Nucleoside analogs play an important role in antiviral drug design, comprising the majority of approved therapeutics. Numerous nucleoside analogs were tested against well-studied viruses, such as HIV-1, Hepatitis C virus, Herpes simplex virus 1, allowing to establish structure-activity relationships. However, approximately 200 pathogenic viruses, including Ebola, dengue, and Zika virus, are studied less thoroughly, and data on antiviral activity of nucleosides against them are scattered. Systematic studies of antiviral chemical space are thus required for successful drug discovery targeting emerging pathogens. In this study antiviral activity of 57 nucleoside analogs, mostly derivatives of N6-benzyladenosine, was assessed against tick-borne encephalitis virus (TBEV), belonging to genus Flavivirus, and against a panel of enteroviruses (enterovirus A71, poliovirus, coxsackieviruses A16 and B1). TBEV is an enveloped virus transmitted by ticks, commonly causing deadly encephalitis in northern Eurasia. Enteroviruses are small widespread non-enveloped picornaviruses, causing poliomyelitis and hand, foot and mouth disease. Anti-TBEV activity was observed for molecules bearing large aromatic moieties in the N6 position of adenosine or bulky hydrophobic moieties in 5’-O position. One of the most important targets of anti-flaviviral nucleosides is non-structural protein 5, the enzyme mediating virus replication, composed of two domains: methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp). 5’-O-Tritylated uridine analogs were earlier shown to inhibit dengue virus replication through RdRp. On the other hand, 5’-O-silylated compounds inhibited dengue MTase activity. To reveal TBEV life cycle stage affected by nucleosides, we conducted a series of time-of-addition experiments. Possible binding modes of the active compounds we predicted by docking studies to the sites in MTase and RdRp. These findings lay the foundation for further search of new nucleoside inhibitors of TBEV reproduction. Replication of enteroviruses was inhibited most efficiently by N6-halobenzyladenosines. Viruses belonging to Enterovirus A species were consistently susceptible to these compounds, whereas for Enterovirus B and C only fluorination of the benzyl led to acceptable activity. Time-of-addition studies revealed inhibition of the viral replication stage, and possible modes interaction with viral proteins were analyzed by docking of the most potent compounds.

N6-benzyladenosine derivatives inhibit replication of RNA viruses from Flavivirus and enterovirus geni

254th National Meeting (2017)

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