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

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

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: seinav@stanford.edu.
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.

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