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While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro\n                      <jats:italic>,<\/jats:italic>\n                      and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (M\n                      <jats:sup>pro<\/jats:sup>\n                      ) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC\n                      <jats:sub>50<\/jats:sub>\n                      of 13.7\u00a0\u00b5M. None of the inhibitors showed significant inhibition of SARS-CoV-2 M\n                      <jats:sup>pro<\/jats:sup>\n                      in our in vitro enzymatic assays up to 100\u00a0\u00b5M concentration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Targeting of SARS-CoV-2 M\n                      <jats:sup>pro<\/jats:sup>\n                      by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 M\n                      <jats:sup>pro<\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12985-020-01457-0","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T07:03:40Z","timestamp":1606374220000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2\u2032s main protease"],"prefix":"10.1186","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-5996","authenticated-orcid":false,"given":"Mohamed","family":"Mahdi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos Andr\u00e1s","family":"M\u00f3ty\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zs\u00f3fia Ilona","family":"Szojka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1ria","family":"Golda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1ri\u00f3","family":"Miczi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f3zsef","family":"T\u0151zs\u00e9r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,26]]},"reference":[{"issue":"3","key":"1457_CR1","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/d41573-020-00016-0","volume":"19","author":"G Li","year":"2020","unstructured":"Li G, De Clercq E. 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