Kappa Opioid Tetrapeptiies from Expanded Deconvolution of a Positional Scanning Library

摘要

We have previously identified novel tetrapeptides for the three opioid receptors from a single tetrapeptide positional scanning combinatorial library [1]. The library contained over 13 million peptides from which we synthesized only 24 peptides to identify novel KOR ligands. The active sequences identified were all D amino acid peptides lacking an N-terminal tyrosine (D-Phe-D-Nal-D-Nle-D-Arg-NH2). With the knowledge that the library contained additional active sequences not identified in the first screen, we have used a similar tetrapeptide library (65 amino acids versus 60 in the first library) and employed a new mixture linking analysis to assist in the library deconvolution. Positional scanning deconvolution can be prohibitive when the combination of all active amino acids requires the synthesis of a large number of peptides. We describe the use of mixture of mixtures and mixture linking analysis for the identification of three clusters of active peptides from the library.