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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 (In Vitro)
Yuan et al., Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, Communications Biology, doi:10.1038/s42003-022-03841-8 (In Vitro)
Sep 2022   Source   PDF  
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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.
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.
14 In Vitro studies support the efficacy of HCQ [Andreani, Clementi, Dang, Delandre, Faísca, Hoffmann, Liu, Ou, Purwati, Sheaff, Wang, Wang (B), Yao, Yuan].
Yuan et al., 14 Sep 2022, peer-reviewed, 10 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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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 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 Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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