Phosphonate inhibitors of West Nile virus NS2B/NS3 protease

J Enzyme Inhib Med Chem. 2019 Dec;34(1):8-14. doi: 10.1080/14756366.2018.1506772.

Abstract

West Nile virus (WNV) is a member of the flavivirus genus belonging to the Flaviviridae family. The viral serine protease NS2B/NS3 has been considered an attractive target for the development of anti-WNV agents. Although several NS2B/NS3 protease inhibitors have been described so far, most of them are reversible inhibitors. Herein, we present a series of α-aminoalkylphosphonate diphenyl esters and their peptidyl derivatives as potent inhibitors of the NS2B/NS3 protease. The most potent inhibitor identified was Cbz-Lys-Arg-(4-GuPhe)P(OPh)2 displaying Ki and k2/Ki values of 0.4 µM and 28 265 M-1s-1, respectively, with no significant inhibition of trypsin, cathepsin G, and HAT protease.

Keywords: NS2B/NS3 protease; West Nile virus; aminophosphonates; enzyme inhibitors; serine proteases.

MeSH terms

  • Dose-Response Relationship, Drug
  • Molecular Docking Simulation
  • Molecular Structure
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • RNA Helicases / antagonists & inhibitors
  • RNA Helicases / metabolism
  • Serine Endopeptidases / metabolism
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • West Nile virus / enzymology*

Substances

  • NS2B protein, flavivirus
  • NS3 protein, flavivirus
  • Organophosphonates
  • Peptides
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • Serine Endopeptidases
  • RNA Helicases

Grants and funding

This work was supported by the Ministry of Science and Higher Education’s Iuventus Plus Programme [IP2012 0556 72]. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. MS and JO are grateful to Wroclaw University of Technology for support [Statute Funds 0401/0195/17]. MS is grateful to National Science Centre [UMO-2013/09/N/ST5/02439]. AM and KP are grateful to National Science Centre [UMO-2016/21/B/NZ6/01307]. Project supported by Wroclaw Centre of Biotechnology, programme The Leading National Research Centre (KNOW) for years 2014–2018.