The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development

Antiviral Res. 2015 Jun;118:148-58. doi: 10.1016/j.antiviral.2015.03.014. Epub 2015 Apr 2.


The flavivirus NS3 protein is associated with the endoplasmic reticulum membrane via its close interaction with the central hydrophilic region of the NS2B integral membrane protein. The multiple roles played by the NS2B-NS3 protein in the virus life cycle makes it an attractive target for antiviral drug discovery. The N-terminal region of NS3 and its cofactor NS2B constitute the protease that cleaves the viral polyprotein. The NS3 C-terminal domain possesses RNA helicase, nucleoside and RNA triphosphatase activities and is involved both in viral RNA replication and virus particle formation. In addition, NS2B-NS3 serves as a hub for the assembly of the flavivirus replication complex and also modulates viral pathogenesis and the host immune response. Here, we review biochemical and structural advances on the NS2B-NS3 protein, including the network of interactions it forms with NS5 and NS4B and highlight recent drug development efforts targeting this protein. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery.

Keywords: Antiviral drug target; Crystal structures; Dengue virus NS2B–NS3 protease; RNA helicase; Replication complex; Serine protease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antiviral Agents / isolation & purification*
  • Antiviral Agents / metabolism
  • Drug Discovery / trends
  • Enzyme Inhibitors / isolation & purification*
  • Enzyme Inhibitors / metabolism
  • Flavivirus / drug effects*
  • Flavivirus / enzymology*
  • Flavivirus / physiology
  • Humans
  • RNA Helicases / antagonists & inhibitors
  • RNA Helicases / metabolism
  • Serine Endopeptidases / metabolism
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / drug effects*


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