期刊
JOURNAL OF LIPID RESEARCH
卷 61, 期 7, 页码 972-982出版社
ELSEVIER
DOI: 10.1194/jlr.R120000851
关键词
severe acute respiratory syndrome coronavirus 2; cholesterol; cholesterol trafficking; lysosomal storage disease; Niemann-Pick disease; dyslipidemias; drug repurposing; pandemic; coronavirus disease 2019; Ebola
资金
- Ara Parseghian Medical Research Foundation
- Dana's Angels Research Trust
- Actelion Pharmaceuticals Ltd.
- National Institutes of Health [DK54320, GM1129465]
- Wellington Medical Research Foundation
- National Niemann-Pick Disease Foundation
- Senior Fellow in Biomedical Sciences of the Charles H. Revson Foundation
- National Institutes of Health Postdoctoral Fellow in Arteriosclerosis [T32 HL07343]
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.
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