The dengue virus NS5 protein as a target for drug discovery

Antiviral Res. 2015 Jul;119:57-67. doi: 10.1016/j.antiviral.2015.04.010. Epub 2015 Apr 24.

Abstract

The non-structural protein 5 (NS5) of flaviviruses is the most conserved amongst the viral proteins. It is about 900 kDa and bears enzymatic activities that play vital roles in virus replication. Its N-terminal domain encodes dual N7 and 2'-O methyltransferase activities (MTase), and possibly guanylyltransferase (GTase) involved in RNA cap formation. The C-terminal region comprises a RNA-dependent RNA polymerase (RdRp) required for viral RNA synthesis. Both MTase and RdRp activities of dengue virus NS5 are well characterized, structurally and functionally. Numerous crystal structures of the flavivirus MTase and RdRp domains have been solved. Inhibitors of both functions have been identified through screening activities using biochemical and cell-based assays, as well as via rational design approaches. This review summaries the current knowledge as well as prospective views on these aspects. This article forms part of a symposium on flavivirus drug discovery in Antiviral Research.

Keywords: Antiviral; Dengue hemorrhagic fever; Dengue virus; Methyltransferase; NS5 protein; RNA polymerase.

Publication types

  • Review

MeSH terms

  • Antiviral Agents / pharmacology
  • Dengue Virus / chemistry*
  • Dengue Virus / drug effects
  • Dengue Virus / genetics
  • Drug Discovery*
  • Enzyme Inhibitors / pharmacology
  • Methyltransferases / antagonists & inhibitors
  • Methyltransferases / chemistry
  • Methyltransferases / metabolism
  • Prospective Studies
  • Protein Structure, Tertiary
  • RNA Replicase* / antagonists & inhibitors
  • RNA Replicase* / chemistry
  • RNA Replicase* / metabolism
  • RNA, Viral / metabolism
  • Severe Dengue / drug therapy
  • Viral Nonstructural Proteins* / antagonists & inhibitors
  • Viral Nonstructural Proteins* / chemistry
  • Viral Nonstructural Proteins* / metabolism
  • Virus Replication

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • NS5 protein, dengue virus
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Methyltransferases
  • RNA Replicase