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Potent CXCR4 antagonists containing amidine type Peptide bond isosteres.

ABSTRACT: 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.

SUBMITTER: Inokuchi E

PROVIDER: S-EPMC4018133 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Potent CXCR4 antagonists containing amidine type Peptide bond isosteres.

Inokuchi Eriko E Oishi Shinya S Kubo Tatsuhiko T Ohno Hiroaki H Shimura Kazuya K Matsuoka Masao M Fujii Nobutaka N

ACS medicinal chemistry letters 20110328 6

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 ...[more]

PMID: 24900333

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