Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity

Abstract

<jats:p>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.</jats:p>

The S1/S2 boundary of SARS-CoV-2 spike protein modulates cell entry pathways and transmission

“…However, unlike our results with the Sdel virus, editing of NPC1 or NPC2 had a negligible impact on Sfull virus infection, raising question of the effectiveness of perturbing cholesterol trafficking with inhibitors such as U18666A in COVID-19 as previously proposed (Ballout et al, 2020;Sturley et al, 2020).…”

Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19

“…By binding to this NSP machinery, CEP blocks the ability of SARS-CoV-2 to replicate and produce relevant proteins. The inhibition of the Niemann-Pick type C disease-causing gene (NPC1) is another mechanism through which CEP has been shown to impair the infectivity of SARS-CoV-2 and subsequent replication [38]. As a NPC1 inhibitor, CEP causes disruption of cellular/lysosomal lipid homeostasis and potentially inhibits the entry, replication, and exit of SARS-CoV-2 [38,39].…”

Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

“…NPC1 has been implicated in the infectivity of Ebola virus, MERS-CoV and SARS-CoV following late entry kinetics and access to cathepsin L in late endosomes and lysosomes ( Shah et al, 2010 ; Mingo et al, 2015 ; Zhou et al, 2016 ; Zheng et al, 2018 ; Ballout et al, 2020 ; ). Because SARS-CoV-2 also uses similar cell entry and cleavage mechanisms, NPC1 might become a target against SARS-CoV-2 infection; the desired effect being endolysosome de-acidification and accumulation of lipids in endolysosomes ( Zheng et al, 2018 ; Wheeler et al, 2019a ; Ballout et al, 2020 ; Pranesh et al, 2020 ; Sturley et al, 2020 ). Indeed, increased levels of 25-hydroxycholesterol (25-HC) restricted viral infection of Filoviruses ( Liu et al, 2013 ), Coronaviridae ( ZhangY.…”