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

摘要

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acuterespiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of morethan 328,000 persons worldwide in the first 5 months of 2020. Herculean effortsto rapidly design and produce vaccines and other antiviral interventions areongoing. However, newly evolving viral mutations, the prospect of only temporaryimmunity, and a long path to regulatory approval pose significant challenges andcall for a common, readily available, and inexpensive treatment. Strategic drugrepurposing combined with rapid testing of established molecular targets couldprovide a pause in disease progression. SARS-CoV-2 shares extensive structuraland functional conservation with SARS-CoV-1, including engagement of the samehost cell receptor (angiotensin-converting enzyme 2) localized incholesterol-rich microdomains. These lipid-enveloped viruses encounter theendosomal/lysosomal host compartment in a critical step of infection andmaturation. Niemann-Pick type C (NP-C) disease is a rare monogenicneurodegenerative disease caused by deficient efflux of lipids from the lateendosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been stronglyassociated with viral infection, both as a filovirus receptor (e.g., Ebola) andthrough LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-Cdisease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there aresuch clinically approved molecules that elicit antiviral activity in preclinicalstudies, without causing NP-C disease. Inhibition of NPC1 may impair viralSARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb themicroenvironment optimum for viral infectivity. We suggest that knownmechanistic information on NPC1 could be utilized to identify existing andfuture drugs to treat COVID-19.