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.
Marwah Karim  1 ,  Sirle Saul  1 ,  Luca Ghita  1 ,  Malaya Kumar Sahoo  2 ,  Chengjin Ye  3 ,  Nishank Bhalla  4 ,  Chieh-Wen Lo  1 ,  Jing Jin  5 ,  Jun-Gyu Park  3 ,  Belén Martinez-Gualda  6 ,  Michael Patrick East  7 ,  Gary L Johnson  8 ,  Benjamin A Pinsky  9 ,  Luis Martinez-Sobrido  3 ,  Christopher R M Asquith  10 ,  Aarthi Narayanan  4 ,  Steven De Jonghe  6 ,  Shirit Einav  11
Affiliations
  • 1. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA.
  • 2. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3. Texas Biomedical Research Institute, San Antonio, TX, USA.
  • 4. National Center for Biodefence and Infectious Disease, Biomedical Research Laboratory, School of Systems Biology, George Mason University, Manassas, VA, USA.
  • 5. Vitalant Research Institute, San Francisco, CA, USA.
  • 6. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
  • 7. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 8. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 9. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 10. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland.
  • 11. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA; Department of Microbiology and Immunology, Stanford University, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA. Electronic address: [email protected].
PMID: 35738348 DOI: 10.1016/j.antiviral.2022.105367
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.
Products