Dengue virus RNA polymerase NS5: a potential therapeutic target?
Dengue fever (DF)/dengue haemorrhagic fever (DHF) is the most common arthropod-borne viral infection, where it is now estimated that 2.5-3 billion people world-wide are at risk of infection. Currently there is no available treatment, in the form of vaccine or drug, making eradication of the mosquito vector the only viable control measure, which has proved costly and of limited success. There are a number of different vaccines undergoing testing, but whilst a dengue vaccine is clearly desirable, there are several issues which make live-attenuated vaccines problematic. These include the phenomenon of antibody-dependent enhancement (ADE) and the possibility of recombination of attenuated vaccine strains with wild-type flavivirus members reverting vaccines to a virulent form. Until we gain a better understanding of these issues and their associated risks, the safety of any live dengue vaccine cannot be assured. It therefore may be safer and more feasible for therapeutic-based approaches to be developed as an alternative to live vaccines. As our understanding of dengue molecular biology expands, new potential targets for drugs are emerging. One of the most promising is the dengue non-structural protein 5 (NS5), the largest and most highly conserved of the dengue proteins. This review examines the unique properties of NS5, including its functions, interactions, subcellular localisation and regulation, and looks at ways in which some of these may be exploited in our quest for effective drugs.
Rawlinson
Stephen M
SM
Nuclear Signalling Laboratory, Dept. of Biochemistry and Molecular Biology, PO Box 13D, Monash University 3800, Australia.
Pryor
Melinda J
MJ
Wright
Peter J
PJ
Jans
David A
DA
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008780:Methyltransferases / Q000737:chemistry; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D014176:Protein Biosynthesis; D020365:RNA Helicases / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019065:Virus Assembly; D014779:Virus Replication; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases; D004791:Enzyme Inhibitors; D008780:Methyltransferases; D019913:Nuclear Localization Signals; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C096041:NS5 protein, flavivirus