ABSTRACT
Split-and-mix libraries of resin-bound "tweezer" receptors have been prepared and screened to identify receptors for dye-labelled tripeptides. The receptors incorporate a diamidopyridine unit to serve as a specific recognition site for the CO2H group, leading to strong and selective receptors for peptide guests with a CO2H terminus. The role of the dye-label, attached to the peptide guest to allow visualisation of selective recognition events in the screening experiments, has also been examined and was found to have a significant influence on the binding selectivities.
Subject(s)
Combinatorial Chemistry Techniques , Peptides/metabolism , Receptors, Peptide/chemistry , Amino Acid Sequence , Drug Design , Molecular Mimicry , Peptide Library , Peptides/chemical synthesis , Protein Binding , Receptors, Peptide/metabolism , Substrate SpecificityABSTRACT
Different dipeptide analogues containing an oxirane ring in the place of the peptidic bond were prepared starting from naturally occurring amino acids. N-Fmoc-amino aldehydes were transformed into the corresponding methoxyvinyl derivatives through a Wittig reaction, and the addition of PhSeCl gave a series of different alpha-phenylselenyl aldehydes. Mukajiama reaction with silylketene acetals gave an intermediate product that was finally transformed into the desired oxiranyl peptidomimetics. Following this strategy we were able to control three new contiguous stereocenters starting from the enantiomerically pure amino acid. The dipeptide analogues could be used in SPPS on a SASRIN resin as the final epoxides were relatively unstable under acidic conditions. Moreover the synthesis of the single dipeptide mimetics was carried out on solid phase to generate a small library of epoxy peptidomimetics. Some of the products prepared in this work resulted as time-dependent reversible inhibitors of cysteine protease.
