Abstract
A combinatorial library of 6,250,000 tetrapeptides in the mixture based positional scanning format was screened in binding assays for the three opioid receptors, mu, delta, and kappa. Three different binding profiles were found. Individual peptides were synthesized representing all possible combinations of the active amino acids identified from the screening data. New, highly active peptides selective for each of the three receptors were chosen. This study demonstrates the power of mixture-based combinatorial libraries to identify distinctly different ligands for closely related receptors.
Highlights
Synthetic combinatorial libraries have gained widespread acceptance for the rapid identification of new drug leads
A second combinatorial library containing 52 million non-acetylated hexapeptides was subsequently used to identify ligands for the opioid receptors, which were closely related to the natural ligands methionine- and leucine-enkephalin (YGGFM, YGGFL) [4]
How many different families of compounds for a particular target exist and can they be identified in a given library? What are the chances of missing the most active compound? What other compounds are present or could be identified from the data that are not immediately obvious? Are similar building blocks universally replaceable? Peptides, because of their ease of synthesis, represent the most convenient compound class for use in the study of mixturebased combinatorial libraries
Summary
The PS-SCL used in this study is composed of 6,250,000 tetrapeptides and contains four sublibraries, in which one of the four positions is defined with a single amino acid (O) and the three remaining positions are a mixture of 50 different L-, D-, and unnatural amino acids (X). Mixture resins (X) were prepared using mixtures of t-butoxycarbonyl-protected amino acids at each coupling step. Each of the amino acids was present in a concentration that yielded close to equimolar coupling of each amino acid. The ratio of the concentrations of the individual amino acids used to yield this approximate equimolar coupling was pre-determined using reverse phase-high pressure liquid chromatography to compare mixture profiles relative to standard mixtures synthesized using the divide, couple, and recombine method [1] as detailed in Ref. 9. Side chain deprotection and cleavage from the resin support were achieved using low hydrogen fluoride [11] and high hydrogen fluoride
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