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

Aleksandra Franczak; Michael Joyce; Joaquin Lopez-Orozco; Holly A Saffran; Max Saito; Amir Asgari; Subha Kalyaanamoorthy; Khaled Barakat; Tom C Hobman; D Lorne Tyrrell; Paul Jurasz

doi:10.1016/j.jtha.2025.03.030

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

J Thromb Haemost. 2025 Jul;23(7):2151-2163. doi: 10.1016/j.jtha.2025.03.030. Epub 2025 Apr 6.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
² Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
³ Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁴ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
⁵ Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.
⁶ Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁷ Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada. Electronic address: jurasz@ualberta.ca.

PMID: 40199448
DOI: 10.1016/j.jtha.2025.03.030

Abstract

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.

Keywords: COVID-19; angiostatin; biomarker; pathophysiology; therapeutics.

MeSH terms

Aged
Angiostatins* / blood
Angiostatins* / pharmacology
Biomarkers / blood
COVID-19* / blood
COVID-19* / physiopathology
COVID-19* / virology
Female
Humans
Male
Middle Aged
SARS-CoV-2* / drug effects
SARS-CoV-2* / metabolism
SARS-CoV-2* / pathogenicity

Substances

Angiostatins
Biomarkers