KVX-053, a protein tyrosine phosphatase 4A3 inhibitor, ameliorates SARS-CoV-2 spike protein subunit 1-induced acute lung injury in mice.
Summary
In a K18-hACE2 mouse model of SARS-CoV-2 spike S1-induced ALI, the selective allosteric PTP4A3 inhibitor KVX-053 reduced inflammation, vascular leak, structural injury, and lung dysfunction. This is the first evidence implicating PTP4A3 as a therapeutic target in COVID-19-associated ALI/ARDS.
Key Findings
- SARS-CoV-2 spike S1 instillation in K18-hACE2 mice induced pulmonary/systemic inflammation, alveolar leak, cytokine overexpression, structural injury, and dysfunction.
- KVX-053, a selective allosteric PTP4A3 inhibitor, ameliorated these injury phenotypes.
- Provides first evidence implicating PTP4A3 in SARS-CoV-2-mediated ALI pathogenesis.
Clinical Implications
PTP4A3 inhibition may complement antivirals by mitigating host-driven vascular leak and inflammation, offering a host-targeted adjunctive strategy for viral ARDS.
Why It Matters
Identifies a new, druggable host pathway (PTP4A3) with translational relevance to COVID-19 and potentially other viral ARDS entities.
Limitations
- Spike S1 protein instillation model does not recapitulate full viral infection dynamics.
- Lack of survival, dose–response, and pharmacokinetic data in the abstract.
Future Directions
Test KVX-053 in live-virus models and diverse ARDS etiologies; define PK/PD and safety; dissect PTP4A3 signaling nodes in pulmonary endothelium/epithelium; explore combination with antivirals.
Study Information
- Study Type
- Case-control
- Research Domain
- Treatment
- Evidence Level
- V - Preclinical animal study demonstrating target engagement and phenotypic rescue.
- Study Design
- OTHER