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Article

Human Superantibodies to 3CLpro Inhibit Replication of SARS-CoV-2 across Variants

by
Kittirat Glab-ampai
1,
Kanasap Kaewchim
1,2,
Thanatsaran Saenlom
1,
Watayagorn Thepsawat
1,
Kodchakorn Mahasongkram
1,
Nitat Sookrung
1,3,
Wanpen Chaicumpa
1 and
Monrat Chulanetra
1,*
1
Center of Research Excellence in Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
2
Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
3
Biomedical Research Incubator Unit, Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(12), 6587; https://doi.org/10.3390/ijms23126587
Submission received: 18 May 2022 / Revised: 8 June 2022 / Accepted: 11 June 2022 / Published: 13 June 2022
(This article belongs to the Special Issue Therapeutic Antibody Development: What Are We Learning along the Way?)
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Abstract

Broadly effective and safe anti-coronavirus agent is existentially needed. Major protease (3CLpro) is a highly conserved enzyme of betacoronaviruses. The enzyme plays pivotal role in the virus replication cycle. Thus, it is a good target of a broadly effective anti-Betacoronavirus agent. In this study, human single-chain antibodies (HuscFvs) of the SARS-CoV-2 3CLpro were generated using phage display technology. The 3CLpro-bound phages were used to infect Escherichia coli host for the production the 3CLpro-bound HuscFvs. Computerized simulation was used to guide the selection of the phage infected-E. coli clones that produced HuscFvs with the 3CLpro inhibitory potential. HuscFvs of three phage infected-E. coli clones were predicted to form contact interface with residues for 3CLpro catalytic activity, substrate binding, and homodimerization. These HuscFvs were linked to a cell-penetrating peptide to make them cell-penetrable, i.e., became superantibodies. The superantibodies blocked the 3CLpro activity in vitro, were not toxic to human cells, traversed across membrane of 3CLpro-expressing cells to co-localize with the intracellular 3CLpro and most of all, they inhibited replication of authentic SARS-CoV-2 Wuhan wild type and α, β, δ, and Omicron variants that were tested. The superantibodies should be investigated further towards clinical application as a safe and broadly effective anti-Betacoronavirus agent.
Keywords: SARS-CoV-2; major protease (3CLpro); human single-chain antibody variable fragments (HuscFvs); cell-penetrating antibody; superantibody SARS-CoV-2; major protease (3CLpro); human single-chain antibody variable fragments (HuscFvs); cell-penetrating antibody; superantibody
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MDPI and ACS Style

Glab-ampai, K.; Kaewchim, K.; Saenlom, T.; Thepsawat, W.; Mahasongkram, K.; Sookrung, N.; Chaicumpa, W.; Chulanetra, M. Human Superantibodies to 3CLpro Inhibit Replication of SARS-CoV-2 across Variants. Int. J. Mol. Sci. 2022, 23, 6587. https://doi.org/10.3390/ijms23126587

AMA Style

Glab-ampai K, Kaewchim K, Saenlom T, Thepsawat W, Mahasongkram K, Sookrung N, Chaicumpa W, Chulanetra M. Human Superantibodies to 3CLpro Inhibit Replication of SARS-CoV-2 across Variants. International Journal of Molecular Sciences. 2022; 23(12):6587. https://doi.org/10.3390/ijms23126587

Chicago/Turabian Style

Glab-ampai, Kittirat, Kanasap Kaewchim, Thanatsaran Saenlom, Watayagorn Thepsawat, Kodchakorn Mahasongkram, Nitat Sookrung, Wanpen Chaicumpa, and Monrat Chulanetra. 2022. "Human Superantibodies to 3CLpro Inhibit Replication of SARS-CoV-2 across Variants" International Journal of Molecular Sciences 23, no. 12: 6587. https://doi.org/10.3390/ijms23126587

APA Style

Glab-ampai, K., Kaewchim, K., Saenlom, T., Thepsawat, W., Mahasongkram, K., Sookrung, N., Chaicumpa, W., & Chulanetra, M. (2022). Human Superantibodies to 3CLpro Inhibit Replication of SARS-CoV-2 across Variants. International Journal of Molecular Sciences, 23(12), 6587. https://doi.org/10.3390/ijms23126587

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