Elucidation of enzymatic mechanisms and structure of Ntaya NS5 enzyme

Katerina Krejcova, Petra Krafcikova, Evzen Boura

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo namesti 542/2, Praha 6, 16610
katerina.krejcova@uochb.cas.cz

Flaviviruses (family Flaviviridae) belong to single-stranded positive sense RNA viruses. They are able to cause human infections such as encephalitis, acute flaccid paralysis etc., therefore effective treatment strategies are urgently needed [1]. Contemporary flaviviral antiviral therapies are based on nucleotide and nucleoside derivatives which target the viral polymerase. It follows that revealing the structure of the polymerase is essential for rational drug design [2]. Our main focus is on the non-structural protein 5 (NS5) of different flaviviruses since it harbors RNA polymerase activity, guanyltransferase and methyltransferase activity which are essential for efficient viral replication. Importantly, NS5 protein possesses highly conserved drug targets shared among flaviviruses [3]. 

Our man goal is to prepare catalytically active methyltransferase and RNA-dependent RNA polymerase from Ntaya virus for testing potent inhibitors and to obtain a crystal structure with selected inhibitors.

[1] Konkolova, E.; Krejčová, K.; Eyer, L.; Hodek, J.; Zgarbová, M.; Fořtová, A.; Jirasek, M.; Teply, F.; Reyes-Gutierrez, P.E.; Růžek, D.; Weber, J.; Boura, E., Molecules 202227, 1894.

[2] Eyer, L., Šmídková, M., Nencka, R., Neča, J., Kastl, T., Palus, M., De Clercq, E., Růžek, D. (2016), Antiviral Research 133, 119–29.

[3] Dubankova, A., Boura, E. (2019), Antiviral Research 169, 104536.

This research was funded by the project the National Institute Virology and Bacteriology (Programme EXCELES, Project No. LX22NPO5103) - Funded by the European Union - Next Generation EU and the Grant Agency of Charles University (Grant No. 408422)