{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:08:51Z","timestamp":1792789731099,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009212","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Hydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike (S) proteins, thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein is ablated or when it is introduced into the SARS-CoV-1 S protein. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited\n                    <jats:italic>in vivo<\/jats:italic>\n                    utility of hydroxychloroquine as a treatment for COVID-19.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009212","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T13:44:20Z","timestamp":1611063860000},"page":"e1009212","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":204,"title":["Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by 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glycoprotein structures inform on virus evolution and furin-cleavage effects.","volume":"2020","author":"AG Wrobel","journal-title":"Nature Structural & Molecular Biology"},{"issue":"20","key":"ppat.1009212.ref041","doi-asserted-by":"crossref","first-page":"11429","DOI":"10.1128\/JVI.78.20.11429-11433.2004","article-title":"Efficient replication of severe acute respiratory syndrome coronavirus in mouse cells is limited by murine angiotensin-converting enzyme 2","volume":"78","author":"W Li","year":"2004","journal-title":"Journal of virology"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1009212","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000}}],"container-title":["PLOS 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