KVX-053, a protein tyrosine phosphatase 4A3 inhibitor, ameliorates SARS-CoV-2 spike protein subunit 1–induced acute lung injury in mice

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 proinflammatory cytokines. This progression from ALI to ARDS is a major contributor to the high mortality observed in patients with COVID-19. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to lung angiotensin-converting enzyme 2 (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. SIGNIFICANCE STATEMENT: This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19-associated ALI/ARDS. 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 and chemokines, structural lung injury, and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings suggest that this novel PTP4A3 inhibitor may be useful against COVID-19 and potentially other viral-induced ARDS.