Structure-based design of P3 moieties in the peptide mimetic factor VIIa inhibitor.
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.
Kadono
Shojiro
S
Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kadonosuj@chugai-pharm.co.jp <kadonosuj@chugai-pharm.co.jp>
Sakamoto
Akihisa
A
Kikuchi
Yasufumi
Y
Oh-eda
Masayoshi
M
Yabuta
Naohiro
N
Yoshihashi
Kazutaka
K
Kitazawa
Takehisa
T
Suzuki
Tsukasa
T
Koga
Takaki
T
Hattori
Kunihiro
K
Shiraishi
Takuya
T
Haramura
Masayuki
M
Kodama
Hirofumi
H
Ono
Yoshiyuki
Y
Esaki
Toru
T
Sato
Haruhiko
H
Watanabe
Yoshiaki
Y
Itoh
Susumu
S
Ohta
Masateru
M
Kozono
Toshiro
T
D000595:Amino Acid Sequence; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010455:Peptides; D015942:Factor VIIa