Binding of Small Oligopeptides

Going now from single amino acids to even larger substrates requires further binding sites attached to the guanidiniocarbonyl pyrroles for additional interactions with the peptides' other binding sites besides the carboxylate (Figure 2.3.1). How should such a peptide receptor look like? In principle there are two distinct approaches [15]. One can try to design a complete receptor de novo, rationally with the help of theoretical calculations. The larger the substrate, the more difficult this becomes, however, because theoretical calculations are not yet sufficiently reliable for complete design of a tailor-made artificial host for a large substrate. Another possibility is to use a random trial and error approach and to identify suitable receptors with the help of combinatorial chemistry [16, 17] (for more work on combinatorial chemistry see Chapters 3.1, 3.3, or 5.4). The best guarantee for success is, of course, to integrate both methods - to use binding motifs designed for a specific target as building blocks for a combinatorial synthesis. In such a focused combinatorial library [18] the chances of finding a hit are much higher than in a completely random library, because the structural diversity is already positively biased for a given problem, e.g. binding of a specific target. It is, therefore, sufficient to use even small libraries with only a couple of hundred different members.

Following this concept, we set out to find efficient receptors for tetrapeptidic substrates. As a first target the hydrophobic tetrapeptide, Ac-Val-Val-Ile-Ala-OH was chosen. This tetrapeptide represents the C-terminal sequence of the amyloid-^-

hydrophobic interactions hydrophobic interactions

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