Design, synthesis, and biological evaluation of CXCR4 ligands
| Autor: | Pierre Lavigne, Emanuel Escher, Christine E. Mona, Élie Besserer-Offroy, Nikolaus Heveker, Jérôme Cabana, Richard Leduc, Eric Marsault |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Receptors CXCR4 Protein Conformation Stereochemistry Sequence (biology) Chemistry Techniques Synthetic Molecular Dynamics Simulation Ligands Biochemistry Small Molecule Libraries 03 medical and health sciences Protein structure Humans Inverse agonist Physical and Theoretical Chemistry Receptor Oligopeptide Chemistry Organic Chemistry HEK 293 cells Total synthesis Combinatorial chemistry Small molecule Chemokine CXCL12 HEK293 Cells 030104 developmental biology Drug Design |
| Zdroj: | Organic & Biomolecular Chemistry. 14:10298-10311 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c6ob01484d |
| Popis: | A combination of the CXCR4 inverse agonist T140 with N-terminal CXCL12 oligopeptides has produced the first nanomolar synthetic CXCR4 agonists. In these agonists, the inverse agonistic portion provides affinity whereas the N-terminal CXCL12 sequence induces receptor activation. Several CXCR4 crystal structures exist with either CVX15, an inverse agonist closely related to T140 and IT1t, a small molecule; we therefore attempted to produce another CXCL12 oligopeptide combination with IT1t. For this purpose, a primary amino group was introduced by total synthesis into one of the methyl groups of IT1t, serving as an anchoring point for the oligopeptide graft. The introduction of the oligopeptides on this analog however yielded antagonists, one compound displaying high affinity. On the other hand, the amino-substituted analogue itself proved to be an inverse agonist with a binding affinity of 2.6 nM compared to 11.5 nM for IT1t. This IT1t-like analog is hitherto one of the most potent non-peptidic CXCR4 inverse agonists reported. |
| Databáze: | OpenAIRE |
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