Two RNA Tunnel Inhibitors Bind in Highly Conserved Sites in Dengue Virus NS5 Polymerase: Structural and Functional Studies
Rishi Arora, Chong Wai Liew, Tingjin Sherryl Soh, Dorcas Adobea Otoo, Cheah C. Seh, Kimberley Yue, Shahul Nilar, Gang Wang, Fumiaki Yokokawa, Christian G. Noble, Yen‐Liang Chen, Pei‐Yong Shi, Julien Lescar, Thomas M. Smith, Timothy E. Benson, Siew Pheng Lim
Abstract
Dengue virus (DENV), an important arthropod-transmitted human pathogen that causes a spectrum of diseases, has spread dramatically worldwide in recent years. Despite extensive efforts, the only commercial vaccine does not provide adequate protection to naive individuals. DENV NS5 polymerase is a promising drug target, as exemplified by the development of successful commercial drugs against hepatitis C virus (HCV) polymerase and HIV-1 reverse transcriptase. High-throughput screening of compound libraries against this enzyme enabled the discovery of inhibitors that induced binding sites in the RNA template channel. Characterizations by biochemical, biophysical, and reverse genetics approaches provide a better understanding of the biological relevance of these allosteric sites and the way forward to design more-potent inhibitors.