Inhibition of hostN-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress from lysosomes and endoplasmic reticulum

Abstract

Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Despite vaccinations, the development and use of neutralizing antibodies against the viral surface spike proteins, and small molecule inhibitors targeting the viral replication machinery, COVID-19 remains a global public health crisis. Emerging mutations in the viral genome have the potential to reduce prophylactic and therapeutic efficacy of virus-directed treatments. Targeting host cell factors required for infection could, therefore, be a potential strategy to overcome this problem since mutations in the viral genome are unlikely to bypass the requirement for the targeted host factor or function. The enzymatic activity of N-myristoyltransferases (NMTs) are essential to mediate stable membrane binding and function of a diverse class of cellular proteins, many of which regulate intracellular membrane trafficking. Here we report that nanomolar concentrations of the NMT inhibitor IMP-1088 inhibited SARS-CoV-2 spreading in human cells by compromising the infectivity of released viral particles, which was reduced by up to 90%. IMP-1088 also inhibited human Respiratory syncytial virus, the main cause of viral death in infants world-wide, but not the mosquito-delivered alphavirus Semliki Forest virus and the vesiculovirus Vesicular stomatitis virus. The antiviral effect of IMP-1088 against SARS-CoV-2 displayed remarkably slow reversibility, was well tolerated by cells, and is, therefore, a promising candidate for COVID-19 prophylaxis and therapy.

Saturated fatty acid-Coenzyme A supplementation restores neuronal energy levels, synaptic function, and protein homeostasis in hereditary spastic paraplegia

“…Human small lung carcinoma A549-AT cells were cultured as described previously 56 . The cells were maintained in Dulbecco’s Modified Eagle’s High Glucose Medium (DMEM, Merck, cat.…”