Drug repositioning: Identification of potent inhibitors of NS3 protease and NS5 RdRp for control of DENV infection

Abstract

Dengue virus (DENV) threatens global health; specific antiviral drugs are required to combat it. Such anti-DENV therapeutics can be rapidly developed by repositioning the drugs approved for other indications. This study investigated six medications of different classes drawn from a library of molecules. In silico analyses were performed to determine potential binding affinity for the DENV non-structural protein NS3 protease and NS5 RNA-dependent RNA polymerase (RdRp). Of the six candidates, galidesivir and tadalafil showed the highest binding affinities for the DENV NS3 protease and NS5 RdRp, with tadalafil demonstrating the highest binding affinity. Galidesivir and tadalafil substantially suppressed viral replication in DENV replicon cells without inducing cytotoxicity and showed half-maximal inhibitory concentrations of 10 μM and 2.56 μM, respectively. Both galidesivir and tadalafil effectively suppress DENV infection in human hepatoma and baby hamster kidney cells, and tadalafil demonstrates protease-inhibitory activity. In an AG129 mouse model of DENV infection, both galidesivir and tadalafil reduced viral loads in the serum, with tadalafil producing a notable reduction by day four. Both drugs markedly suppressed DENV replication in the hepatic tissue. Histopathologically, both galidesivir- and tadalafil-treated mice showed alleviation of DENV-induced lesions in the spleen and liver, indicating the potential therapeutic effects of these drugs. These findings highlight the potential of repositioning galidesivir and tadalafil as effective anti-DENV therapies with low cytotoxicity, meeting the urgent global need for new therapeutic agents against this pathogen.

Keywords: Dengue virus; Galidesivir; NS3 protease; NS5 RdRp; Tadalafil.