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

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 is an urgent need to develop new antiviral agents that inhibit DENV infectivity.[1] Currently, no licensed antiviral drugs are available to block DENV infection and vector control efforts remain the only means to stop the spread of the infection. In the present study, we focused our attention on the identification of potential anti-DENV inhibitors by targeting the enzymatic activities of the NS5 RdRp polymerase and NS3 protease, in vitro and in vivo. As part of a continuation of our studies,[2,3] we developed new pyrazole derivatives 1-3 as inhibitors of NS5 RdRp polymerase (Chart 1). Furthermore, virtual screening studies on the NS2B/NS3 protease led us to identify indole derivatives 4-5 as inhibitors of NS3 protease. New compounds exhibited anti-DENV replication activity without cytotoxicity; two compounds exhibited anti-DENV activity in ICR suckling mouse model of DENV infection. Interestingly, combination treatment with several compounds demonstrated a synergistic inhibitory effect on DENV replication. References [1] Wilder-Smith, A.; Ooi, E. E.; Vasudevan, S. G. et al. Curr. Infect. Dis. Rep. 2010, 12, 157-164. [2] Silvestri, R.; Cascio, M. G.; La Regina, G. et al. J. Med. Chem. 2008, 51, 1560-1576. [3] La Pietra, V.; La Regina, G.; Coluccia, A. et al. J. Med. Chem. 2013, 56, 10066-10078.