Biosynthetic redesign of small molecules aimed for the concurrent improvements of cell permeability and water solubility

• Project Area: Creation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries
• Project/Area Number: 16H06445
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Fukui Prefectural University
• Principal Investigator: Hamano Yoshimitsu 福井県立大学, 生物資源学部, 教授 (50372834)
• Co-Investigator(Kenkyū-buntansha): 丸山 千登勢 福井県立大学, 生物資源学部, 准教授 (20452120) ; 山中 一也 関西大学, 化学生命工学部, 准教授 (30756870)
• Project Period (FY): 2016-06-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥72,020,000 (Direct Cost: ¥55,400,000、Indirect Cost: ¥16,620,000); Fiscal Year 2020: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2019: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2018: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2017: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2016: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000)
• Keywords: ポリリジン / 細胞膜透過性 / CPP / ポリカチオン / 生体膜 / 応用微生物 / 有機化学 / 生理活性 / 生体膜透過性 / アミノ酸ポリマー

Outline of Final Research Achievements

Our research aims include chemical modification (polycationic modification) of small molecule compounds with bacterial polycationic peptides to improve the water solubility and the cell membrane permeability simultaneously. New small compounds generated by biosynthetic re-design and known small compounds were our target molecules for the polycationic modification approach, and biosynthetic studies were performed to generate new peptide compounds in this study. In addition, we identified novel bacterial polycationic peptides and demonstrated their biosynthetic mechanisms. The polycationic modification of known compounds were achieved with clickable ε-poly-α-L-lysine and ε-oligo-β-L-lysine, which were produced by microbial transformation and enzymatic reaction, respectively.

Academic Significance and Societal Importance of the Research Achievements

薬物である機能性低分子・中分子化合物の細胞膜透過性を改善できれば、生理活性の増強が期待できる。細胞膜透過性を改善するための一般的な戦略は、化合物の疎水化である。しかし、その反面生じる水溶性の低下は、予期しない副作用の出現や製剤調製の複雑化など新たな問題を生む。したがって、生体膜透過性と水溶性を一挙に改善させる薬剤の化学修飾技術を開発できれば、現在の創薬スピードを加速させることができる。そこで本研究では、細胞膜透過性と水溶性を一挙に改善する化学修飾分子として、微生物由来ポリカチオン性ペプチドに着目し、実践的なポリカチオン化修飾法を確立した。