Antiviral Activity of 7-Substituted 7-Deazapurine Ribonucleosides, Monophosphate Prodrugs, and Triphoshates against Emerging RNA Viruses

0541460 - ÚOCHB 2022 RIV US eng J - Journal Article
Milisavljevič, Nemanja - Konkoľová, Eva - Kozák, Jaroslav - Hodek, Jan - Veselovská, Lucia - Sýkorová, Veronika - Čížek, Karel - Pohl, Radek - Eyer, Luděk - Svoboda, P. - Růžek, Daniel - Weber, Jan - Nencka, Radim - Bouřa, Evžen - Hocek, Michal
Antiviral Activity of 7-Substituted 7-Deazapurine Ribonucleosides, Monophosphate Prodrugs, and Triphoshates against Emerging RNA Viruses.
ACS Infectious Diseases. Roč. 7, č. 2 (2021), s. 471-478. ISSN 2373-8227
R&D Projects: GA ČR(CZ) GA19-08124S; GA MZd(CZ) NU20-05-00472; GA MŠMT(CZ) LTAUSA18016; GA MŠMT(CZ) EF16_019/0000729
Grant - others:AV ČR(CZ) AP1501
Program: Akademická prémie - Praemium Academiae
Institutional support: RVO:61388963 ; RVO:60077344
Keywords : 7-deazapurine ribonucleosides * monophosphate prodrugs * triphoshates * RNA viruses * 7-deazapurine ribonucleosides monophosphate prodrugs triphoshates RNA viruses antiviral activity
OECD category: Organic chemistry; Biochemistry and molecular biology (BC-A)
Impact factor: 5.578, year: 2021
Method of publishing: Limited access
https://doi.org/10.1021/acsinfecdis.0c00829

A 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.
Permanent Link: http://hdl.handle.net/11104/0319010