Towards the design of antiviral inhibitors against flaviviruses: the case for the multifunctional NS3 protein from Dengue virus as a target.
New treatments are urgently needed to combat the increasing number of dengue fever cases in endemic countries as well as amongst a large number of travellers from non-endemic countries. Of the 10 virus encoded proteins, NS3 (non-structural 3) and NS5 carry out all the enzymatic activities needed for polyprotein processing and genome replication, and are considered to be amenable to antiviral inhibition by analogy with successes for similar targets in human immunodeficiency virus and hepatitis C virus. The multifunctional NS3 protein of flavivirus forms a non-covalent complex with the NS2B cofactor and contains the serine-protease activity domain at its N-terminus that is responsible for proteolytic processing of the viral polyprotein and a ATPase/helicase and RNA triphosphatase at its C-terminal end that are essential for RNA replication. In addition, NS3 seems to be also involved in virus assembly. This review covers the recent biochemical and structural advances on the NS2B-NS3 protease-helicase and presents an outlook for the development of small molecules as antiviral drugs targeting this fascinating multifunctional protein.
Lescar
Julien
J
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. julien@ntu.edu.sg
Luo
Dahai
D
Xu
Ting
T
Sampath
Aruna
A
Lim
Siew Pheng
SP
Canard
Bruno
B
Vasudevan
Subhash G
SG
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005416:Flavivirus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases