Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies
Karim, M. et al. (2022) Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies. Antiviral Res. 204, 105367. DOI: 10.1016/j.antiviral.2022.105367
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus that continues to infect humans globally, causing coronavirus disease 2019 (COVID-19) in the population. Members of the Numb-associated kinase (NAK) family have been reported to control cellular trafficking, both during entry as well as assembly and egress, of several RNA viruses. Earlier research showed NAK activity was inhibited by known or novel small molecules, suggesting targeting this family of serine/threonine kinases could be a useful antiviral target.
This study investigated if NAK family members adaptor-associated kinase 1 (AAK1), BMP-2 inducible kinase (BIKE/BMP2K), cyclin G-associated kinase (GAK) and serine/threonine kinase 16 (STK16) could play a role in SARS-CoV-2 infection and be potential antiviral candidates. Using a human lung epithelial cell line, all four NAKs were depleted from the cells, reducing both SARS-CoV-2 infection by 89–96%, depending on the NAK target, and viral titer. When known NAK inhibitors were applied to cells prior to SARS-CoV-2 infection, the results showed various levels of viral suppression. Combining two compounds that targeted three different NAKs (BIKE, AAK1 and GAK) increased the SARS-CoV-2 inhibition, suggesting that NAKs are a viable antiviral target. Other novel compounds that target NAKs and had previously demonstrated activity against other viruses were also effective at reducing SARS-CoV-2 infection.
To examine when NAK inhibitors are effective antivirals, the potent AAK1/BIKE inhibitor RMC-76 treated cells various times after infection and the effects assessed at various intervals up to 10 hours, which is one cycle of SARS-CoV-2 infection. This experiment revealed RMC-76 inhibited SARS-CoV-2 both in the early viral entry stage and the later viral assemble/exit stage. Finally, each individual NAK was depleted from cells before wild-type SARS-CoV-2 infected the cells, resulting in intracellular viral RNA reduced by 70–93%. The researchers state that their experiments not only show NAKs play a role in SARS-CoV-2 infection but are also antiviral treatment candidates.
Keywords: host-targeted antivirals, kinase inhibitors, Numb-associated kinases, SARS-CoV-2
