In the course of antiviral screening programme we assessed activity of more than 600 compounds 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 several classes of nucleoside analogs and small organic molecules belonging to different chemical classes. Nucleosides bearing large aromatic moieties in the N6 position of adenosine or bulky hydrophobic moieties in 5’-O position were found specifically active against TBEV and mildly cytotoxic. Possible mechanism of action was suggested through time-of-addition experiments and binding modes of the active compounds were predicted by docking studies to the sites in MTase and RdRp. Phenotypic screening of ten organoselenium and one organosulfur compound classes also revealed a specific inhibition of TBEV reproduction. Seven classes showed micromolar activity while being moderately cytotoxic. The inhibitory activity of these compound series is probably realized by different mechanisms including inhibition of the virus entry process or interfering with the host cell targets, thus preparing the ground for the development of new anti-TBEV compounds classes. We searched for the active compound scaffolds in ViralChEMBL database, containing antiviral compounds extracted from ChEMBL and properly curated, to reveal similar compounds possessing antiviral activity realizing through known mechanisms. Several close analogs were identified that allowed us to suggest possible mechanisms of action for our compounds. 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. Enterovirus A-71 and coxsackievirus A16 species were consistently susceptible to these compounds, whereas for coxsackievirus B1 and poliovirus 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 analysed by docking of the most potent compounds.

Design and antiviral activity evaluation of small molecule compounds against viruses from Flavivirus and Enterovirus genera

256th National Meeting (2018)

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