Dengue virus (DENV) infection is one of the most emerging arboviral infections in humans. DENV is a positive-stranded RNA virus in the Flaviviridae family consisting of an 11 kb genome. DENV non-structural protein 5 (DENV-NS5) constitutes the largest among the non-structural proteins, which act as two domains, the RNA-dependent RNA polymerase (RdRp) and RNA methyltransferase enzyme (MTase). The DENV-NS5 RdRp domain contributes to the viral replication stages, whereas the MTase initiates viral RNA capping and facilitates polyprotein translation. Given the functions of both DENV-NS5 domains have made them an important druggable target. Possible therapeutic interventions and drug discoveries against DENV infection were thoroughly reviewed; however, a current update on the therapeutic strategies specific to DENV-NS5 or its active domains was not attempted. Since most potential compounds and drugs targeting the DENV-NS5 were evaluated in both in vitro cultures and animal models, a more detailed evaluation of molecules/drug candidates still requires investigation in randomized controlled clinical trials. This review summarizes current perspectives on the therapeutic strategies adopted to target the DENV-NS5 (RdRp and MTase domains) at the host-pathogen interface and further discusses the directions to identify candidate drugs to combat DENV infection.
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