8XTD

SARS-CoV-2 papain-like-protease (PLpro) in complex with inhibitor Linagliptin

Summary for 8XTD

• Entry DOI: 10.2210/pdb8xtd/pdb
• Related: 8X1X
• Descriptor: Non-structural protein 3, 8-[(3R)-3-Aminopiperidin-1-yl]-7-but-2-yn-1-yl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-d ione, GLYCEROL, ... (4 entities in total)
• Functional Keywords: sars-cov-2, plpro, linagliptin, nsp3, complex, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 36680.54

Authors

Choudhary, S.,Verma, S.,Kumar, P.,Tomar, S. (deposition date: 2024-01-10, release date: 2025-07-16, Last modification date: 2026-01-28)

Primary citation

Choudhary, S.,Nehul, S.,Nagaraj, S.K.,Narayan, R.,Verma, S.,Sharma, S.,Kumari, A.,Rani, R.,Saha, A.,Sircar, D.,Kaliappan, A.,Tripathi, S.,Sharma, G.K.,Kumar, P.,Tomar, S.
Deubiquitinase inhibitors: Targeting SARS-CoV-2 papain-like protease with antiviral efficacy in a murine model.
Febs J., 2026

PubMed Abstract: SARS-CoV-2 papain-like protease (PLpro) is a key antiviral target as it plays a dual role in viral replication and modulation of innate immune responses by deubiquitinating or deISGylating host proteins. Therefore, therapeutically targeting PLpro may serve as a two-pronged approach to mitigate SARS-CoV-2 infection. Interestingly, PLpro shares structural and functional similarities with cellular deubiquitinating enzymes (DUBs), and this fact was leveraged in our study to identify DUB inhibitors that target the ubiquitin/ISG15-binding site and the known substrate-binding pocket of PLpro. Among the identified compounds, flupenthixol, lithocholic acid, teneligliptin, and linagliptin markedly inhibited the proteolytic activity of purified PLpro and demonstrated potent antiviral effects against SARS-CoV-2 infection in a dose-dependent manner. Treatment with lithocholic acid and linagliptin suppressed the expression of inflammatory mediators, thereby restoring immune responses. Here, crystal structures of SARS-CoV-2 PLpro in complex with linagliptin and with lithocholic acid were determined, revealing insights into the mechanism of inhibition and unique interactions within the ubiquitin/ISG15-binding site (S2 site; Phe69, His73, Asn128, and His175) and the substrate-binding cleft. Additionally, oral and intraperitoneal treatments with linagliptin increased survival, reduced lung viral load, and ameliorated histopathological damage in a mouse-adapted model of SARS-CoV-2 infection. This study demonstrates for the first time that using DUB inhibitors that target the proteolytic activity of PLpro can simultaneously reinstate the host's immune response against SARS-CoV-2, highlighting the potential of this two-pronged therapeutic approach.

PubMed: 41527419
DOI: 10.1111/febs.70399

Experimental method

X-RAY DIFFRACTION (2.7 Å)