Using combinatorial methods to arrive at a quantitative structure-stability relationship for a new class of one-armed cationic peptide receptors targeting the C-terminus of the amyloid beta-peptide.
A new class of one-armed tripeptide based cationic guanidiniocarbonyl pyrrole receptors is shown to strongly bind the tetrapeptide L-Val-L-Val-L-Ile-L-Ala, representing the C-terminus of the amyloid beta-peptide even under polar conditions. A medium sized combinatorial library of 125 receptors was synthesized on a solid support and their binding properties determined on bead using a quantitative fluorescence assay. The binding constants are in the order of 10(3)-10(4) M-1 (in the presence of a formate counter ion in methanol) for the most efficient ones but differ by more than a factor of 100 among the 125 library members. Based on the binding data of 12 receptors a structure-stability relationship was established for peptide binding by this new receptor class. Complex formation is controlled by a fine balanced interplay of hydrophobic and electrostatic interactions with none of these two interactions alone being strong enough to ensure complexation under these polar conditions.
Schmuck
Carsten
C
Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany. schmuck@chemie.uni-wuerzburg.de
Heil
Martin
M
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D019151:Peptide Library; D011485:Protein Binding; D011758:Pyrroles; D018000:Receptors, Peptide / Q000737:chemistry*; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D019151:Peptide Library; D011758:Pyrroles; D018000:Receptors, Peptide