Restoring tissue homeostasis by regulating TGF-beta signaling by using macrocyclic peptides

• Project/Area Number: 15H06073
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry
• Research Institution: University of Tsukuba
• Principal Investigator: Hipolito Chris 筑波大学, 医学医療系, 助教 (20759914)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: macrocyclic peptides / in vitro selection / RaPID system / receptors / signaling / TGFbeta / cancer / cancer signaling

Outline of Final Research Achievements

TGF-beta signaling is implicated in cancer progression. The goal of this project is to regulate TGF-beta signaling by preventing signal transduction into the cell. We aim to identify a macrocyclic peptide or macrocyclic peptides that bind to the type 1 receptor ALK1 and prevent its interaction with the cytokine BMP and/or the type 2 receptor, thereby blocking signal transduction. After in vitro selection, a promising macrocyclic peptide, ALK1-3R6-5, was identified from a diverse library of over 10^12 unique macrocyclic peptides. Chemical synthesis of ALK1-3R6-5 derivatives is underway.

Research Products

• [Journal Article] <i>In Vitro</i> Selected Macrocyclic Peptides: Tools for Regulating the Conformational Freedom of Transmembrane Proteins (2016)
  • Author(s): Hipolito CJ, Nishio K, Suga H.
  • Journal Title: YAKUGAKU ZASSHI Volume: 136 Issue: 2 Pages: 191-196
  • DOI: 10.1248/yakushi.15-00229-4
  • NAID: 130005121477
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2016-02-01
  • Peer Reviewed
• [Journal Article] A current perspective on applications of macrocyclic-peptide-based high-affinity ligands. (2016)
  • Author(s): Leenheer, D.; ten Dijke, P.; Hipolito C. J.
  • Journal Title: Biopolymers. Peptide Science. Volume: 106(6) Issue: 6 Pages: 889-900
  • DOI: 10.1002/bip.22900
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LCP crystallization and X-ray diffraction analysis of VcmN, a MATE transporter from Vibrio cholerae. (2016)
  • Author(s): 2.Kusakizako, T.; Tanaka, Y.; Hipolito, C. J.; Kuroda, T.; Ishitani, R.; Suga, H.; Nureki, O.
  • Journal Title: Acta Crystallogr. F Struct. Biol. Commun. Volume: 72(Pt 7) Issue: 7 Pages: 552-557
  • DOI: 10.1107/s2053230x16008931
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor. (2016)
  • Author(s): Bayo;-Puxan N, Rodriguez-Mias R, Goldflam M, Kotev M, Ciudad S, Hipolito CJ, Varese M, Suga H, Campos-Olivas R, Barril X, Guallar V, Teixid&#243; M, Garcia J, Giralt E.
  • Journal Title: ChemMedChem Volume: 11(8) Issue: 8 Pages: 928-939
  • DOI: 10.1002/cmdc.201500467
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Selection-based discovery of macrocyclic peptides for the next generation therapeutics. (2015)
  • Author(s): T. Morioka; N.D. Loik; C.J. Hipolito; Y. Goto; H. Suga
  • Journal Title: Current opinion in chemical biology Volume: 26C Pages: 34-41
  • DOI: 10.1016/j.cbpa.2015.01.023
  • Peer Reviewed / Open Access
• [Presentation] Restoring tissue homeostasis by using macrocyclic peptides (2016)
  • Author(s): Christopher John Hipolito, Stef Jansen, Wei Li, Mitsuyasu Kato, Peter ten Dijke
  • Organizer: TGFbeta Meeting
  • Place of Presentation: Leiden University Medical Center(Leiden, Netherland)
  • Year and Date: 2016-08-21
• [Presentation] Targeting ABC transporters with macrocyclic peptides. (2015)
  • Author(s): Hipolito CJ, Beis K, Suga H
  • Organizer: International Conference on Circular Proteins.
  • Place of Presentation: Moreton Island, Australia
  • Year and Date: 2015-11-01
  • Int'l Joint Research / Invited
• [Presentation] Macrocyclic peptide ligands that inhibit transporter function and improve protein crystallization. (2015)
  • Author(s): Hipolito, CJ, Suga H
  • Organizer: 11th Australian Peptide Conference
  • Place of Presentation: Pepper Salt Resort, NSW, Australia
  • Year and Date: 2015-10-25
  • Int'l Joint Research