Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates

Prakash Jadhav, Xueying Liang, Ahmadullah Ansari, Bin Tan, Haozhou Tan, Kan Li, Xiang Chi, Alexandra Ford, Francesc Xavier Ruiz (), Eddy Arnold (), Xufang Deng () and Jun Wang ()
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Prakash Jadhav: the State University of New Jersey
Xueying Liang: Oklahoma State University
Ahmadullah Ansari: the State University of New Jersey
Bin Tan: the State University of New Jersey
Haozhou Tan: the State University of New Jersey
Kan Li: the State University of New Jersey
Xiang Chi: Oklahoma State University
Alexandra Ford: Oklahoma State University
Francesc Xavier Ruiz: the State University of New Jersey
Eddy Arnold: the State University of New Jersey
Xufang Deng: Oklahoma State University
Jun Wang: the State University of New Jersey

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PLpro) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70Ub binding site in PLpro, we designed a series of quinoline analogs demonstrating potent PLpro inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70Ub site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PLpro inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment.

Date: 2025
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DOI: 10.1038/s41467-025-56902-x

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