A novel methodology for generation of molecular-targeting drugs via directed evolution in combinatorial libraries of conformationally constrained peptides

2015 Fiscal Year Final Research Report

• Project/Area Number: 25242068
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: Osaka Prefecture University
• Principal Investigator: Fujii Ikuo 大阪府立大学, 理学(系)研究科(研究院), 教授 (70189984)
• Co-Investigator(Kenkyū-buntansha): TSUMURAYA Takeshi 大阪府立大学, 大学院理学系研究科, 准教授 (00372855)
• Co-Investigator(Renkei-kenkyūsha): FUJIWARA Daisuke 大阪府立大学, 大学院理学系研究科, 助教 (30611420)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 分子標的医薬品 / ペプチド / 進化分子工学 / ファージ表層提示法 / ヘリックス構造

Outline of Final Research Achievements

Despite intense research into the design of small ligands that target protein-protein interaction, a novel methodology for the rational design of such ligands remains an elusive goal. To design such ligands, our group has examined the directed evolution in a phage-displayed library of helix-loop-helix peptides. Screening of the library against targeted proteins provided bioactive peptides, whose rigid structures showed the spatial orientation of the pharmacophores, thus facilitating structure-based design of peptidomimetics. We constructed a phage-displayed library of the peptides and screened the library against several targeted proteins. The obtained peptide showed a strong binding affinity (Kd of 4 nM) , and a long half-life (>2 weeks) in mouse sera. In addition, the peptides provide structural information of the pharmacophores to facilitate structure-based design of peptidomimetics. Finally, we succeeded to generate biphenyl compounds binding to the targeted proteins.

Free Research Field

ケミカルバイオロジー，タンパク質化学