ml200047e_si_001.pdf (6.51 MB)
Download file

Potent CXCR4 Antagonists Containing Amidine Type Peptide Bond Isosteres

Download (6.51 MB)
journal contribution
posted on 09.06.2011, 00:00 authored by Eriko Inokuchi, Shinya Oishi, Tatsuhiko Kubo, Hiroaki Ohno, Kazuya Shimura, Masao Matsuoka, Nobutaka Fujii
A series of FC131 [cyclo(-d-Tyr-Arg-Arg-Nal-Gly-)] analogues containing amidine type peptide bond isosteres were synthesized as selective CXC chemokine receptor type 4 (CXCR4) antagonists. An isosteric amidine substructure was constructed by a macrocyclization process using nitrile oxide-mediated C−N bond formation. All of the amidine-containing FC131 analogues exhibited potent SDF-1 binding inhibition to CXCR4. The Nal-Gly-substituted analogue was characterized as one of the most potent cyclic pentapeptide-based CXCR4 antagonists reported to date. The improved activity against human immunodeficiency virus (HIV) type-1 X4 strains suggested that addition of another basic amidine group to the peptide backbone effectively increases the selective binding of the peptides to CXCR4 receptor.