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

Yuan et al., Communications Biology, doi:10.1038/s42003-022-03841-8
Sep 2022  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
 
*, now with p < 0.00000000001 from 411 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19hcq.org
In Vitro study showing that HCQ blocks SARS-CoV-2 entry into the endocytic pathway, and that HCQ was more effective with higher cholesterol.
High cholesterol drives ACE2 association with rafts/endosomes, enabling more efficient SARS-CoV-2 infection1,2. HCQ blocks this by separating ACE2 receptors from lipid rafts and clusters, showing greater efficacy for higher cholesterol levels.
Authors also obtained lung samples from adults with chronic obstructive pulmonary disease, finding that lung tissue had significantly higher free-cholesterol levels compared to cultured lung cell lines; and noting that animal and cultured-cell experiments in low cholesterol likely fail to capture the full benefits of HCQ.
Authors note that omicron has been shown to enter primarily through the endocytic pathway. Delandre et al. also predict better efficacy of CQ with omicron compared to most previous variants.
34 preclinical studies support the efficacy of HCQ for COVID-19:
Yuan et al., 14 Sep 2022, peer-reviewed, 10 authors. Contact: shansen@scripps.edu.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperHCQAll
Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture
Zixuan Yuan, Mahmud Arif Pavel, Hao Wang, Jerome C Kwachukwu, Sonia Mediouni, Joseph Anthony Jablonski, Kendall W Nettles, Chakravarthy B Reddy, Susana T Valente, Scott B Hansen
Communications Biology, doi:10.1038/s42003-022-03841-8
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 2 ) 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 2 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 2 clusters, and HCQ moves ACE2 away from PIP 2 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.
Author contributions Competing interests The authors declare no competing interests. Additional information Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s42003-022-03841-8. Correspondence and requests for materials should be addressed to Scott B. Hansen. Peer review information Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editors: Manuel Breuer. Reprints and permission information is available at http://www.nature.com/reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Dis.'}, { 'key': '3841_CR70', 'doi-asserted-by': 'publisher', 'first-page': '588', 'DOI': '10.1038/s41586-020-2575-3', 'volume': '585', 'author': 'M Hoffmann', 'year': '2020', 'unstructured': 'Hoffmann, M. et al. Chloroquine does not inhibit infection of human lung ' 'cells with SARS-CoV-2. Nature 585, 588–590 (2020).', 'journal-title': 'Nature'}, { 'key': '3841_CR71', 'doi-asserted-by': 'publisher', 'first-page': '584', 'DOI': '10.1038/s41586-020-2558-4', 'volume': '585', 'author': 'P Maisonnasse', 'year': '2020', 'unstructured': 'Maisonnasse, P. et al. Hydroxychloroquine use against SARS-CoV-2 ' 'infection in non-human primates. Nature 585, 584–587 (2020).', 'journal-title': 'Nature'}, { 'key': '3841_CR72', 'doi-asserted-by': 'publisher', 'first-page': '277', 'DOI': '10.1080/22221751.2021.2023329', 'volume': '11', 'author': 'H Zhao', 'year': '2022', 'unstructured': 'Zhao, H. et al. 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Heal'}, { 'key': '3841_CR75', 'doi-asserted-by': 'publisher', 'first-page': '495', 'DOI': '10.1038/nature10370', 'volume': '477', 'author': 'SB Hansen', 'year': '2011', 'unstructured': 'Hansen, S. B., Tao, X. & MacKinnon, R. Structural basis of PIP2 ' 'activation of the classical inward rectifier K+ channel Kir2.2. Nature ' '477, 495–498 (2011).', 'journal-title': 'Nature'}, { 'key': '3841_CR76', 'doi-asserted-by': 'publisher', 'author': 'NM Schmidt', 'year': '2022', 'unstructured': 'Schmidt, N. M. et al. An ACAT inhibitor regulates SARS-CoV-2 replication ' 'and antiviral T cell activity. BioRxiv ' 'https://doi.org/10.1101/2022.04.12.487988 (2022).', 'journal-title': 'BioRxiv', 'DOI': '10.1101/2022.04.12.487988'}, { 'key': '3841_CR77', 'doi-asserted-by': 'publisher', 'unstructured': 'Fantini, J., Scala, C. Di, Chahinian, H. & Yahi, N. Structural and ' 'molecular modeling studies reveal a new mechanism of action of ' 'chloroquine and hydroxychloroquine against SARS-CoV-2 infection. 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Effect of high vs low doses of chloroquine ' 'diphosphate as adjunctive therapy for patients hospitalized with Severe ' 'Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection: a ' 'randomized clinical trial. JAMA Netw. open 3, e208857 (2020).', 'journal-title': 'JAMA Netw. open'}, { 'key': '3841_CR80', 'doi-asserted-by': 'publisher', 'first-page': '1371', 'DOI': '10.1097/ALN.0000000000003256', 'volume': '132', 'author': 'S Kheterpal', 'year': '2020', 'unstructured': 'Kheterpal, S. et al. Sugammadex versus neostigmine for reversal of ' 'neuromuscular blockade and postoperative pulmonary complications ' '(STRONGER). Anesthesiology 132, 1371–1381 (2020).', 'journal-title': 'Anesthesiology'}, { 'key': '3841_CR81', 'doi-asserted-by': 'publisher', 'first-page': '404', 'DOI': '10.1016/j.bbrc.2010.02.007', 'volume': '393', 'author': 'M Kosicek', 'year': '2010', 'unstructured': 'Kosicek, M., Malnar, M., Goate, A. & Hecimovic, S. Cholesterol ' 'accumulation in Niemann Pick type C (NPC) model cells causes a shift in ' 'APP localization to lipid rafts. Biochem. Biophys. Res. Commun. 393, ' '404–409 (2010).', 'journal-title': 'Biochem. Biophys. Res. Commun.'}, { 'key': '3841_CR82', 'doi-asserted-by': 'crossref', 'unstructured': 'Moon, S. et al. Spectrally Resolved, Functional Super-Resolution ' 'Microscopy Reveals Nanoscale Compositional Heterogeneity in Live-Cell ' 'Membranes. J. Am. Chem. Soc. 139, 10944–10947 (2017).', 'DOI': '10.1021/jacs.7b03846'}, { 'key': '3841_CR83', 'doi-asserted-by': 'publisher', 'first-page': '1', 'DOI': '10.1371/journal.ppat.1009501', 'volume': '17', 'author': 'H Mou', 'year': '2021', 'unstructured': 'Mou, H. et al. Mutations derived from horseshoe bat ACE2 orthologs ' 'enhance ACE2-Fc neutralization of SARS-CoV-2. PLoS Pathog. 17, 1–17 ' '(2021).', 'journal-title': 'PLoS Pathog.'}, { 'key': '3841_CR84', 'doi-asserted-by': 'publisher', 'first-page': '15009', 'DOI': '10.1364/OE.19.015009', 'volume': '19', 'author': 'MJ Mlodzianoski', 'year': '2011', 'unstructured': 'Mlodzianoski, M. J. et al. Sample drift correction in 3D fluorescence ' 'photoactivation localization microscopy. Opt. Express 19, 15009–15019 ' '(2011).', 'journal-title': 'Opt. Express'}, { 'key': '3841_CR85', 'doi-asserted-by': 'publisher', 'first-page': '1212', 'DOI': '10.1038/s41433-020-0939-4', 'volume': '34', 'author': 'D Ma', 'year': '2020', 'unstructured': 'Ma, D. et al. Expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in ' 'human primary conjunctival and pterygium cell lines and in mouse cornea. ' 'Eye 34, 1212–1219 (2020).', 'journal-title': 'Eye'}, { 'key': '3841_CR86', 'doi-asserted-by': 'publisher', 'first-page': '142', 'DOI': '10.1096/fj.05-3881fje', 'volume': '20', 'author': 'S Paruch', 'year': '2006', 'unstructured': 'Paruch, S., El‐Benna, J., Djerdjouri, B., Marullo, S. & Périanin, A. A ' 'role of p44/42 mitogen‐activated protein kinases in formylpeptide ' 'receptor‐mediated phospholipase D activity and oxidant production. FASEB ' 'J. 20, 142–144 (2006).', 'journal-title': 'FASEB J.'}, { 'key': '3841_CR87', 'doi-asserted-by': 'crossref', 'unstructured': 'Hammond, G. R. V. et al. Elimination of plasma membrane ' 'phosphatidylinositol (4,5)-bisphosphate is required for exocystosis from ' 'mast cells. J. Cell Sci. 119, 2084–2094 (2006).', 'DOI': '10.1242/jcs.02912'}], 'container-title': 'Communications Biology', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s42003-022-03841-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s42003-022-03841-8', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s42003-022-03841-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 9, 15]], 'date-time': '2022-09-15T09:34:34Z', 'timestamp': 1663234474000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s42003-022-03841-8'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 9, 14]]}, 'references-count': 87, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2022, 12]]}}, 'alternative-id': ['3841'], 'URL': 'http://dx.doi.org/10.1038/s42003-022-03841-8', 'relation': {}, 'ISSN': ['2399-3642'], 'subject': [ 'General Agricultural and Biological Sciences', 'General Biochemistry, Genetics and Molecular Biology', 'Medicine (miscellaneous)'], 'container-title-short': 'Commun Biol', 'published': {'date-parts': [[2022, 9, 14]]}, 'assertion': [ { 'value': '8 November 2021', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '12 August 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '14 September 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'The authors declare no competing interests.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '958'}
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