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 is characterized by the accumulation of inflammatory fluid in the lung alveoli and is the main factor responsible for the high mortality in patients with COVID-19. In addition to the obvious pathogenic function of SARS-CoV-2 viral RNA, surface proteins, in particular, the Spike protein, which binds to the human angiotensin-converting enzyme 2 and is primed by the host serine protease TMPRSS2, play an important role in the development of the ARDS. The clinical worsening in the later phases of COVID-19 is thought to result from Spike protein binding to the pulmonary microvascular endothelium and epithelium, which leads to a damaged respiratory tract and ultimately a systemic inflammatory response or cytokine storm. In this study, we used our SARS-CoV-2 Spike protein Subunit 1-induced K18-hACE2 mouse model to develop an entirely new therapeutic strategy using the reversible, selective, allosteric inhibitor of PTP4A3 phosphatase KVX-053. Our findings suggest that this novel PTP4A3 inhibitor prevents or mitigates the initial pulmonary damage and halts the lethal cytokine storm.