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Review
. 2024 Apr 18;31(4):632-657.
doi: 10.1016/j.chembiol.2024.03.008.

SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Sho Iketani  1 , David D Ho  2
Affiliations
Review

SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Sho Iketani et al. Cell Chem Biol. .

Abstract

Over four years have passed since the beginning of the COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies and small molecules developed for clinical use. However, given the ability for viruses to become resistant to antivirals, it is perhaps no surprise that the field has identified resistance to nearly all of these compounds. Here, we provide a comprehensive review of the resistance profile for each of these therapeutics. We hope that this resource provides an atlas for mutations to be aware of for each agent, particularly as a springboard for considerations for the next generation of antivirals. Finally, we discuss the outlook and thoughts for moving forward in how we continue to manage this, and the next, pandemic.

Keywords: COVID-19; SARS-CoV-2; antibody; antiviral; drug resistance; small-molecule inhibitor.

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Conflict of interest statement

Declaration of interests S.I. and D.D.H. have sponsored research agreements with Enanta Pharmaceuticals, Shionogi & Co., Ltd., and Regeneron Pharmaceuticals. S.I. and D.D.H. are inventors on patent applications related to SARS-CoV-2 monoclonal antibodies as well as to SARS-CoV-2 3CL protease inhibitors. D.D.H. is a co-founder of TaiMed Biologics and RenBio, consultant to WuXi Biologics, Brii Biosciences, Apexigen, and Veru Inc., and board director for Vicarious Surgical.

Figures

Figure 1.
Figure 1.. Residues altered in RdRp in remdesivir-resistant viruses.
The RdRp, nsp7, nsp8, template RNA, primer RNA, and remdesivir triphosphate are colored light sky blue, lawn green, gold, plum, medium orchid, and crimson, respectively. The specific residue of interest within each panel is colored royal blue. Panels may differ in viewpoint to allow for full visualization of the residues of interest. The structure was downloaded from PDB under code 7BV2.
Figure 2.
Figure 2.. Residues altered in 3CLpro in nirmatrelvir-resistant viruses.
Protomer A of 3CLpro, protomer B of 3CLpro, and nirmatrelvir are colored light sky blue, gold, and orange red, respectively. The specific residue of interest within each panel is colored royal blue. Panels may differ in viewpoint to allow for full visualization of the residues of interest. Hydrogen bonds are shown as dashed lines in deep pink. The structure was downloaded from PDB under code 7VH8.
Figure 3.
Figure 3.. Residues altered in 3CLpro in ensitrelvir-resistant viruses.
Protomer A of 3CLpro, protomer B of 3CLpro, and ensitrelvir are colored light sky blue, gold, and coral, respectively. The specific residue of interest within each panel is colored royal blue. Panels may differ in viewpoint to allow for full visualization of the residues of interest. Hydrogen bonds are shown as dashed lines in deep pink. The structure was downloaded from PDB under code 8HBK.
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