Document Type
Article
Publication Date
2024
Publication Title
Journal of Pharmacology and Experimental Therapeutics
Volume
Advance online publication
Pages
33 pp.
DOI
10.1124/jpet.124.002154
Abstract
The Acute Respiratory Distress Syndrome (ARDS), often preceded by acute lung injury (ALI), is characterized by the accumulation of inflammatory fluid in the lung alveoli, leaky alveolar epithelium and endothelium, and overexpression of pro-inflammatory cytokines. This progression from ALI to ARDS is a major contributor to the high mortality observed in COVID-19 patients. The Spike protein of SARS-CoV-2 binds to lung ACE2 and, in addition to facilitating viral cell entry, it plays an important role in the development of ALI and ARDS, especially in the later phases of COVID-19 as well as long COVID. Protein tyrosine phosphatase (PTP) 4A3 is a key mediator of ARDS pathology. This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19 associated ALI. Intratracheal administration of SARS-CoV-2 Spike protein Subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines, structural lung injury and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings provide the first evidence supporting a role for PTP4A3 in the development of SARS-CoV-2- mediated ALI.
Rights
© 2024 The Authors.
This is an open access article under the terms of the Creative Commons Attribution Non-Commercial 4.0 International (CC BY-NC 4.0) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
Data Availability
Article states: "All data/datasets are contained in the paper."
Original Publication Citation
Solopov, P. A., Colunga Biancatelli, R. M. L., Day, T., Gregory, B., Sharlow, E. R., Lazo, J. S., & Catravas, J. D. (2024). KVX-053, a protein tyrosine phosphatase 4A3 inhibitor, ameliorates SARS-CoV-2 Spike protein Subunit 1 - induced acute lung injury in mice. Journal of Pharmacology and Experimental Therapeutics. Advance online publication. https://doi.org/10.1124/jpet.124.002154
Repository Citation
Solopov, Pavel A.; Colunga Biancatelli, Ruben Manuel Luciano; Day, Tierney; Gregory, Betsy; Sharlow, Elizabeth R.; Lazo, John S.; and Catravas, John D., "KVX-053, A Protein Tyrosine Phosphatase 4A3 Inhibitor, Ameliorates SARS-CoV-2 Spike Protein Subunit 1 - Induced Acute Lung Injury in Mice" (2024). Bioelectrics Publications. 372.
https://digitalcommons.odu.edu/bioelectrics_pubs/372
ORCID
0000-0002-1705-027X (Solopov), 0000-0002-1174-3876 (Colunga Biancatelli), 0000-0002-5098-295X (Catravas)
Included in
Gastroenterology Commons, Pharmacology, Toxicology and Environmental Health Commons, Pulmonology Commons