De novo design of alpha-amylase inhibitor: a small linear mimetic of macromolecular proteinaceous ligands.
We report a low molecular weight inhibitor of alpha-amylases based on a linear peptidic scaffold designed de novo through the use of combinatorial chemistry. The inhibitory motif denoted PAMI (peptide amylase inhibitor) was selected by using L-peptide libraries and was fine-tuned by the introduction of unnatural modifications. PAMI specifically inhibits glycoside hydrolases of family 13. Its interaction with porcine pancreatic alpha-amylase was characterized by inhibition kinetics, fluorescence competition assays with natural alpha-amylase inhibitors, and isothermal titration calorimetry. We demonstrate that the critical amino acid residues in PAMI are shared with those in the macromolecular proteinaceous inhibitors that, however, bind to alpha-amylases through a spatially scattered set of intermolecular contacts. Thus, natural molecular evolution as well as combinatorial evolution selected the same alpha-amylase binding determinants for completely different spatial frameworks.[1]References
- De novo design of alpha-amylase inhibitor: a small linear mimetic of macromolecular proteinaceous ligands. Dolecková-Maresová, L., Pavlík, M., Horn, M., Mares, M. Chem. Biol. (2005) [Pubmed]
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