Prof. John D. Catravas and Prof. John S. Lazo project awarded NIH Small Business Innovation Research (SBIR) funding
March 2nd 2022
Prof. John D. Catravas
Prof. John S. Lazo
Prof. John Lazo of KeViRX Company and Prof. John Catravas of ODU have been awarded a National Institutes of Health R43 Phase 1 Small Business Innovation Research (SBIR) grant (HL158409) titled "A PTP4A3 inhibitor for SARS-CoV-2-mediated acute lung injury".
Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) is responsible for the current COVID-19 pandemic. SAR-CoV-2, like other coronaviruses, infects human airways and enters cells via its S (Spike) protein. A subset of COVID-19 patients develops acute respiratory distress syndrome (ARDS) and multi-organ failure; about half will die. The clinical worsening in the later phases of COVID-19 appear to be caused by pulmonary microvascular damage and permeability changes, which results in the influx of neutrophils and monocytes-macrophages and ultimately a systemic inflammatory response or cytokine storm. There are currently no FDA-approved therapeutics that treat the pulmonary damage and ARDS associated with COVID-19.The PTP4A3 phosphatase appears to control pulmonary cellular permeability changes after SARS-CoV infection and to control cytokine release. KVX-053 is a novel, potent, reversible, selective, allosteric inhibitor of PTP4A3 phosphatase with excellent in vivo pharmacokinetic and drug-like properties. The overall hypothesis of this Phase I SBIR application is that the PTP4A phosphatase family has a sentinel role in the acute lung injury (ALI) of ARDS and the systemic inflammatory response in viral infections.
This Phase I SBIR application has three proof-of-concept Tasks. Task 1 will determine the ability of KVX-053 to block SARS-CoV-2 Spike 1 protein-mediated loss of pulmonary endothelial barrier function and cytokine release in vitro. Task 2 will determine the ability of KVX-053 to block SARS-CoV-2 Spike 1 protein-mediated loss of pulmonary alveolar epithelial barrier function and cytokine release in vitro. Task 3 will determine the ability of KVX-053 to inhibit the ALI in mice induced by the SARS-CoV-2 Spike protein. Successful completion of these tasks should enable KeViRx to continue developing an entirely new therapeutic strategy that could prevent or mitigate the initial pulmonary damage and halt the lethal cytokine storm caused by SARS-CoV-2 and possibly other viruses including influenza.
Histological evaluation of lungs of K18-hACE2 transgenic mice instilled with saline (left), Spike Protein subunit 1 (S1SP - centre), and S1Sp and treated with the PTP4A3 inhibitor, KVX-053. KVX-053 ameliorated the development of Acute Lung injury mediated by SARS-CoV-2.