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Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for therapy
Marwah Karim; Sirle Saul; Luca Ghita; Malaya Kumar Sahoo; Chengjin Ye; Nishank Bhalla; Jing Jin; Jun-Gyu Park; Belen Martinez-Gualda; Michael Patrick East; Gary L. Johnson; Benjamin A. Pinsky; Luis Martinez-Sobrido; Christopher R. M. Asquith; Aarthi Narayanan; Steven De Jonghe; Shirit Einav.
Afiliación
  • Marwah Karim; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA
  • Sirle Saul; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA
  • Luca Ghita; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA
  • Malaya Kumar Sahoo; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
  • Chengjin Ye; Texas Biomedical Research Institute, San Antonio, Texas, USA
  • Nishank Bhalla; National Center for Biodefence and Infectious Disease, Biomedical Research Laboratory, School of Systems Biology, George Mason University, Manassas, VA, USA.
  • Jing Jin; Vitalant Research Institute, San Francisco, CA, USA
  • Jun-Gyu Park; Texas Biomedical Research Institute, San Antonio, Texas, USA
  • Belen Martinez-Gualda; KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Bel
  • Michael Patrick East; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
  • Gary L. Johnson; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA, Lineberger Comprehensive Cancer Center,
  • Benjamin A. Pinsky; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA, Department of Pathology, Stanford University Scho
  • Luis Martinez-Sobrido; Texas Biomedical Research Institute, San Antonio, Texas, USA
  • Christopher R. M. Asquith; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA, School of Pharmacy, University of Easte
  • Aarthi Narayanan; National Center for Biodefence and Infectious Disease, Biomedical Research Laboratory, School of Systems Biology, George Mason University, Manassas, VA, USA.
  • Steven De Jonghe; KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Bel
  • Shirit Einav; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, CA, USA, Department of Microbiology and Immunology, Stanfo
Preprint en En | PREPRINT-BIORXIV | ID: ppbiorxiv-484178
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.
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Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2022 Tipo del documento: Preprint
Texto completo
Añadir a Mi BVS
Imprimir
XML
Buscar en Google
Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2022 Tipo del documento: Preprint