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Comment
. 2021 Jun;42(6):431-433.
doi: 10.1016/j.tips.2021.03.006. Epub 2021 Mar 26.

Therapeutic Potential of Targeting Plasminogen Activator Inhibitor-1 in COVID-19

Tahsin F Kellici  1 , Ewa S Pilka  2 , Michael J Bodkin  2
Affiliations
Comment

Therapeutic Potential of Targeting Plasminogen Activator Inhibitor-1 in COVID-19

Tahsin F Kellici et al. Trends Pharmacol Sci. 2021 Jun.

Abstract

Latest research shows that SERPINE1 overexpression has an important role in Coronavirus 2019 (COVID-19)-associated coagulopathy leading to acute respiratory distress syndrome (ARDS). However, ways to target this protein remain elusive. In this forum, we discuss recent evidence linking SERPINE1 with COVID-19-related ARDS and summarize the available data on inhibitors of this target.

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Conflict of interest statement

All the authors are employees of Evotec (UK) Ltd.

Figures

Figure 1
Figure 1
SERPINE1 Structure, Inhibitors, and its Role in Fibrinolysis. (A) SERPINE1 structure and its inhibitors. Tiplaxtinin and aleplasinin are vitronectin (VN) dependent, whereas CDE-096, TM5614, and MDI-2268 are not. However, precise binding pockets for these inhibitors have not yet been identified. (B) Fibrinolysis in Coronavirus 2019 (COVID-19). Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (AngII) to angiotensin 1–7 (Ang1–7) under normal circumstances. When ACE-2 is hindered by Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-Cov2), this pathway is affected, increasing the levels of Ang2 in the blood. AngII and AngII receptor 1 (AT1) enhance the release of SERPINE1 (PAI-1) by endothelial cells. Most SERPINE1 is likely to be bound to VN, given the high concentration of the latter. SERPINE1 inhibits tPA, limiting the conversion of plasminogen to plasmin and leading to hypofibrinolysis.
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Comment on

  • Complement activation and endothelial perturbation parallel COVID-19 severity and activity.
    Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, Lonati P, Grossi C, Borghi MO, Novembrino C, Boscolo M, Uceda Renteria SC, Valenti L, Lamorte G, Manunta M, Prati D, Pesenti A, Blasi F, Costantino G, Gori A, Bandera A, Tedesco F, Peyvandi F. Cugno M, et al. J Autoimmun. 2021 Jan;116:102560. doi: 10.1016/j.jaut.2020.102560. Epub 2020 Oct 29. J Autoimmun. 2021. PMID: 33139116 Free PMC article.

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