TY - JOUR
T1 - Factor XII/XIIa inhibitors
T2 - Their discovery, development, and potential indications
AU - DAVOINE, Clara
AU - BOUCKAERT, Charlotte
AU - Fillet, Marianne
AU - POCHET, Lionel
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Serine proteinase inhibitors
KW - Drug development
KW - Antithrombotic agents
KW - Anti-inflammatory agents
KW - Contact pathway
KW - Factor XII
KW - Anti-inflammatory agents
KW - Antithrombotic agents
KW - Contact pathway
KW - Drug development
KW - Factor XII
KW - Serine proteinase inhibitors
UR - https://doi.org/10.1016/j.ejmech.2020.112753
UR - http://www.scopus.com/inward/record.url?scp=85090047896&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2020.112753
DO - 10.1016/j.ejmech.2020.112753
M3 - Review article
SN - 0223-5234
VL - 208
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 112753
ER -