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Review

Structural Basis and Inhibitor Development of SARS-CoV-2 Papain-like Protease

by
Junshuai Wang
1,2,†,
Yuancong Xu
1,†,
Yishu Yang
1,
Botao Zhang
1,2,
Sixu Chen
1,2,
Zhaoyang Li
1,2,
Haojia Zhu
1,
Huai Yang
1,2,
Hongtao Wang
3,
Yubai Zhou
1,
Peng Cao
1,4,
Baiqiang Zhai
3,* and
Yong Gong
2,*
1
College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
2
Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
3
Railway Food Safety Management Engineering Technology Research Center, Zhengzhou Railway Vocational & Technology College, Zhengzhou 451400, China
4
Institute of Matter Science, Beijing University of Technology, Beijing 100124, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2026, 31(3), 474; https://doi.org/10.3390/molecules31030474
Submission received: 30 November 2025 / Revised: 9 January 2026 / Accepted: 12 January 2026 / Published: 29 January 2026
(This article belongs to the Section Chemical Biology)
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Abstract

Papain-like protease (PLpro), a crucial functional domain of the SARS-CoV-2 non-structural protein 3 (nsp3), plays a dual role in both hydrolyzing viral polyprotein precursors and modulating host immune responses. These critical functions position PLpro as a key target in the ongoing development of antiviral therapies for SARS-CoV-2. This review analyzes more than 100 PLpro-ligand co-crystal structures and summarizes the major binding modes between these ligands and PLpro. Most of these ligands bind to sites analogous to those targeted by the classical non-covalent inhibitor GRL0617, primarily involving the P3 and P4 subsites and the BL2 loop. Based on these structural insights, optimized inhibitors have expanded targeting beyond the canonical binding site to auxiliary regions such as the BL2 groove and the Val70 site, and in some cases toward the catalytic Cys111 buried within a narrow pocket. Certain ligands identified through various screening approaches bind to non-canonical or allosteric regions, such as the S1 and S2 sites or the zinc-finger domain, engaging PLpro through distinct interaction modes and thereby offering additional opportunities for PLpro inhibitor design. The review also discusses potential strategies for future PLpro inhibitor development informed by recent structural advances. Taken together, these structural and functional insights support ongoing efforts in the structure-guided design and optimization of PLpro inhibitors.
Keywords: SARS-CoV-2; papain-like protease; crystal structure; drug discovery SARS-CoV-2; papain-like protease; crystal structure; drug discovery
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MDPI and ACS Style

Wang, J.; Xu, Y.; Yang, Y.; Zhang, B.; Chen, S.; Li, Z.; Zhu, H.; Yang, H.; Wang, H.; Zhou, Y.; et al. Structural Basis and Inhibitor Development of SARS-CoV-2 Papain-like Protease. Molecules 2026, 31, 474. https://doi.org/10.3390/molecules31030474

AMA Style

Wang J, Xu Y, Yang Y, Zhang B, Chen S, Li Z, Zhu H, Yang H, Wang H, Zhou Y, et al. Structural Basis and Inhibitor Development of SARS-CoV-2 Papain-like Protease. Molecules. 2026; 31(3):474. https://doi.org/10.3390/molecules31030474

Chicago/Turabian Style

Wang, Junshuai, Yuancong Xu, Yishu Yang, Botao Zhang, Sixu Chen, Zhaoyang Li, Haojia Zhu, Huai Yang, Hongtao Wang, Yubai Zhou, and et al. 2026. "Structural Basis and Inhibitor Development of SARS-CoV-2 Papain-like Protease" Molecules 31, no. 3: 474. https://doi.org/10.3390/molecules31030474

APA Style

Wang, J., Xu, Y., Yang, Y., Zhang, B., Chen, S., Li, Z., Zhu, H., Yang, H., Wang, H., Zhou, Y., Cao, P., Zhai, B., & Gong, Y. (2026). Structural Basis and Inhibitor Development of SARS-CoV-2 Papain-like Protease. Molecules, 31(3), 474. https://doi.org/10.3390/molecules31030474

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