VERSATILITY OF POSITIONAL SCANNING SYNTHETIC COMBINATORIAL LIBRARIES FOR THE IDENTIFICATION OF INDIVIDUAL COMPOUNDS

Positional scanning synthetic combinatorial libraries (PS-SCLs) offer a unique and rapid approach for the identification of individual active compounds from libraries made up of millions of compounds fro basic research and drug discovery. As presented here, PS-SCLs are free to interact in solution, and therefore can be screened in virtually any assay system to rapidly identify compounds. For example, a PS-SCL made up of hexapeptides consists of six separate positional libraries, each composed of mixtures having a single position defined with an amino acid and the remaining positions as mixtures of amino acids. The screening of PS-SCLs, in most instances, permits the identification of the most active amino acids at each position of a peptide in a single assay. To illustrate the versatility of this combinatorial library approach, three different hexapeptide PS-SCLs are described: (1) N-terminal acetylated, (2) N-terminal non-acetylated (both composed of L-amino acids), and (3) N-terminal acetylated composed of D-amino acids. Each of the PS-SCLs is composed of more than 50 million peptides; they are used here to identify; an antigenic determinant recognized by a monoclonal antibody; non-acetylated peptide sequences that bind to delta opioid receptors; acetylated and non-acetylated peptide inhibitors of melittin's hemolytic activity; and D-amino acid peptide inhibitors of trypsin. (C) 1994 Wiley-Liss, Inc.