dengue, Zika, tick-borne encephalitis, West Nile, and SARS-CoV-2). The modified triphosphates inhibited the viral RNA-dependent RNA polymerases at micromolar concentrations through the incorporation of the modified nucleotide and stopping a further extension of the RNA chain. 7-Deazaadenosine nucleosides bearing ethynyl or small hetaryl groups at position 7 showed (sub)micromolar antiviral activities but significant cytotoxicity, whereas the nucleosides bearing bulkier heterocycles were still active but less toxic. Unexpectedly, the monophosphate prodrugs were similarly or less active than the corresponding nucleosides in the in vitro antiviral assays, although the bis(S-acylthioethanol) prodrug 14h was transported to the Huh7 cells and efficiently released the nucleoside monophosphate.
Nemanja Milisavljevic, Eva Konkolová, Jaroslav Kozák, Jan Hodek, Lucia Veselovská, Veronika Sýkorová, Karel Čížek, Radek Pohl, Luděk Eyer, Pavel Svoboda, Daniel Růžek, Jan Weber, Radim Nencka, Evžen Bouřa, Michal Hocek. Antiviral Activity of 7-Substituted 7-Deazapurine Ribonucleosides, Monophosphate Prodrugs, and Triphoshates against Emerging RNA Viruses. ACS infectious diseases. 2021 Feb 12;7(2):471-478
PMID: 33395259
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