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Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host\u2019s innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.<\/jats:p>","DOI":"10.1038\/s42003-022-03737-7","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T07:06:45Z","timestamp":1660201605000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8895-5885","authenticated-orcid":false,"given":"Vasundara","family":"Srinivasan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9vila","family":"Brognaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prince R.","family":"Prabhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmarcia Elisa","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7329-6653","authenticated-orcid":false,"given":"Sebastian","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick Y. 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