Tick-borne diseases represent a significant health concern in the Northern Hemisphere. Whereas bacterial diseases transmitted by ticks may be successfully treated by common antibiotics, viral tick-borne diseases may be prevented only by vaccination, and post-tick-bite treatment opportunities are limited. Although such diseases as tick-borne encephalitis (TBE), Powassan encephalitis, and Omsk hemorrhagic fever, can be considered as rather rare, serious consequences including death and neurological disabilities make the search of small molecule drugs against them an important task. Given the high similarity between the tick-borne and mosquito-borne flaviviruses, such molecules can be further repurposed for the treatment of dengue fever and West Nile fever. We have developed a virtual screening scheme for TBE virus (TBEV) reproduction inhibitors based on molecular docking into the detergent binding pocket of the envelope proteins homology models. Up to 10% of compounds selected based on this search scheme, belonging to the series of 1,4-dihydropyridines [1], 1,3,5-thiadiazolines [1], and 4-aminotetrahydroquinazolines [2], show antiviral activity against various strains of TBEV and related viruses. This activity is revealed in vitro only upon the incubation of the compounds with the virus, but not when compounds are preincubated with the cells or all the components are mixed simultaneously. Non-enveloped viruses, such as poliovirus, are not sensitive to these molecules, confirming the selectivity of interaction with the envelope proteins. Structure-activity relationships and antiviral profile of the compounds are being studied and optimized. Another group of effective inhibitors of tick-borne viruses reproduction was found among the so-called rigid amphipathic fusion inhibitors, presumably interacting with the membranes of the virions. The studies of the putative mechanism of action of these compounds will be presented. 1. D.I. Osolodkin et al. Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening. ACS Med. Chem. Lett., 2013, 4, 869–874. 2. K.N. Sedenkova et al. Synthesis and assessment of 4-aminotetrahydroquinazoline derivatives as tick-borne encephalitis virus reproduction inhibitors. Org. Biomol. Chem., 2015, 13, 3406–3415.

Small molecules against tick-borne flaviviruses

251st National Meeting (2016)

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