A Review on the Progress and Prospects of Dengue Drug Discovery Targeting NS5 RNA- Dependent RNA Polymerase

Abstract

: 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.

Molecular Dynamics Simulations Reveal the Interaction Fingerprint of Remdesivir Triphosphate Pivotal in Allosteric Regulation of SARS-CoV-2 RdRp

“…So, we believe that if NNIs are designed for this site based on the aforementioned residues this may result in a similar mechanism of inhibition by causing displacement of the Δ1 loop, which will disrupt the functionality of the RdRp. T2 site : As per the T2 site of HCV RdRp ( Mittal et al, 2020 ) and allosteric site 1 of DENV RdRp ( Maddipati et al, 2020 ) below the thumb domain and C-terminal, we did not find any relevant or conserved residues in CoV-2 RdRp. P1 site: As per the P1 site of HCV RdRp (present adjacent to the active site on palm subdomain) ( Mittal et al, 2020 ), we found residues T687, N691, S759, D760, D761, and C813 of CoV-2 RdRp as structurally well-conserved residues with their corresponding residues T287, N291, G317, D318, D319, and C366 in HCV RdRp ( Figure 9B ).…”

“…T2 site : As per the T2 site of HCV RdRp ( Mittal et al, 2020 ) and allosteric site 1 of DENV RdRp ( Maddipati et al, 2020 ) below the thumb domain and C-terminal, we did not find any relevant or conserved residues in CoV-2 RdRp.…”

“…Since RdRps are structurally and functionally well conserved, we have mapped the possible allosteric sites for SARS-CoV-2 RdRp based on literature and crystallographic data of RdRp of HCV ( Mittal et al, 2020 ), BVDV ( Mittal et al, 2019 ), and DENV ( Maddipati et al, 2020 ). Allosteric inhibitors customize the internal motions and conformational states of the enzyme and are very specific to a target, thus avoiding off-target effects ( Davis et al, 2016 ; Mittal et al, 2020 ).…”

“…The protein structure of the SARS-CoV-2 RdRp was retrieved from the RCSB protein data bank (PDB ID: 7BV2, 7BV1). We also included crystal structures of HCV, BVDV, and DENV RdRp (PDB-ID:4NLD (for T1 and P2 site), 3FRZ (for T2 site), 4EAW (P1 site), 5I3Q (Thumb and Palm junction), and 3FRZ, 5IQ6, and 1S48 (for Template entrance site) ( Mittal et al, 2019 , 2020 ; Maddipati et al, 2020 ) to identify the probable allosteric sites in RdRp protein employed on the basis of a literature survey. The protein structure was prepared using the Protein Preparation Wizard module of Maestro ( Sastry et al, 2013 ; Anang et al, 2018 ) (Schrödinger release 2020–1: Maestro, Schrödinger, LLC, New York, NY, 2020.)…”

“…SARS-CoV-2 genome consists of a (+) ssRNA virus and its RNA-dependent RNA polymerase (RdRp) which help in viral replication and synthesis of its genome ( Eastman et al, 2020 ; Gao et al, 2020 ). RdRp has a high sequence and structural conservation that makes it an attractive drug target for various RNA viruses diseases ( Mittal et al, 2019 , 2020 ; Gao et al, 2020 ; Maddipati et al, 2020 ). Currently, RDV is one of the most promising drugs for COVID-19 being evaluated in phase III clinical trials in China and the United States ( Eastman et al, 2020 ).…”