Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge

Abstract

The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approvals of sofosbuvir and remdesivir against Hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. In this work, we overview the main sequence and structural features of the RdRp of emerging RNA viruses such as Coronaviruses, Flaviviruses, and HCV, as well as inhibition strategies implemented so far. While analyzing the structural information available on the RdRp of emerging RNA viruses, we provide examples of success stories such as for HCV and SARS-CoV-2. In contrast, Flaviviruses’ story has raised attention about how the lack of structural details on catalytically-competent or ligand-bound RdRp strongly hampers the application of structure-based drug design, either in repurposing and conventional approaches.

Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

“…Therefore, this triple mutant was not investigated in silico. The ZIKV RdRp WT sequence was retrieved from the Uniprot database [ 61 ] (entry Q32ZE1) and used as a query, while the highest-sequence homology was observed in WNV RdRp [ 18 ]. The catalytically competent RNA-bound WNV RdRp model generated and validated in a previous work [ 27 ] was thus used as a structural template in the homology modeling of all the ZIKV RdRp structures described in this work, including WT and mutant RdRp as well as the variants in the RNA template sequence.…”

“…Currently, there are different clinical trials testing at least 16 ZIKV vaccine candidates, ( (accessed on 5 March 2021)), however, vaccine development is challenged by safety concerns, due to the risk of vaccine-associated GBS and the enhancement of diseases with other endemic flaviviruses [ 16 ]. Candidate targets for anti-ZIKV drugs include viral proteins such as protease located in the NS3 viral gene and RNA-dependent RNA polymerase (RdRp) located in the NS5 viral gene as well as host targets used during viral entry and replication [ 17 , 18 ]. To address the urgent need for anti-ZIKV therapy, repurposing of licensed antivirals is under evaluation [ 19 , 20 , 21 , 22 ].…”

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

“…RdRp represents the main target of anti-HCoV nucleoside drugs. Though the alignment of the amino acid sequences of the RdRp found in the three highly pathogenic coronaviruses revealed high homology and conservation rates, in close analogy with other positive-sense RNA viruses (like HCV [ 145 ]), among HCoVs SARS-CoV-2 RdRp shares 96% homology with SARS-CoV-1 RdRp, but only 70% with MERS-CoV RdRp [ 146 ]. MERS RdRp structure has not yet been solved experimentally.…”

SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19

“…With remdesivir, another broad range antiviral initially developed to combat Ebola virus and eventually approved under emergency use for the treatment of SARS-CoV-2, the presence of the 3ʹ-OH group allows the formation of the phosphodiester bond to the next incoming nucleotide and the elongation of the growing RNA chain. However, viral RNA synthesis is blocked following the addition of another three NTPs as a result of the steric hindrance caused by the 1ʹ-CN group with the S861 residue [ 30 ]. Other NAs (i.e.…”