Angiostatin—a novel SARS-CoV-2 inhibitor and biomarker underlying COVID-19 pathophysiology

Background

Despite efficacious vaccines, many individuals remain at risk of severe illness and death from COVID-19 due to immune-escape variants. Hence, a better understanding of biomarkers underlying COVID-19 pathophysiology is needed to improve disease progression prediction and identify new drug targets. Angiostatin is a plasmin(ogen)-derived protein generated by platelets. As microvascular thrombosis, a key pathologic feature of COVID-19, can create microenvironments of both high angiostatin concentration and hypoxia/acidosis, conditions known to favor angiostatin’s proapoptotic actions on endothelial and epithelial cells, angiostatin may be a biomarker contributing to COVID-19 pathophysiology.

Objectives

To assess the role of angiostatin in COVID-19.

Methods

Plasma angiostatin concentrations were compared between COVID-19 patients and COVID-19-negative controls, as were temporal changes in plasma angiostatin in COVID-19 patients. Subsequent mechanistic cellular studies investigated the effects of angiostatin and its neutralization on both SARS-CoV-2 infection and subsequent cell death.

Results

Plasma angiostatin concentrations increased following SARS-CoV-2 infection and remained elevated in COVID-19 patients for 21 to 28 days. Angiostatin at concentration that would be generated within a clot over 7 to 8 hours promoted cell death in acidic microenvironments characteristic of severe COVID-19. Irrespective of pH, angiostatin reduced SARS-CoV-2 cellular entry of multiple variants by interfering with spike protein proteolysis. Selective angiostatin-neutralizing peptides inhibited angiostatin-induced cell death, but not angiostatin’s ability to reduce infection.

Conclusion

Angiostatin has dual roles during COVID-19, both preventing infection and promoting cell death. Selective angiostatin-neutralizing peptides may be novel therapeutics for further preclinical evaluation in models of severe COVID-19.