Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors

Antiviral Res. 2021 Jun:190:105074. doi: 10.1016/j.antiviral.2021.105074. Epub 2021 Apr 16.

Abstract

Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. The NS2B-NS3 protease is essential for flaviviral life cycle and has been studied as a target for the design of inhibitors against several well-known flaviviruses, but not TBEV. In the present study, Compound 86, a known tripeptidic inhibitor of dengue (DENV), West Nile (WNV) and Zika (ZIKV) proteases, was predicted to be active against TBEV protease using a combination of in silico techniques. Further, Compound 86 was found to inhibit recombinant TBEV protease with an IC50 = 0.92 μM in the in vitro enzymatic assay. Additionally, two more peptidic analogues were synthetized and they displayed inhibitory activities against both TBEV and ZIKV proteases. In particular, Compound 104 inhibited ZIKV protease with an IC50 = 0.25 μM. These compounds represent the first reported inhibitors of TBEV protease to date and provides valuable information for the further development of TBEV as well as pan-flavivirus protease inhibitors.

Keywords: Docking; MD simulations; NS2B-NS3 serine protease; Peptide hybrids; Tick-borne encephalitis virus; Zika virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Computer Simulation
  • Encephalitis Viruses, Tick-Borne / drug effects*
  • Encephalitis Viruses, Tick-Borne / enzymology
  • Encephalitis, Tick-Borne / drug therapy
  • Encephalitis, Tick-Borne / virology
  • Molecular Docking Simulation
  • Peptide Hydrolases / chemistry
  • Protease Inhibitors / classification
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology*
  • RNA Helicases / antagonists & inhibitors
  • RNA Helicases / metabolism
  • Serine Endopeptidases / metabolism
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • NS2B protein, flavivirus
  • NS3 protein, flavivirus
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • Peptide Hydrolases
  • Serine Endopeptidases
  • RNA Helicases