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- Title
A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells.
- Authors
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.
- 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. PAV-104, a small molecule, potently inhibits SARS-CoV-2 replication in human airway epithelial cells by disrupting viral particle assembly and release. These findings suggest that PAV-104 holds significant promise as a therapeutic for COVID-19.
- Subjects
EPITHELIAL cells; SARS-CoV-2; TYPE I interferons; LIFE cycles (Biology); COVID-19 vaccines
- Publication
Communications Biology, 2024, Vol 7, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-024-06130-8