A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells

  • Commun Biol. 2024 Apr 22;7(1):486. doi: 10.1038/s42003-024-06130-8.
Li Du  1  2 ,  Fred Deiter  2  3 ,  Mohamed S Bouzidi  1  2 ,  Jean-Noël Billaud  4 ,  Graham Simmons  1  2 ,  Prerna Dabral  1  2 ,  Suganya Selvarajah  5 ,  Anuradha F Lingappa  5 ,  Maya Michon  5 ,  Shao Feng Yu  5 ,  Kumar Paulvannan  5 ,  Balaji Manicassamy  6 ,  Vishwanath R Lingappa  5 ,  Homer Boushey  2 ,  John R Greenland  2  3 ,  Satish K Pillai  7  8
Affiliations
  • 1. Vitalant Research Institute, 360 Spear St., San Francisco, CA, 94105, USA.
  • 2. University of California, San Francisco, CA, 94143, USA.
  • 3. Veterans Administration Health Care System, 4150 Clement St., San Francisco, CA, 94121, USA.
  • 4. DNAnexus, 1975 W EI Camino Real, Mountain View, CA, 94040, USA.
  • 5. Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USA.
  • 6. University of Iowa, Iowa City, IA, 52242, USA.
  • 7. Vitalant Research Institute, 360 Spear St., San Francisco, CA, 94105, USA. [email protected].
  • 8. University of California, San Francisco, CA, 94143, USA. [email protected].
PMID: 38649430 DOI: 10.1038/s42003-024-06130-8
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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