Discovery of INSL7 analogue with agonistic activity for RXFP3 in the brai
| Project/Area Number |
16K08332
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Kobe Gakuin University |
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Principal Investigator |
Hojo Keiko 神戸学院大学, 薬学部, 助教 (20289028)
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| Co-Investigator(Kenkyū-buntansha) |
津田 裕子 神戸学院大学, 薬学部, 教授 (10098478)
日高 興士 神戸学院大学, 薬学部, 講師 (30445960)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | ペプチドアナログ / インスリンファミリー / GPCR / ステープルペプチド / ヘリックス / 神経ペプチド / ペプチド合成 / リラキシン / アゴニスト / アンタゴニスト / ペプチド固相合成 / モダリティー / PPI / リラキシンスーパーファミリー / ステープルヘリックス / 二次構造 / CD / 肥満 / 薬学 / 脳・神経 / 有機化学 |
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| Outline of Final Research Achievements |
Relaxin-3 is a two-chain neuropeptide that plays a key role in stress responses, arousal and affective behaviors through interaction with RXFP3 that is highly expressed in the brain. From detailed structure-activity relationship studies together with the known tertiary structure of relaxin-3 and molecular modeling of the RXFP3-relaxin-3 complex, the central B-chain α-helical region of relaxin-3 is essential for the binding to RXFP3 as it contains several key residues. The C-terminal residues are critical for activation of RXFP3. Although all the critical residues are located within the B-chain, the native relaxin-3 B-chain alone displays only weak agonistic activity at RXFP3 probably due to loss of the native helical binding conformation when separated from the stabilizing A-chain. In this study we applied this stapling system to stabilize the α-helix of single B-chain and showed that it mimics the native conformation of B-chain and possesses potent RXFP3 agonist activity.
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| Academic Significance and Societal Importance of the Research Achievements |
リラキシン-3は、インスリンスーパーファミリーに属ている神経ペプチドの一つである。このスーパーファミリーに属するペプチドの構造改変はあまり研究がなされてこなかった。その理由は、二本鎖の中分子であるが故に、低分子化、改変分子におけるNativeコンフォメーションの再現に困難が伴うからである。しかし、リラキシン-3をB鎖のみのステープルペプチドとすると、その合成は容易となり改変も可能である。更には、多分子間相互作用を狙った二価性、三価性のアナログ等の創製も可能となる。このような高機能なペプチド性医薬品の投入は、規模を拡大し続けている精神疾患の創薬マーケットにインパクトを持って迎えらえるはずである。
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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Identification of dipeptidic inhibitors targeting DPP7 derived from multiple drug resistant bacteria Stenotrophomonas maltophilia2018
Author(s)
Yuki Sakurai, Koushi Hidaka, Anna Miyazaki, Keiko Hojo, Saori Roppongi, Yasumitsu Sakamoto, Yasuhiro Ito, Yoshiyuki Suzuki, Wataru Ogasawara, Nobutada Tanaka, Yuko Tsuda
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Journal Title
Peptide Science
Volume: 54
Related Report
Peer Reviewed
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[Journal Article] Keiko Hojo, Hossain A. Hossain, K. Johan Rosengren, Sheri Ma, Andrew. L. Gundlach, Yuko Tsuda, Koushi Hidaka, R. A. D. Bathgate, John D. Wade. Design, synthesis and biological activity of hydrocarbon stapled single-chain relaxin-3 analogue.2017
Author(s)
Keiko Hojo, Hossain A. Hossain, K. Johan Rosengren, Sheri Ma, Andrew. L. Gundlach, Yuko Tsuda, Koushi Hidaka, R. A. D. Bathgate, John D. Wade
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Journal Title
Peptides
Volume: 34
Pages: 148-149
Related Report
Int'l Joint Research
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[Journal Article] Development of a Single-Chain Peptide Agonist of the Relaxin‐3 Receptor Using Hydrocarbon Stapling2016
Author(s)
Keiko Hojo, Mohammed Akhter Hossain, Julien Tailhades, Fazel Shabanpoor, LilianL.L.Wong, EmmaE.K.Ong-Palsson, HannaE.Kastman, SherieMa, AndrewL.Gundlach, K. Johan Rosengren, John D. Wade, and Ross A. D. Bathgate
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Journal Title
Journal of Medicinal Chemistry
Volume: 59
Issue: 16
Pages: 7445-7456
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Presentation] Identification of dipeptidic inhibitors targeting DPP7 derived from multiple drug resistant bacteria Stenotrophomonas maltophilia2017
Author(s)
Yuki Sakurai, Koushi Hidaka, Anna Miyazaki, Keiko Hojo, Saori Roppongi, Yasumitsu Sakamoto, Yasuhiro Ito, Yoshiyuki Suzuki, Wataru Ogasawara, Nobutada Tanaka, Yuko Tsuda
Organizer
The 54th Japanese Peptide Symposium
Related Report
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