From One-Bead One-Compound Combinatorial Libraries to Chemical Microarrays

Abstract

In 1984, Geysen et al. reported the synthesis of peptides on polyethylene pins in a 96-well foot-print (the multi-pin system) [45]. In 1992, Frank et al. described the synthesis of multiple different peptides on cellulose paper [40]. The number of compounds prepared by these parallel synthesis techniques is limited, but they represent the early development of synthetic combinatorial chemistry and chemical arrays. Geysen et al. applied the multi-pin system to synthesize peptide mixtures on individual pins, and applied iterative screening (enzyme-linked immunoabsorbant assay) and synthesis approaches to elucidate the chemical structure of the biologically active peptides [46]. Fodor et al. first reported the minaturization of the chemical arrays by using light-directed photolithographic chemical synthesis techniques to construct 1042 peptides on a glass chip [38]. Such spatially-addressable peptide microarrays were probed with fluorescent-labeled antibodies, and quantitated with a fluorescent scanner. About the same time, we described the use of split-mix synthesis method to generate millions of random peptide-beads such that each bead displayed only one peptide entity [84]. These “one-bead one-compound” (OBOC) peptide libraries were then screened with an enzyme-linked colorimetric assay, and positive peptide-beads were physically isolated for structural analysis. Such bead libraries can be considered as chemical microarrays that are not addressable but spatially separable.