title: The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development.
abstract: 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.
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, 61 Biopolis Drive, Proteos Building, #07-03, Singapore 138673, Singapore. Electronic address: luodahai@ntu.edu.sg.
authors.forename: Dahai
authors.initials: D
authors.lastname: Luo
authors.affiliation: Program in Emerging Infectious Diseases, DUKE-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore. Electronic address: subhash.vasudevan@duke-nus.edu.sg.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; UPMC UMRS CR7 - CNRS ERL 8255-INSERM U1135 Centre d'Immunologie et des Maladies Infectieuses, Centre Hospitalier Universitaire Pitié-Salpêtrière, Faculté de Médecine Pierre et Marie Curie, Paris, France. Electronic address: julien@ntu.edu.sg.
authors.forename: Julien
authors.initials: J
authors.lastname: Lescar
mesh_terms: D000998:Antiviral Agents / Q000302:isolation & purification* / Q000378:metabolism; D055808:Drug Discovery / Q000639:trends; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000378:metabolism; D005416:Flavivirus / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: 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
keywords: Antiviral drug target; Crystal structures; Dengue virus NS2B–NS3 protease; RNA helicase; Replication complex; Serine protease