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A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells.
Du, Li; Deiter, Fred; Bouzidi, Mohamed S; Billaud, Jean-Noël; Simmons, Graham; Dabral, Prerna; Selvarajah, Suganya; Lingappa, Anuradha F; Michon, Maya; Yu, Shao Feng; Paulvannan, Kumar; Manicassamy, Balaji; Lingappa, Vishwanath R; Boushey, Homer; Greenland, John R; Pillai, Satish K.
Afiliación
  • Du L; Vitalant Research Institute, 360 Spear St., San Francisco, CA, 94105, USA.
  • Deiter F; University of California, San Francisco, CA, 94143, USA.
  • Bouzidi MS; University of California, San Francisco, CA, 94143, USA.
  • Billaud JN; Veterans Administration Health Care System, 4150 Clement St., San Francisco, CA, 94121, USA.
  • Simmons G; Vitalant Research Institute, 360 Spear St., San Francisco, CA, 94105, USA.
  • Dabral P; University of California, San Francisco, CA, 94143, USA.
  • Selvarajah S; DNAnexus, 1975 W EI Camino Real, Mountain View, CA, 94040, USA.
  • Lingappa AF; Vitalant Research Institute, 360 Spear St., San Francisco, CA, 94105, USA.
  • Michon M; University of California, San Francisco, CA, 94143, USA.
  • Yu SF; Vitalant Research Institute, 360 Spear St., San Francisco, CA, 94105, USA.
  • Paulvannan K; University of California, San Francisco, CA, 94143, USA.
  • Manicassamy B; Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USA.
  • Lingappa VR; Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USA.
  • Boushey H; Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USA.
  • Greenland JR; Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USA.
  • Pillai SK; Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USA.
Commun Biol ; 7(1): 486, 2024 Apr 22.
Article en En | MEDLINE | ID: mdl-38649430
ABSTRACT
The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore, there is pronounced interest in identifying new pharmacological targets in the SARS-CoV-2 viral life cycle. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly. In this study, we investigate the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). We show that PAV-104 inhibits >99% of infection with diverse SARS-CoV-2 variants in immortalized AECs, and in primary human AECs cultured at the air-liquid interface (ALI) to represent the lung microenvironment in vivo. Our data demonstrate that PAV-104 inhibits SARS-CoV-2 production without affecting viral entry, mRNA transcription, or protein synthesis. PAV-104 interacts with SARS-CoV-2 nucleocapsid (N) and interferes with its oligomerization, blocking particle assembly. Transcriptomic analysis reveals that PAV-104 reverses SARS-CoV-2 induction of the type-I interferon response and the maturation of nucleoprotein signaling pathway known to support coronavirus replication. Our findings suggest that PAV-104 is a promising therapeutic candidate for COVID-19 with a mechanism of action that is distinct from existing clinical management approaches.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Replicación Viral / Células Epiteliales / SARS-CoV-2 Límite: Humans Idioma: En Revista: Commun Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Replicación Viral / Células Epiteliales / SARS-CoV-2 Límite: Humans Idioma: En Revista: Commun Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido