Kadono Shojiro, Sakamoto Akihisa, Kikuchi Yasufumi, Oh-eda Masayoshi, Yabuta Naohiro, Yoshihashi Kazutaka, Kitazawa Takehisa, Suzuki Tsukasa, Koga Takaki, Hattori Kunihiro, Shiraishi Takuya, Haramura Masayuki, Kodama Hirofumi, Ono Yoshiyuki, Esaki Toru, Sato Haruhiko, Watanabe Yoshiaki, Itoh Susumu, Ohta Masateru, Kozono Toshiro
Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Biochem Biophys Res Commun. 2005 Feb 11;327(2):589-96. doi: 10.1016/j.bbrc.2004.12.042.
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is seen as a promising target for developing new anticoagulant drugs. Structure-based designs of the P3 moiety in the peptide mimetic factor VIIa inhibitor successfully lead to novel inhibitors with selectivity for FVIIa/TF and extrinsic coagulation the same as or even higher than those of previously reported peptide mimetic factor VIIa inhibitors. X-ray crystal structure analysis reveals that one of the novel inhibitors shows improved selectivity by forming interactions between the inhibitor and FVIIa as expected. Another of the novel inhibitors achieves improved selectivity through an unexpected hydrogen bond with Gln217, with a unique bent conformation in FVIIa/TF accompanied by conformational changes of the inhibitor and the protein.
选择性抑制因子VIIa-组织因子复合物（FVIIa/TF）被视为开发新型抗凝药物的一个有前景的靶点。基于结构设计的肽模拟物因子VIIa抑制剂中的P3部分成功地产生了对FVIIa/TF和外源性凝血具有选择性的新型抑制剂，其选择性与先前报道的肽模拟物因子VIIa抑制剂相同甚至更高。X射线晶体结构分析表明，其中一种新型抑制剂如预期那样通过在抑制剂与FVIIa之间形成相互作用而显示出改善的选择性。另一种新型抑制剂通过与Gln217形成意外的氢键实现了选择性的提高，在FVIIa/TF中具有独特的弯曲构象，同时伴随着抑制剂和蛋白质的构象变化。
