KVX-053, a Protein Tyrosine Phosphatase 4A3 inhibitor, ameliorates
SARS‐CoV‐2 Spike protein subunit 1 – induced acute lung injury in mice.
- Pavel Solopov,
- Ruben Colunga Biancatelli,
- Tierney Day,
- Betsy Gregory,
- Elizabeth Sharlow,
- John Lazo,
- John Catravas
Abstract
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.