Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies

Antiviral Res. 2022 Aug;204:105367. doi: 10.1016/j.antiviral.2022.105367. Epub 2022 Jun 20.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose serious threats to global health. We previously reported that AAK1, BIKE and GAK, members of the Numb-associated kinase family, control intracellular trafficking of multiple RNA viruses during viral entry and assembly/egress. Here, using both genetic and pharmacological approaches, we probe the functional relevance of NAKs for SARS-CoV-2 infection. siRNA-mediated depletion of AAK1, BIKE, GAK, and STK16, the fourth member of the NAK family, suppressed SARS-CoV-2 infection in human lung epithelial cells. Both known and novel small molecules with potent AAK1/BIKE, GAK or STK16 activity suppressed SARS-CoV-2 infection. Moreover, combination treatment with the approved anti-cancer drugs, sunitinib and erlotinib, with potent anti-AAK1/BIKE and GAK activity, respectively, demonstrated synergistic effect against SARS-CoV-2 infection in vitro. Time-of-addition experiments revealed that pharmacological inhibition of AAK1 and BIKE suppressed viral entry as well as late stages of the SARS-CoV-2 life cycle. Lastly, suppression of NAKs expression by siRNAs inhibited entry of both wild type and SARS-CoV-2 pseudovirus. These findings provide insight into the roles of NAKs in SARS-CoV-2 infection and establish a proof-of-principle that pharmacological inhibition of NAKs can be potentially used as a host-targeted approach to treat SARS-CoV-2 with potential implications to other coronaviruses.

Keywords: Host-targeted antivirals; Kinase inhibitors; Numb-associated kinases; SARS-CoV-2.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • COVID-19* / drug therapy
  • Humans
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Pandemics
  • Protein Serine-Threonine Kinases
  • SARS-CoV-2
  • Transcription Factors
  • Virus Internalization

Substances

  • Antiviral Agents
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Numb protein, human
  • Transcription Factors
  • Protein Serine-Threonine Kinases
  • STK16 protein, human