Chemical Biology Researches Using Recognition Units for GPCR Dimers

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K15139
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TAMAMURA Hirokazu 東京医科歯科大学, 生体材料工学研究所, 教授 (80217182)
• Research Collaborator: NOMURA Wataru ; MIZUGUCHI Takaaki ; OHASHI Nami
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: GPCR二量体 / 2価型リガンド / CXCR4 / プローブ / がん

Outline of Final Research Achievements

Interaction of CXCR4 with its endogenous ligand, stromal-cell derived factor-1 (SDF-1)/CXCL12, induces various physiological functions involving chemotaxis. Bivalent ligands with a polyproline helix bearing a cyclic pentapeptide, FC131, were previously shown to have higher binding affinities for CXCR4 than the corresponding monovalent ligands. Bivalent ligands based on a 14-mer peptide T140 derivative with polyproline linkers have been designed and synthesized. Heterological bivalent ligands recognizing heterological GPCR dimers as well as homological bivalent ligands recognizing homological dimers have been developed in a similar way. In addition, a methodology to develop drug-shuttle compounds using recognition probes for GPCR dimers has been established. The activity of these peptides as well as the effect of bivalency of the ligand on GPCR binding has been assessed. The effective functions of bivalent ligands indicates the therapeutic potential.

Free Research Field

創薬化学