6TWC

Crystal Structure of the Catalytic Domain of the Coagulation Factor XIa in Complex with Double Bridged Peptide F21

6TWC の概要

• エントリーDOI: 10.2210/pdb6twc/pdb
• 分子名称: Coagulation factor XI, Double Bridged Peptide F21, ACETONE, ... (4 entities in total)
• 機能のキーワード: protease, coagulation factors, inhibitor, double bridged peptide, phage display, blood clotting
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 31304.73

構造登録者

Kong, X.D.,Pojer, F.,Heinis, C. (登録日: 2020-01-13, 公開日: 2020-05-20, 最終更新日: 2024-01-24)

主引用文献

Kong, X.D.,Moriya, J.,Carle, V.,Pojer, F.,Abriata, L.A.,Deyle, K.,Heinis, C.
De novo development of proteolytically resistant therapeutic peptides for oral administration.
Nat Biomed Eng, 4:560-571, 2020

PubMed Abstract: The oral administration of peptide drugs is hampered by their metabolic instability and limited intestinal uptake. Here, we describe a method for the generation of small target-specific peptides (less than 1,600 Da in size) that resist gastrointestinal proteases. By using phage display to screen large libraries of genetically encoded double-bridged peptides on protease-resistant fd bacteriophages, we generated a peptide inhibitor of the coagulation Factor XIa with nanomolar affinity that resisted gastrointestinal proteases in all regions of the gastrointestinal tract of mice after oral administration, enabling more than 30% of the peptide to remain intact, and small quantities of it to reach the blood circulation. We also developed a gastrointestinal-protease-resistant peptide antagonist for the interleukin-23 receptor, which has a role in the pathogenesis of Crohn's disease and ulcerative colitis. The de novo generation of targeted peptides that resist proteolytic degradation in the gastrointestinal tract should help the development of effective peptides for oral delivery.

PubMed: 32393891
DOI: 10.1038/s41551-020-0556-3

実験手法

X-RAY DIFFRACTION (2.86 Å)