Non-Nucleotide RNA-Dependent RNA Polymerase Inhibitors That Block SARS-CoV-2 and Flaviviral Replication

Katerina Krejcova, Eva Konkolova, Evzen Boura, Milan Dejmek, Radim Nencka

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 160 00, Praha 6, Czech Republic

Flaviviruses (family Flaviviridae) and coronaviruses (family Coronaviridae) both belong to single-stranded positive-sense RNA (+RNA) viruses. Unfortunately both of these families proved that they have a pandemic potential which was demonstrated recently by the ZIKV, MERS-CoV and SARS-CoV outbreaks. Therefore, effective treatment strategies are urgently needed to treat patients infected with flaviviruses [1, 2].

Flaviviruses are large group of viruses known for their ability to cause human infections. These viruses can cause diverse diseases, such as encephalitis, acute flaccid paralysis, hemorrhagic fevers or congenital abnormalities and fetal death [3].

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets [4].

We demonstrate that various compounds inhibit RNA synthesis by viral RdRps. We use in vitro polymerase assays to show that these compounds interfere with RNA syntheses performed by the RdRps.

[1] Lindenbach, B.D, Murray, C.L., Thiel, H.J., Rice C.M. (2013). Flaviviridae. Fields Virology. Lippincott Williams & Wilkins, Philadelphia, 712-746.

[2]Abdelaziz, O.S. and Waffa, Z. (2020) Neuropathogenic human coronaviruses: A review. Reviews in medical virology, 30, e2118.

[3] Kok, W.M. (2016) New developments in flavivirus drug discovery. Expert Opinion on Drug Discovery 11, 433–45.

[4] Vicenti I., Zazzi M., Saladini F. (2021) SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19. Expert Opin. Ther. Pat., 31, 325–337.