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

• Published in: Antiviral research Vol. 204; p. 105367
• Main Authors: Karim, Marwah, Saul, Sirle, Ghita, Luca, Sahoo, Malaya Kumar, Ye, Chengjin, Bhalla, Nishank, Lo, Chieh Wen, Jin, Jing, Park, Jun-Gyu, Martinez-Gualda, Belén, East, Michael Patrick, Johnson, Gary L., Pinsky, Benjamin A., Martinez-Sobrido, Luis, Asquith, Christopher R.M., Narayanan, Aarthi, De Jonghe, Steven, Einav, Shirit
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2022
• Subjects: Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; COVID-19 Drug Treatment; Host-targeted antivirals; Humans; Kinase inhibitors; Membrane Proteins; Nerve Tissue Proteins; Numb-associated kinases; Pandemics; Protein Serine-Threonine Kinases; SARS-CoV-2; Transcription Factors; Virus Internalization; Host-targeted antivirals; SARS-CoV-2; Numb-associated kinases; Kinase inhibitors
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2022.105367

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.