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: Dengue virus (DENV) infection threatens the health and wellbeing of almost 100 million people in the world. Vectored by mosquitoes, DENV may cause severe disease in human hosts called Dengue hemorrhagic fever (DHF)/Dengue shock syndrome (DSS), which are not preventable by any known drug. In the absence of a universally-accepted vaccine, a drug capable of inhibiting DENV multiplication is an urgent and unmet clinical need. Here we summarize inhibitory strategies by targeting either host biochemical pathways or virus-encoded proteins. A variety of approaches have been generated to design Directly-acting antivirals or DAAs targeting different DENV proteins, with mixed success. Among them, DAAs targeting genome replicating viral enzymes have proven effective against many viruses including, Human Immuno-deficiency Virus and Hepatitis C Virus. DAAs may be derived either from existing compound libraries of novel molecules and plant secondary metabolites or devised through Computeraided Drug design (CADD) methods. Here, we focus on compounds with reported DAA-activity against the DENV RNA-dependent RNA polymerase (RdRp), which replicates the viral RNA genome. The structure-activity relation (SAR) and toxicity of the natural compounds, including secondary plant metabolites, have been discussed in detail. We have also tabulated the novel compounds with known anti-RdRp activity. We conclude with a list of DAAs for which a co-crystal structure with RdRp is reported. Promising hit compounds are often discarded due to poor selectivity or unsuitable pharmacokinetics. We hope this review will provide a useful reference for further studies into the development of an anti-DENV drug.

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