Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture

{ 'indexed': {'date-parts': [[2022, 9, 16]], 'date-time': '2022-09-16T06:23:53Z', 'timestamp': 1663309433452}, 'reference-count': 87, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2022, 9, 14]], 'date-time': '2022-09-14T00:00:00Z', 'timestamp': 1663113600000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2022, 9, 14]], 'date-time': '2022-09-14T00:00:00Z', 'timestamp': 1663113600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [ { 'DOI': '10.13039/100000065', 'name': 'U.S. Department of Health & Human Services | NIH | National Institute of ' 'Neurological Disorders and Stroke', 'doi-asserted-by': 'publisher', 'award': ['R01NS112534']}, { 'DOI': '10.13039/100000005', 'name': 'U.S. Department of Defense', 'doi-asserted-by': 'publisher', 'award': ['W81XWH1810782']}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:p>Hydroxychloroquine (HCQ), a drug used to treat lupus ' 'and malaria, was proposed as a treatment for SARS-coronavirus-2 (SARS-CoV-2) infection, ' 'albeit with controversy. In vitro, HCQ effectively inhibits viral entry, but its use in the ' 'clinic has been hampered by conflicting results. A better understanding of HCQ’s mechanism of ' 'actions in vitro is needed. Recently, anesthetics were shown to disrupt ordered clusters of ' 'monosialotetrahexosylganglioside1 (GM1) lipid. These same lipid clusters recruit the ' 'SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to endocytic lipids, away ' 'from phosphatidylinositol 4,5 bisphosphate (PIP<jats:sub>2</jats:sub>) clusters. Here we ' 'employed super-resolution imaging of cultured mammalian cells (VeroE6, A549, H1793, and ' 'HEK293T) to show HCQ directly perturbs clustering of ACE2 receptor with both endocytic lipids ' 'and PIP<jats:sub>2</jats:sub> clusters. In elevated (high) cholesterol, HCQ moves ACE2 ' 'nanoscopic distances away from endocytic lipids. In cells with resting (low) cholesterol, ' 'ACE2 primarily associates with PIP<jats:sub>2</jats:sub> clusters, and HCQ moves ACE2 away ' 'from PIP<jats:sub>2</jats:sub> clusters—erythromycin has a similar effect. We conclude HCQ ' 'inhibits viral entry through two distinct mechanisms in high and low tissue cholesterol and ' 'does so prior to inhibiting cathepsin-L. HCQ clinical trials and animal studies will need to ' 'account for tissue cholesterol levels when evaluating dosing and efficacy.</jats:p>', 'DOI': '10.1038/s42003-022-03841-8', 'type': 'journal-article', 'created': {'date-parts': [[2022, 9, 15]], 'date-time': '2022-09-15T09:29:55Z', 'timestamp': 1663234195000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture', 'prefix': '10.1038', 'volume': '5', 'author': [ { 'ORCID': 'http://orcid.org/0000-0003-0665-5086', 'authenticated-orcid': False, 'given': 'Zixuan', 'family': 'Yuan', 'sequence': 'first', 'affiliation': []}, {'given': 'Mahmud Arif', 'family': 'Pavel', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hao', 'family': 'Wang', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-4313-9187', 'authenticated-orcid': False, 'given': 'Jerome C.', 'family': 'Kwachukwu', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sonia', 'family': 'Mediouni', 'sequence': 'additional', 'affiliation': []}, {'given': 'Joseph Anthony', 'family': 'Jablonski', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-2917-7574', 'authenticated-orcid': False, 'given': 'Kendall W.', 'family': 'Nettles', 'sequence': 'additional', 'affiliation': []}, {'given': 'Chakravarthy B.', 'family': 'Reddy', 'sequence': 'additional', 'affiliation': []}, {'given': 'Susana T.', 'family': 'Valente', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-0086-9753', 'authenticated-orcid': False, 'given': 'Scott B.', 'family': 'Hansen', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2022, 9, 14]]}, 'reference': [ { 'key': '3841_CR1', 'doi-asserted-by': 'publisher', 'first-page': '71', 'DOI': '10.1016/j.ijsu.2020.02.034', 'volume': '76', 'author': 'C Sohrabi', 'year': '2020', 'unstructured': 'Sohrabi, C. et al. 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