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Principal Investigator: JOHN S. LAZO
Organization: KEVIRX INC.
Fiscal Year: 2021
Award: $252,208
Funding agency: National Heart Lung and Blood Institute
The 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,
which binds to the human angiotensin-converting enzyme 2 (ACE2) and is primed by the host serine protease
TMPRSS2. Both ACE2 and TMPRSS2 have been observed on pulmonary microvascular epithelium and
endothelium. A subset of COVID-19 patients develop acute respiratory distress syndrome (ARDS) and
subsequently septic shock and multi-organ failure; about half will die. The clinical worsening in the later phases
of COVID-19 are 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. There are currently no FDA-approved drugs/therapeutics that treat the pulmonary damage and
ARDS associated with COVID-19. KeViRx is proposing to develop an entirely new therapeutic strategy that
prevents or mitigates the initial pulmonary damage and halts the lethal cytokine storm.
Our lead compound, KVX-053, is a reversible, selective, allosteric inhibitor of PTP4A3 phosphatase with
excellent in vivo pharmacokinetic properties and drug-like properties. Moreover, mice tolerated multiple
exposures to KVX-053 In culture KVX-053 was not cytotoxic to human ovarian epithelial cells or fibroblasts at
concentrations up to 25 µM. Surprisingly, we found that KVX-053 markedly enhanced the pulmonary
microvascular barrier function before and after injury caused by bacterial lipopolysaccharide and vascular
endothelial growth factor. PTP4A3 phosphatase is known to be induced in lung cells 12 h after SARS-CoV
infection and to control cytokine release. The overall hypothesis of this Phase I SBIR application is that the
PTP4A phosphatase family has a sentinel role in the acute lung injury of ARDS and the systemic inflammatory
response in COVID-19.The goal of the project is to repurpose KVX-053 for use in individuals with COVID-19 and
for future pandemics involving acute lung injury. This Phase I SBIR application has three proof-of-concept
Specific Tasks. Specific Task 1 will determine the ability of a novel, potent, allosteric, small molecule PTP4A3
inhibitor, KVX-053, to block SARS-CoV-2 Spike 1 protein-mediated loss of pulmonary endothelial barrier function
and cytokine release in vitro. Specific Task 2 will determine the ability of KVX-053 to block SARS-CoV-2 Spike
1 protein-mediated pulmonary alveolar epithelial barrier function and cytokine release in vitro. Specific Task 3
will determine the ability of KVX-053 to inhibit acute lung injruy in mice caused by the SARS-CoV-2 Spike 1
protein.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><ARDS><Acute><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Binding><Binding Proteins><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Vessels><Blood monocyte><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global 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syndrome><Marrow Neutrophil><Marrow monocyte><Measures><Mediating><Medication><Mice><Mice Mammals><Modern Man><Molecular Interaction><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><OV1><Outcome><Ovarian><PRL2><PRSS10><PTP(CAAX2)><PTP4A><PTP4A1><PTP4A2 gene><Pathologic><Pathway interactions><Pb element><Permeability><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phase><Phosphatase of Regenerating Liver 2><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Physiopathology><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Pre-Clinical Model><Preclinical Models><Prevention><Property><Protein Binding><Protein-Tyrosine Phosphatase, Type 4A, 2><Proteins><Pulmonary Body System><Pulmonary Organ System><Recombinants><Respiratory System><Respiratory Tracts><Respiratory tract structure><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 inhibitor><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SBIR><Sentinel><Septic Shock><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Small Business Innovation Research><Small Business Innovation Research Grant><Specificity><Stiff lung><TMPRSS2><TMPRSS2 gene><Testing><Therapeutic><Time><VEGF><VEGFs><Vascular Endothelial Growth Factors><Viral><Virus><Wuhan coronavirus><alveolar epithelium><analog><angiotensin converting enzyme 2><angiotensin converting enzyme II><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><bound protein><clinical development><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus S protein><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 pandemic><coronavirus disease 2019 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patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome-CoV><small molecule><social role><systemic inflammation><systemic inflammatory response><vascular><wet lung>