Inhibition of dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities

Abstract

Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. In the present study, we identified new compounds with anti-DENV replication activity by targeting viral replication enzymes – NS5, RNA-dependent RNA polymerase (RdRp) and NS3 protease, using cell-based reporter assay. Subsequently, we performed an enzyme-based assay to clarify the action of these compounds against DENV RdRp or NS3 protease activity. Moreover, these compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication. These results describe novel prototypical small anti-DENV molecules for further development through compound modification and provide potential antivirals for treating DENV infection and DENV-related diseases.

Keywords:

• DENV inhibitors
• RdRp
• NS3 protease
• ICR-suckling mouse
• synergy

Acknowledgements

The authors would like to thank Dr. Huey-Nan Wu (Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan) for giving DENV-2 (type-2 strain 16681) and Dr. Charles Rice (Rockefeller University and Apath, LCC, USA) for kindly providing human hepatoma Huh-7 cells.

Disclosure statement

The authors report no declarations of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by grant from the Ministry of Science and Technology of Taiwan [MOST104–2320-B-037–025-MY3], and Kaohsiung Medical University under Aim for the Top Universities, Taiwan [KMU-TP105H02].