Potent CXCR4 antagonists containing amidine type Peptide bond isosteres

  • ACS Med Chem Lett. 2011 Mar 28;2(6):477-80. doi: 10.1021/ml200047e.
Eriko Inokuchi  1 ,  Shinya Oishi  1 ,  Tatsuhiko Kubo  1 ,  Hiroaki Ohno  1 ,  Kazuya Shimura  2 ,  Masao Matsuoka  2 ,  Nobutaka Fujii  1
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
  • 2. Institute for Virus Research, Kyoto University , Sakyo-ku, Kyoto 606-8507, Japan.
PMID: 24900333 DOI: 10.1021/ml200047e
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.

Keywords
Amidine; CXCR4 antagonist; FC131; chemokine; nitrile oxide; peptidomimetics.