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.