Introduction
On January 30th, 2020, the World Health Organization declared an International Health Emergency in connection with a coronavirus disease 2019 (COVID-19), caused by a mutated RNA coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (Sohrabi et al., 2020). As of June 2023, more than 767 million cases have been identified with over 6.9 million deaths. Despite active vaccination, the virus continues to mutate and cause new infections, the most severe of which result in Acute Respiratory Distress Syndrome (ARDS). The acute stage of ARDS is characterized by increased vascular permeability, vascular leak, diffuse alveolar infiltrates, and loss of aerated alveolar surfaces, leading to reduced lung compliance and hypoxemia (Hussain et al., 2021). Although a few potential therapeutics are under investigation (Horie et al., 2020), the only FDA-approved interventions are methylprednisolone (Ranjbar et al., 2021), the antiviral drug remdesivir (Veklury) and the immune modulator baricitinib (Olumiant). Thus, there continues to be a significant need to identify new therapeutic targets for COVID-19 related ARDS.
We recently established an animal model of COVID-19-related ARDS by exposing K18–human ACE2 (K18-hACE2) transgenic mice to the surface elements, i.e., the Spike Protein (SP), of SARS-CoV-2 (Colunga Biancatelli et al., 2021). The SP is responsible for the binding to the Angiotensin Converting Enzyme 2 (ACE2) receptor and the internalization of the viral material into the cell (Ni et al., 2020). During this process, the SP undergoes two cleavage processes, mediated by furin and furin-like proteases, that results in the release of the subunit 1 of the Spike Protein (S1SP), while the subunit 2 mediates membrane fusion (Peacock et al., 2021). Up to 45% of the S1SP monomers can be found in the extracellular medium, vascular compartment or alveolar structures after viral internalization, where they can exert pathologically relevant functions (Ke et al., 2020). COVID-19 vaccines also increase the S protein content in blood named “Spike effect” of vaccination (Angeli et al., 2022; Cognetti & Miller, 2021; Solopov, 2023). Besides the ACE2 receptor, other cell proteins can interact with the S protein, including, CORO1C, STON2, the neuropilin-1 (NRP1) receptor and the transmembrane glycoprotein, CD147 (Zhou et al., 2023).
We hypothesized that S1SP exerts a direct role in lung injury and intratracheally instilled it in K18-hACE2 transgenic mice. Three days after exposure, mice displayed histological evidence of lung injury and strong alveolar inflammation reminiscent of cytokine storm including the activation of two main inflammatory pathways, Signal Transducer and Activator of Transcription 3 (STAT3) and Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-kB) (Colunga Biancatelli et al., 2021).
In this study, we tested whether a novel Protein Tyrosine Phosphatase 4A3 (PTP4A3) inhibitor, KVX-053, also known as JMS-053 (Salamoun et al., 2016), could prevent SARS-CoV-2 S1SP-induced ARDS. PTP4A3 (also known as PRL3) is a prenylated dual-specificity phosphatase that regulates vascular barrier function (McQueeney et al., 2017) and mediates the release of cytokines TNF-α, IL-1α, IL-1β, MCP-1, MCP-2 and VEGF in LPS-challenged mice (Tang et al., 2010). Furthermore, VEGF-mediated vascular permeability, in vivo, was significantly attenuated in PTP4A3-deficient mice (Zimmerman et al., 2014). The PTP4A3 inhibitor KVX-053 displays a potent, selective, allosteric inhibitory activity in vitro [13,14], as well as anti-tumor activity in in vivo models of ovarian cancer (Lazo et al., 2021). Importantly, PTP4A3 is involved in STAT3 activation and NF-κB nuclear translocation, suggesting that its inhibition could be beneficial in inflammatory diseases (Angeli et al., 2022). We previously have demonstrated that KVX-053 reduced VEGF- and LPS-induced endothelial dysfunction and vascular permeability (McQueeney et al., 2017).
Here, we show how KVX-053 exerts a strong therapeutic effect against SARS-CoV-2 S1SP-induced lung injury, local and systemic inflammation, vascular permeability, and lung dysfunction. These results support further studies on the potential use of KVX-053 for therapeutic intervention against SARS-CoV-2 and future coronavirus diseases.