tetano
Editor, Senior Moderator
J Lipid Res
. 2020 May 26;jlr.R120000851.
doi: 10.1194/jlr.R120000851. Online ahead of print.
Potential COVID-19 Therapeutics From a Rare Disease: Weaponizing Lipid Dysregulation to Combat Viral Infectivity
Stephen Sturley[SUP] 1 [/SUP], Tamayanthi Rajakumar[SUP] 2 [/SUP], Natalie Hammond[SUP] 2 [/SUP], Katsumi Higaki[SUP] 3 [/SUP], Zsuzsa M?rka[SUP] 4 [/SUP], Szabolcs M?rka[SUP] 4 [/SUP], Andrew Munkacsi[SUP] 5 [/SUP]
Affiliations
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (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 (ACE2) 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, as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests 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 pre-clinical 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.
Keywords: Cholesterol; Cholesterol/Trafficking; Dyslipidemias; LDL/Metabolism; Lipase/Lysosomal; Niemann-Pick disease; SARS-CoV-2; Storage diseases; coronavirus; drug repurposing; lysosomal storage disease; pandemic.
. 2020 May 26;jlr.R120000851.
doi: 10.1194/jlr.R120000851. Online ahead of print.
Potential COVID-19 Therapeutics From a Rare Disease: Weaponizing Lipid Dysregulation to Combat Viral Infectivity
Stephen Sturley[SUP] 1 [/SUP], Tamayanthi Rajakumar[SUP] 2 [/SUP], Natalie Hammond[SUP] 2 [/SUP], Katsumi Higaki[SUP] 3 [/SUP], Zsuzsa M?rka[SUP] 4 [/SUP], Szabolcs M?rka[SUP] 4 [/SUP], Andrew Munkacsi[SUP] 5 [/SUP]
Affiliations
- PMID: 32457038
- DOI: 10.1194/jlr.R120000851
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (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 (ACE2) 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, as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests 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 pre-clinical 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.
Keywords: Cholesterol; Cholesterol/Trafficking; Dyslipidemias; LDL/Metabolism; Lipase/Lysosomal; Niemann-Pick disease; SARS-CoV-2; Storage diseases; coronavirus; drug repurposing; lysosomal storage disease; pandemic.