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

Autor: Yuan Z; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA.; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, 33458, USA., Pavel MA; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA., Wang H; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA.; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, 33458, USA., Kwachukwu JC; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA., Mediouni S; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, 33458, USA., Jablonski JA; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, 33458, USA., Nettles KW; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA., Reddy CB; Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, 84112, USA., Valente ST; Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, 33458, USA., Hansen SB; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA. shansen@scripps.edu.; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA. shansen@scripps.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2022 Sep 14; Vol. 5 (1), pp. 958. Date of Electronic Publication: 2022 Sep 14.
DOI: 10.1038/s42003-022-03841-8
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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