ReviewStructural biology of dengue virus enzymes: Towards rational design of therapeutics

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.

► Review of the latest structural data for the dengue MTase, protease and polymerase. ► First MTase structure with a flavivirus-specific compound. ► First crystal structure of the 'active' conformation of the dengue protease. ► First dengue polymerase structure bound to a small molecule.