| Project/Area Number |
15H04658
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Drug development chemistry
|
|---|
| Research Institution | Tokyo University of Pharmacy and Life Science |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
高山 健太郎 東京薬科大学, 薬学部, 講師 (70611482)
|
|---|
| Research Collaborator |
KANGAWA Kenji
MIYAZATO Mikiya
MORI Kenji
MINAMINO Naoto
YAMAMOTO Akira
SAKANE Toshiyasu
TANAKA Akiko
NEGISHI Yoichi
|
|---|
| Project Period (FY) |
2015-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2016: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
|
|---|
| Keywords | ペプチド / ニューロメジンU / マイオスタチン / 構造活性相関研究 / アゴニスト / 阻害剤 / 受容体選択性 / 構造活性相関 / ペプチド誘導体 / αヘリックス |
|---|
| Outline of Final Research Achievements |
This medicinal chemistry research focuses on two biomolecules called “neuromedin U (NMU)” and “myostatin” that are deeply involved in obesity and muscle weakness caused by modern lifestyle and aging.
(1) NMU activates two NMU receptors (NMUR1 and NMUR2), and is a useful anti-obesity drug lead. Here, we discovered a novel NMUR1 selective hexapeptide agonist CPN-267 that suppressed body weight gain in wild-type mice. CPN-267 showed improved NMUR1 selectivity, serum stability, and pharmacokinetics compared with conventional agonist CPN-170.
(2) Inhibition of myostatin is a promising strategy for treatment of muscle atrophic disorders. We had already identified a 23-mer peptide (1) as a synthetic myostatin inhibitor. Structure-activity relationship studies based on 1 consequently afforded 16-mer inhibitory peptide MIPE-1686, which significantly increased not only muscle mass but also hindlimb grip strength in Duchenne muscular dystrophic model mice.
|
| Academic Significance and Societal Importance of the Research Achievements |
(1) 創製した１型NMU受容体選択的アゴニストCPN-267は、２型NMU受容体選択的アゴニストCPN-116と共に、今後の抗肥満創薬研究や受容体機能解析研究において、有望なシーズあるいはツールとなることが期待される。CPN-267の代謝安定化においては、基質切断部位から離れた部位の構造変換による安定化が可能なことを示すことができ、ペプチド創薬における有益な知見の一つとして提案できるものである。
(2) マイオスタチン阻害戦略において、有望なペプチドシーズMIPE-1686を創出することができた。またSARにより得られた知見は今後の医薬品開発における有用な情報として活用できるものである。
|
