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. 2022 Dec 6:10:1062352.
doi: 10.3389/fchem.2022.1062352. eCollection 2022.

Therapeutic potential of compounds targeting SARS-CoV-2 helicase

Matthew T J Halma  1   2 , Mark J A Wever  3   4 , Sanne Abeln  5 , Didier Roche  4 , Gijs J L Wuite  1
Affiliations

Therapeutic potential of compounds targeting SARS-CoV-2 helicase

Matthew T J Halma et al. Front Chem. .

Abstract

The economical and societal impact of COVID-19 has made the development of vaccines and drugs to combat SARS-CoV-2 infection a priority. While the SARS-CoV-2 spike protein has been widely explored as a drug target, the SARS-CoV-2 helicase (nsp13) does not have any approved medication. The helicase shares 99.8% similarity with its SARS-CoV-1 homolog and was shown to be essential for viral replication. This review summarizes and builds on existing research on inhibitors of SARS-CoV-1 and SARS-CoV-2 helicases. Our analysis on the toxicity and specificity of these compounds, set the road going forward for the repurposing of existing drugs and the development of new SARS-CoV-2 helicase inhibitors.

Keywords: COVID-19; SARS-CoV-2; drug repurposing; helicase; natural products; nsp13; small-molecule inhibitors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Binding sites of SARS-CoV-Nsp13 helicase. Panel (A) Structure of SARS-CoV-Nsp13 helicase (PDB ID: 7NN0) (Newman et al., 2021). V570, the single different residue from SARS Helicase (I570) is highlighted in red. The residues constituting the ATP binding site are shown in the enlarged window bound with AMP-PNP, an AMP analog. Panel (B) Possible binding pockets from Nsp13 fragment screening. Reproduced from Newman et al., 2021 under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
FIGURE 2
FIGURE 2
Suitability of the nsp13 protein as a drug target. Panel (A) Time course of selection pressures on SARS-CoV-2 helicase from August 2020 to January 2022. Blue lines show the extent of negative selection, defined as the number of sites under negative selection normalized by kilobase of gene length and the internal tree length. Red lines how the positive selection force, defined as the number of positively selected sites with the same normalization. Over the time history, more sites show negative (purifying) selection, suggesting evolutionary stability. Panel (B) Phylogenetic tree of the coronavirus family based on nsp13 protein sequences. Legend: alpha-CoV (blue), beta-CoV (black), delta-CoV (red), and gamma-CoV (green). Within the beta-CoVs, there is high nsp13 conservation shown by the short tree lengths. Given the low variance amongst this clade, it may be possible that a SARS-CoV-2 nsp13 inhibitor also inhibits the other clade members. Panel (C) Energetics and selection on residues in SARS-CoV-2 nsp13 helicase. Stem plots show positive (red) or negative (blue) selection, expressed as FEL rate. Color plot shows the average energetic change in kcal/mol of all mutations at the site.
FIGURE 3
FIGURE 3
Structures of the nine most promising SARS-CoV-2 helicase inhibitors for further development and drug repurposing.
See this image and copyright information in PMC

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