The dengue virus NS5 protein as a target for drug discovery.
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.
Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Singapore. Electronic address: siew_pheng.lim@novartis.com.
Siew Pheng
SP
Lim
Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Singapore. Electronic address: christian.noble@novartis.com.
Christian G
CG
Noble
Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Singapore.
Pei-Yong
PY
Shi
D000998:Antiviral Agents / Q000494:pharmacology; D003716:Dengue Virus / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011446:Prospective Studies; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D019595:Severe Dengue / Q000188:drug therapy; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C582223:NS5 protein, dengue virus; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D008780:Methyltransferases; D012324:RNA-Dependent RNA Polymerase
Antiviral; Dengue hemorrhagic fever; Dengue virus; Methyltransferase; NS5 protein; RNA polymerase