A Novel Viral Assembly Inhibitor Blocks SARS-CoV-2 Replication in Airway Epithelial Cells

  • Res Sq. 2023 May 17:rs.3.rs-2887435. doi: 10.21203/rs.3.rs-2887435/v1.
Satish Pillai  1 ,  Li Du  2 ,  Fred Deiter  3 ,  Mohamed Bouzidi  4 ,  Jean-Noel Billaud  5 ,  Simmons Graham  1 ,  Dabral Prerna  1 ,  Suganya Selvarajah  6 ,  Anuradha Lingappa  6 ,  Maya Michon  6 ,  Shao Yu  6 ,  Kumar Paulvannan  6 ,  Vishwanath Lingappa  6 ,  Homer Boushey  7 ,  John Greenland  8
Affiliations
  • 1. Vitalant Research Institute / UCSF.
  • 2. Vitalant Research Institute/UCSF.
  • 3. Veterans Administration Health Care System/UCSF.
  • 4. Vitalant Research Institute.
  • 5. QIAGEN Digital Insights.
  • 6. Prosetta Biosciences Inc.
  • 7. University of California San Francisco.
  • 8. University of California, San Francisco.
PMID: 37292622 DOI: 10.21203/rs.3.rs-2887435/v1
Abstract

The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for novel therapies with high genetic barriers to resistance. 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. Here, we investigated the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). Our data demonstrate that PAV-104 inhibited > 99% of Infection with diverse SARS-CoV-2 variants in primary and immortalized human AECs. PAV-104 suppressed SARS-CoV-2 production without affecting viral entry or protein synthesis. PAV-104 interacted with SARS-CoV-2 nucleocapsid (N) and interfered with its oligomerization, blocking particle assembly. Transcriptomic analysis revealed that PAV-104 reversed 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.

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