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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
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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 infection Kumar, Wang. 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 also predict better efficacy of CQ with omicron compared to most previous variants.
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.
References
Arshad, Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19, Int. J. Infect. Dis
Bayati, Kumar, Francis, Mcpherson, SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis, J. Biol. Chem
Bleyzac, Goutelle, Bourguignon, Tod, Azithromycin for COVID-19: more than just an antimicrobial?, Clin. Drug Investig
Borba, 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
Cairoli, Rebella, Danese, Garra, Borba, Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect, Lupus
Carstea, Niemann-Pick C1 disease gene: Homology to mediators of cholesterol homeostasis, Science
Cervin, Anderson, Modulation of coronavirus-mediated cell fusion by homeostatic control of cholesterol and fatty acid metabolism, J. Med. Virol
Chang, Liu, Wang, Hung, Chen, Chloroquine for prolonged skin analgesia in rats, Neurosci. Lett
Chen, Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial, doi:10.1101/2020.03.22.20040758
Chojnacki, Eggeling, Super-resolution fluorescence microscopy studies of human immunodeficiency virus, Retrovirology
Cloete, Paediatric hospitalisations due to COVID-19 during the first SARS-CoV-2 omicron (B.1.1.529) variant wave in South Africa: a multicentre observational study, Lancet Child Adolesc. Heal
Cortegiani, Ingoglia, Ippolito, Giarratano, Einav, A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19, J. Crit. Care, doi:10.1016/j.jcrc.2020.03.005
Curthoys, Influenza hemagglutinin modulates phosphatidylinositol 4,5-bisphosphate membrane clustering, Biophys. J
Dicken, Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2. bioRxiv Prepr, Serv. Biol, doi:10.1101/2021.03.22.436468
Ewers, Helenius, Lipid-mediated endocytosis, Cold Spring Harb. Perspect. Biol
Fan, Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating patients with Coronavirus Disease 2019, Clin. Infect. Dis
Fantini, Scala, Di, Chahinian, Yahi, Structural and molecular modeling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.105960
Gautret, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.105949
Gielen, Johnston, Edwards, Azithromycin induces anti-viral responses in bronchial epithelial cells, Eur. Respir. J
Gosztyla, Brothers, Robinson, Alzheimer's amyloid-β is an antimicrobial peptide: a review of the evidence, J. Alzheimer's Dis
Guo, The important role of lipid raft-mediated attachment in the infection of cultured cells by coronavirus infectious bronchitis virus beaudette strain, PLoS ONE
Hammond, Elimination of plasma membrane phosphatidylinositol (4,5)-bisphosphate is required for exocystosis from mast cells, J. Cell Sci
Hansen, Lipid agonism: The PIP2 paradigm of ligand-gated ion channels, Biochim. Biophys. Acta
Hansen, Tao, Mackinnon, Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2, Nature
Hoffmann, Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, Nature
Hoffmann, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Hollmann, Durieux, Fisher, Local anesthetics and the inflammatory response: a new therapeutic indication?, Anesthesiology
Holly, Biernacka, Maskell, Perks, Obesity, diabetes and COVID-19: an infectious disease spreading from the east collides with the consequences of an unhealthy Western Lifestyle, Front. Endocrinol
Hu, Chen, Wu, He, Ye, Low serum cholesterol level among patients with COVID-19 infection in Wenzhou, SSRN Electron. J, doi:10.2139/ssrn.3544826
Kheterpal, Sugammadex versus neostigmine for reversal of neuromuscular blockade and postoperative pulmonary complications (STRONGER), Anesthesiology
Kosicek, Malnar, Goate, Hecimovic, Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts, Biochem. Biophys. Res. Commun
Krogstad, Schlesinger, The basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH, Am. J. Trop. Med. Hyg
Kumar, Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease, Sci. Transl. Med
Kumar, Chawla, Goyal, Topical anesthesia, J. Anaesthesiol. Clin. Pharmacol
Kuo, APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort, Journals Gerontol. Ser. A, doi:10.1093/gerona/glaa131
Kupferschmidt, Big studies dim hopes for hydroxychloroquine, Science
Ledford, Safety fears over drug hyped to treat the coronavirus spark global confusion, Nature
Li, Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus, Nature
Li, Li, Yamate, Li, Ikuta, Lipid rafts play an important role in the early stage of severe acute respiratory syndromecoronavirus life cycle, Microbes Infect
Lingwood, Simons, Lipid rafts as a membrane-organizing principle, Science
Liu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
Luo, Yang, Song, Mechanisms and regulation of cholesterol homeostasis, Nat. Rev. Mol. Cell Biol
Ma, Expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in human primary conjunctival and pterygium cell lines and in mouse cornea, Eye
Maisonnasse, Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates, Nature
Mandel, A new local anesthetic with anticoagulant properties, chloroquine (aralen) dihydrochloride, Arch. Dermatol
Mascio, Alder, Silverman, Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells, Antimicrob. Agents Chemother
Mediouni, Oregano oil and its principal component, carvacrol, inhibit HIV-1 fusion into target cells, J. Virol
Meng, Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity, Nature
Miller, Lenard, Antihistaminics, local anesthetics, and other amines as antiviral agents
Million, Clinical Efficacy of Chloroquine derivatives in COVID-19 Infection: comparative meta-analysis between the Big data and the real world, N. Microbes N. Infect, doi:10.1016/j.nmni.2020.100709
Min, Jang, Macrolide therapy in respiratory viral infections, Mediators Inflamm
Mlodzianoski, Sample drift correction in 3D fluorescence photoactivation localization microscopy, Opt. Express
Moon, Spectrally Resolved, Functional Super-Resolution Microscopy Reveals Nanoscale Compositional Heterogeneity in Live-Cell Membranes, J. Am. Chem. Soc
Moore, Retroviruses pseudotyped with the severe acute respiratory syndrome coronavirus spike protein efficiently infect cells expressing angiotensin-converting enzyme 2, J. Virol
Mou, Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2, PLoS Pathog
Ortiz, Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract, EBioMedicine
Ou, Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, PLoS Pathog
Paruch, El-Benna, Djerdjouri, Marullo, Périanin, A role of p44/42 mitogen-activated protein kinases in formylpeptide receptor-mediated phospholipase D activity and oxidant production, FASEB J
Pavel, Chung, Petersen, Hansen, Polymodal mechanism for TWIK-related K+ channel inhibition by local anesthetic, Anesth. Analg
Pavel, Petersen, Wang, Lerner, Hansen, Studies on the mechanism of general anesthesia, Proc. Natl Acad. Sci
Petersen, Chung, Nayebosadri, Hansen, Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D, Nat. Commun
Petersen, Clowes, Hansen, Measuring anesthetic resistance in Drosophila by VAAPR, doi:10.1101/797209
Petersen, Lipid rafts transduce force to TREK-1 channels via phospholipase D, FASEB J
Petersen, Pavel, Wang, Hansen, Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels, Biochim. Biophys. Acta Biomembr
Quinlan, The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing resonse without antibody-dependent enhancement, doi:10.1101/2020.04.10.036418
Ren, Analysis of ACE2 in polarized epithelial cells: Surface expression and function as receptor for severe acute respiratory syndrome-associated coronavirus, J. Gen. Virol
Robinson, Rohacs, Hansen, Tools for understanding nanoscale lipid regulation of ion channels, Trends Biochem. Sci
Ruiz, Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19, Int. J. Antimicrob. Agents
Schmidt, An ACAT inhibitor regulates SARS-CoV-2 replication and antiviral T cell activity, BioRxiv, doi:10.1101/2022.04.12.487988
Schmidt, Wing, Mckeating, Maini, Cholesterolmodifying drugs in COVID-19, Oxf. Open Immunol
Schögler, Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells, Eur. Respir. J
Sengupta, Lippincott-Schwartz, Revisiting membrane microdomains and phase separation: a viral perspective, Viruses
Sezgin, Levental, Mayor, Eggeling, The mystery of membrane organization: composition, regulation and roles of lipid rafts, Nat. Rev. Mol. Cell Biol
Sieben, Sezgin, Eggeling, Manley, Influenza A viruses use multivalent sialic acid clusters for cell binding and receptor activation, PLoS Pathog
Sohrabi, World Health Organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19), Int. J. Surg
Sullivan, Gluzman, Russell, Goldberg, On the molecular mechanism of chloroquine's antimalarial action, Proc. Natl Acad. Sci
Tall, Yvan-Charvet, Cholesterol, inflammation and innate immunity, Nat. Rev. Immunol
Van Den Bogaart, Membrane protein sequestering by ionic proteinlipid interactions, Nature
Varma, Ocular fluid as a replacement for serum in cell cryopreservation media, PLoS ONE
Wang, Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol, Proc. Natl Acad. Sci
Wang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Wang, Yuan, Pavel, Hansen, The role of high cholesterol in aged related COVID19 lethality, doi:10.1101/2020.05.09.086249
Westerterp, Cholesterol accumulation in dendritic cells links the inflammasome to acquired immunity, Cell Metab
Yang, Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis, Int. J. Infect. Dis
Zhang, Barraza, Beauchamp, Cholesterol provides nonsacrificial protection of membrane lipids from chemical damage at air-water interface, Proc. Natl Acad. Sci
Zhao, SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells, Emerg. Microbes Infect
Zinellu, Cholesterol and triglyceride concentrations, COVID-19 severity, and mortality: a systematic review and meta-analysis with metaregression, Front. Public Heal
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