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Novel inhibitors against COVID-19 main protease suppressed viral infection

Vijayan Ramachandran, Yanyun Liu, Qianying He, Andrew Tang, Patrick Ronaldson, Dominik Schenten, Rui Chang
doi: https://doi.org/10.1101/2022.11.05.515305
Vijayan Ramachandran
1The Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ, USA
2Department of Neurology, University of Arizona, Tucson, AZ, USA
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Yanyun Liu
1The Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ, USA
2Department of Neurology, University of Arizona, Tucson, AZ, USA
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Qianying He
3Department of Biosystems Engineering, University of Arizona, Tucson, AZ, USA
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Andrew Tang
4Neuroscience Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA
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Patrick Ronaldson
5Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
6PATH Biotech LLC, Tucson, AZ, USA
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Dominik Schenten
7Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA
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Rui Chang
1The Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ, USA
2Department of Neurology, University of Arizona, Tucson, AZ, USA
6PATH Biotech LLC, Tucson, AZ, USA
8INTelico Therapeutics LLC, Tucson, AZ, USA
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  • For correspondence: ruichang@email.arizona.edu
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Summary

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can cause severe disease with high mortality rates, especially among older and vulnerable populations. Despite the recent success of vaccines and approval of first-generation anti-viral inhibitor against SARS-CoV-2, an expanded arsenal of anti-viral compounds that limit viral replication and ameliorate disease severity is still urgently needed in light of the continued emergence of viral variants of concern (VOC). The main protease (Mpro) of SARS-CoV-2 is the major non-structural protein required for the processing of viral polypeptides encoded by the open reading frame 1 (ORF1) and ultimately replication. Structural conservation of Mpro among SARS-CoV-2 variants make this protein an attractive target for the anti-viral inhibition by small molecules. Here, we developed a structure-based in-silico screening of approximately 11 million compounds in ZINC15 database inhibiting Mpro, which prioritized 9 lead compounds for the subsequent in vitro validation in SARS-CoV-2 replication assays using both Vero and Calu-3 cells. We validated three of these compounds significantly inhibited SARS-CoV-2 replication in the micromolar range. In summary, our study identified novel small-molecules significantly suppressed infection and replication of SARS-CoV-2 in human cells.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 07, 2022.
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Novel inhibitors against COVID-19 main protease suppressed viral infection
Vijayan Ramachandran, Yanyun Liu, Qianying He, Andrew Tang, Patrick Ronaldson, Dominik Schenten, Rui Chang
bioRxiv 2022.11.05.515305; doi: https://doi.org/10.1101/2022.11.05.515305
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Novel inhibitors against COVID-19 main protease suppressed viral infection
Vijayan Ramachandran, Yanyun Liu, Qianying He, Andrew Tang, Patrick Ronaldson, Dominik Schenten, Rui Chang
bioRxiv 2022.11.05.515305; doi: https://doi.org/10.1101/2022.11.05.515305

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