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

J Lipid Res. 2020 Jul;61(7):972-982. doi: 10.1194/jlr.R120000851. Epub 2020 May 26.


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.

Keywords: Ebola; Niemann-Pick disease; cholesterol; cholesterol trafficking; coronavirus disease 2019; drug repurposing; dyslipidemias; lysosomal storage disease; pandemic; severe acute respiratory syndrome coronavirus 2.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Androstenes / therapeutic use
  • Angiotensin-Converting Enzyme 2
  • Anticholesteremic Agents / therapeutic use*
  • Antiviral Agents / therapeutic use*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / metabolism
  • Betacoronavirus / pathogenicity
  • COVID-19
  • Cholesterol / metabolism
  • Coronavirus Infections / diagnosis
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / epidemiology
  • Drug Repositioning / methods
  • Humans
  • Hydroxychloroquine / therapeutic use
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Lysosomes / virology
  • Niemann-Pick C1 Protein
  • Niemann-Pick Disease, Type C / drug therapy*
  • Niemann-Pick Disease, Type C / genetics
  • Niemann-Pick Disease, Type C / metabolism
  • Niemann-Pick Disease, Type C / pathology
  • Pandemics*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / diagnosis
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / epidemiology
  • Protein Binding
  • Receptors, Virus / antagonists & inhibitors
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism


  • Androstenes
  • Anticholesteremic Agents
  • Antiviral Agents
  • Intracellular Signaling Peptides and Proteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one
  • Hydroxychloroquine
  • Cholesterol
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2