title: Structural biology of dengue virus enzymes: towards rational design of therapeutics.
abstract: Development of anti-dengue therapy represents an urgent un-met medical need. Towards antiviral therapy, recent advances in crystal structures of DENV enzymes have led to the possibility of structure-based rational design of inhibitors for anti-dengue therapy. These include (i) the structure of the 'active' form of the DENV protease in complex with a peptide substrate; (ii) the structure of DENV methyltransferase bound to an inhibitor that selectively suppresses viral methyltransferase, but not human methyltransferases; (iii) the structure of DENV RNA-dependent RNA polymerase in complex with a small-molecule compound. This review summarizes the structural biology of these three key enzymes (protease, methyltransferase, and polymerase) that are essential for DENV replication. The new structural information has provided new avenues for development of anti-dengue therapy.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore. christian.noble@novartis.com
authors.forename: Christian G
authors.initials: CG
authors.lastname: Noble
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003716:Dengue Virus / Q000201:enzymology*; D015195:Drug Design; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D008780:Methyltransferases; D012324:RNA-Dependent RNA Polymerase; D010447:Peptide Hydrolases