Structure-Based Drug Design of Peptide Mimetics Containing Large P3 Moieties as Inhibitors of Factor VIIa

Title: Structure-Based Drug Design of Peptide Mimetics Containing Large P3 Moieties as Inhibitors of Factor VIIa

Volume: 6 Issue: 2

Author(s): Kunihiro Hattori, Toshiro Kozono, Haruhiko Sato, Masateru Ohta, Keiko Esaki, Takehisa Kitazawa, Kazutaka Yoshihashi, Akihisa Sakamoto, Yoshiaki Watanabe, Takuya Shiraishi, Takaki Koga, Tohru Esaki, Hitoshi Iikura, Yoshiyuki Ono, Hirofumi Kodama, Masayuki Haramura and Shojiro Kadono

Affiliation:

Keywords: Structure-based drug design, Serine protease, FVIIa inhibitor, 2 x APTT/2 x PT ratio, X-ray crystal structure, Ligand-induced conformational change

Abstract: Peptide mimetic compounds 9d and 9h showed good selectivity for FVIIa/TF over other serine proteases. Xray crystal structure analysis revealed that a large moiety at P3 interacted in a novel manner with the 170-loop and was accompanied by ligand-induced conformational change of the 170-loop. From additional optimization, we discovered compound 10b, an excellent extrinsic pathway-selective inhibitor.

Cite this article as:

Hattori Kunihiro, Kozono Toshiro, Sato Haruhiko, Ohta Masateru, Esaki Keiko, Kitazawa Takehisa, Yoshihashi Kazutaka, Sakamoto Akihisa, Watanabe Yoshiaki, Shiraishi Takuya, Koga Takaki, Esaki Tohru, Iikura Hitoshi, Ono Yoshiyuki, Kodama Hirofumi, Haramura Masayuki and Kadono Shojiro, Structure-Based Drug Design of Peptide Mimetics Containing Large P3 Moieties as Inhibitors of Factor VIIa, Letters in Drug Design & Discovery 2009; 6 (2) . https://dx.doi.org/10.2174/157018009787582606