Journal article
A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells
Communications biology, Vol.7(1), 486
04/22/2024
DOI: 10.1038/s42003-024-06130-8
PMCID: PMC11035691
PMID: 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.
Details
- Title: Subtitle
- A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells
- Creators
- Li Du - Pacific Research InstituteFred Deiter - University of California, San FranciscoMohamed S Bouzidi - VitalantJean-Noël Billaud - DNAnexusGraham Simmons - University of California, San FranciscoPrerna Dabral - University of California, San FranciscoSuganya Selvarajah - Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USAAnuradha F Lingappa - Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USAMaya Michon - Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USAShao Feng Yu - Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USAKumar Paulvannan - Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USABalaji Manicassamy - University of IowaVishwanath R Lingappa - Prosetta Biosciences Inc, 670 5th St., San Francisco, CA, 94107, USAHomer Boushey - University of California, San FranciscoJohn R Greenland - San Francisco VA Health Care SystemSatish K Pillai - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- Communications biology, Vol.7(1), 486
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/s42003-024-06130-8
- PMID
- 38649430
- PMCID
- PMC11035691
- eISSN
- 2399-3642
- Grant note
- U19 AI171443 / NIAID NIH HHS I01 CX002011 / CSRD VA R01 HL151552 / NHLBI NIH HHS R01 MH112457 / NIMH NIH HHS
- Language
- English
- Date published
- 04/22/2024
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984618501302771
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