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Potent CXCR4 Antagonists Containing Amidine Type Peptide Bond Isosteres
journal contributionposted on 2011-06-09, 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.
immunodeficiency virusanalogueHIVisosteric amidine substructureCXC chemokine receptor type 4Potent CXCR 4 Antagonists Containing Amidine Type Peptide Bond IsosteresA seriesCXCR 4 receptoramidine type peptide bond isosterespeptide backbonemacrocyclization processantagonistbinding inhibitionamidine groupX 4 strainsSDFFC 131CXCR 4.