Factor XII/XIIa inhibitors: Their discovery, development, and potential indications

Eur J Med Chem. 2020 Dec 15:208:112753. doi: 10.1016/j.ejmech.2020.112753. Epub 2020 Aug 20.

Abstract

Coagulation factor XII (FXII), a S1A serine protease, was discovered more than fifty years ago. However, its in vivo functions and its three-dimensional structure started to be disclosed in the last decade. FXII was found at the crosstalk of several physiological pathways including the intrinsic coagulation pathway, the kallikrein-kinin system, and the immune response. The FXII inhibition emerges as a therapeutic strategy for the safe prevention of artificial surface-induced thrombosis and in patients suffering from hereditary angioedema. The anti-FXII antibody garadacimab discovered by phage-display library technology is actually under phase II clinical evaluation for the prophylactic treatment of hereditary angioedema. The implication of FXII in neuro-inflammatory and neurodegenerative disorders is also an emerging research field. The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, RNA-based technologies, and, to a lesser extent, small-molecular weight inhibitors. Most of them are proteins, mainly isolated from hematophagous arthropods and plants. The discovery and development of these FXII inhibitors and their potential indications are discussed in the review.

Keywords: Anti-inflammatory agents; Antithrombotic agents; Contact pathway; Drug development; Factor XII; Serine proteinase inhibitors.

Publication types

  • Review

MeSH terms

  • Animals
  • Anticoagulants / chemistry
  • Anticoagulants / pharmacology*
  • Drug Discovery
  • Factor XII / antagonists & inhibitors*
  • Factor XII / chemistry
  • Factor XIIa / antagonists & inhibitors*
  • Factor XIIa / chemistry
  • Humans
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*

Substances

  • Anticoagulants
  • Serine Proteinase Inhibitors
  • Factor XII
  • Factor XIIa