Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture
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)
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.
Contact:
shansen@scripps.edu.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: ARTICLE
https://doi.org/10.1038/s42003-022-03841-8
OPEN
Hydroxychloroquine blocks SARS-CoV-2 entry into
the endocytic pathway in mammalian cell culture
1234567890():,;
Zixuan Yuan 1,2,3,7, Mahmud Arif Pavel1,2,7, Hao Wang1,2,3, Jerome C. Kwachukwu 4, Sonia Mediouni5,
Joseph Anthony Jablonski5, Kendall W. Nettles 4, Chakravarthy B. Reddy6, Susana T. Valente5 &
Scott B. Hansen 1,2 ✉
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 (PIP2) 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 PIP2 clusters. In elevated (high)
cholesterol, HCQ moves ACE2 nanoscopic distances away from endocytic lipids. In cells with
resting (low) cholesterol, ACE2 primarily associates with PIP2 clusters, and HCQ moves
ACE2 away from PIP2 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.
1 Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA. 2 Department of Neuroscience, The Scripps Research Institute,
Jupiter, FL 33458, USA. 3 Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL 33458, USA. 4 Department
of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL 33458, USA. 5 Department of Immunology and Microbiology,
The Scripps Research Institute, Jupiter, FL 33458, USA. 6 Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT
84112, USA. 7These authors contributed equally: Zixuan Yuan, Mahmud Arif Pavel. ✉email: shansen@scripps.edu
COMMUNICATIONS BIOLOGY | (2022)5:958 | https://doi.org/10.1038/s42003-022-03841-8 | www.nature.com/commsbio
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ARTICLE
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COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-022-03841-8
oronavirus disease 2019 (COVID-19), a viral infection
caused by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), recently emerged as a serious public
health problem1,2. Currently, millions of people have been
infected with SARS-CoV-2 worldwide. Proposed treatments for
severe symptoms include a well-known FDA-approved antimalarial and anti-inflammatory agents chloroquine (CQ) and its
derivative hydroxychloroquine (HCQ)3–7, but their mechanisms
of action are poorly understood in human cells (and in particular
in the presence of underlying conditions). A retrospective study
claimed a benefit in particular with the macrolide antibiotic
azithromycin8. However, their use is not without controversy9,10,
and randomized control studies without an antibiotic appeared to
have no..
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physician who can provide personalized advice and details of risks and
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