Using cyclic peptide mixtures as probes for metal ion host-guest interactions

Summary Mixtures of cyclic peptides, formed by head-to-tail cyclizations of side-chain resin-bound linear sequences, have been prepared using solid-phase synthesis. Fast atom bombardment mass spectrometry of cyclic peptides with various metal ions can reveal preferred modes of host-guest patterns, albeit in a nonquantitative manner. This approach could prove useful for more rapid screening of potential peptide ionophores. A cyclic heptapeptide with a dipeptide tail proved to be a particularly effective host for a Ca²⁺ ion; in a small three-component mixture, cycloGly-Asp-d-Pro-Xxx-Asp-d-Pro-Asp(Aca-Phe-NH₂)], binding to Ca²⁺ varied from Xxx=N-MeAla>GlySar. In a 15-component mixture, cycloPro-Xxx-Asn-Pro-Xxx-Asn] where Xxx=Ala, Glu, Leu, Lys or Phe, there were no significant differences with respect to binding to metal ions. We believe this to be the first reported use of cyclic peptide libraries for screening metal ions to discern host-guest relationships.Abbreviations Aca aminocaproic acid - Boc tert-butyloxycarbonyl - BOP benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate - DCM dichloromethane - DIEA diisopropylethylamine - DMF N,N-dimethylformamide - ESI electrospray ionization - FABMS fast atom bombardment mass spectrometry - pMBHA 4-methylbenzhydrylamine - TFA trifluoroacetic acid This paper is based on a presentation given at the Symposium on Peptide Structure and Design as part of the 31st Annual ACS Western Regional Meeting held in San Diego, CA, USA, October 18–21, 1995.