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Therefore, therapeutically targeting PLpro may serve as a two\u2010pronged approach to mitigate SARS\u2010CoV\u20102 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\u2010binding site and the known substrate\u2010binding 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\u2010CoV\u20102 infection in a dose\u2010dependent manner. Treatment with lithocholic acid and linagliptin suppressed the expression of inflammatory mediators, thereby restoring immune responses. Here, crystal structures of SARS\u2010CoV\u20102 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\u2010binding site (S2 site; Phe69, His73, Asn128, and His175) and the substrate\u2010binding cleft. Additionally, oral and intraperitoneal treatments with linagliptin increased survival, reduced lung viral load, and ameliorated histopathological damage in a mouse\u2010adapted model of SARS\u2010CoV\u20102 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\u2010CoV\u20102, highlighting the potential of this two\u2010pronged therapeutic approach.<\/jats:p>","DOI":"10.1111\/febs.70399","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:27:53Z","timestamp":1768292873000},"page":"2969-2998","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Deubiquitinase inhibitors: Targeting\n                    <scp>SARS<\/scp>\n                    \u2010\n                    <scp>CoV<\/scp>\n                    \u20102 papain\u2010like protease with antiviral efficacy in a murine model"],"prefix":"10.1111","volume":"293","author":[{"given":"Shweta","family":"Choudhary","sequence":"first","affiliation":[{"name":"Department of Biosciences and Bioengineering Indian 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