The combinatorial peptide library is a powerful method in which a vast number of various peptides are synthesized.

The first use of synthetic peptide libraries was reported by Geysen et al. in 1984, using the pin method, and since then many papers describing different methods of synthesizing and screening peptide libraries have been published.

The combinatorial peptide library approach is mainly based on three methods. In one, peptide libraries are synthesized and cleaved from a solid support to be screened as free compounds. In a second, synthetic combinatorial libraries of peptides are assayed on their solid support. The third method is based on phage-display, which enables selection of clones of interest rather than screening, because large phage libraries can be panned against a target molecule by standard protocols, allowing enrichment of only a few hundred specific phages that can easily be screened for positive ligands in a single test. Specific phages are then treated for DNA sequencing and peptide genes are revealed for subsequent chemical synthesis.

The above three technologies for selection of peptide ligands fall into two groups: libraries that allow the selection of ligands in their final unlabeled and soluble form and those by which peptides are selected while still linked to their support, either synthetic or biological, or to a labeling molecule.

Synthetic combinatorial libraries, especially synthetic peptide libraries, are generally prepared by two different methods, the “divide, couple, recombine” (DCR) method, also referred to as  “pool/split, portion/mix, split-and-mix”, and the “amino acid mixture” method. The DCR method involves dividing resin into pools, coupling amino acids to individual aliquots of resin, mixing them and dividing them for next amino acid coupling. This process generates “one-bead one-compound (OBOC)” libraries containing millions of random peptides, each bead expressing only one peptide and each peptide having equal distribution in the library.

The advantage of the OBOC technique – a large number (106−108) of peptides can be synthesized and screened rapidly. One major disadvantage of the OBOC technique – each library compound is tethered to the solid support via a linker such as polyethylene glycol and may result in steric hindrance between the cellular receptor and the library substance.

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