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Sequence-selective nonmacrocyclic two-armed receptors for peptides

Summary

Tweezer-like receptor molecules have proven their potential for molecular recognition on several occasions. We decided to make twofold use of this receptor design: firstly to learn whether simple molecular forceps consisting of two peptide chains linked by a spacer are able to selectively bind to small peptides, and secondly to investigate the importance of structural preorganization for the characteristics of the receptors. We prepared two encoded combinatorial libraries based on this design, featuring two combinatorial tripeptide chains held by different scaffolds: the use of chenodeoxycholic acid as spacer provided a rigid scaffold for the forceps, whereas linking the peptide chains by a pentamethylene chain yielded a very flexible forceps structure. Molecules from the cholic acid library recognize and discriminate various enkephalins with micromolar affinities. Molecules from the flexible library show distinct interactions with the enkephalins as well, but the specificity and affinity are clearly diminished. Thus, although the interactions of molecular forceps with peptides are not crucially dependent on structural preorganization, receptors with a rigid design are clearly superior to flexible molecular forceps.

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Supplementary Material comprising procedures for the preparation and spectroscopical data of compounds5 through8, as well as a listing of the 104 decoded sequences from the assay of the flexible library with5Leu-enkephalin/Disperse Red, can be obtained from the author on request.

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Nestler, H.P. Sequence-selective nonmacrocyclic two-armed receptors for peptides. Mol Divers 2, 35–40 (1996). https://doi.org/10.1007/BF01718698

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Keywords

  • Combinatorial libraries
  • Molecular recognition
  • Receptor libraries
  • Sulfonamides
  • Peptides
  • Steroids