Peptide combinatorial library design strategies

The design strategies employed to improve combinatorial chemistry have evolved considerably since the early days of peptide and peptidomimetic libraries. The main concern early was on the availability of suitable synthetic methods that could be applied to the synthesis of libraries of small molecules however, this early obstacle has been intensively addressed and at this point can be considered overcome (for examples of new methodology developed for library production see Ref 21). With the ability in hand to prepare many different types of molecules in a variety of formats, the current challenge is to decide what compounds to make. As a consequence, much attention is now focused on the definition and analysis of chemical diversity. 

Designed antimicrobials from host defense peptides using multivalent and combinatorial library strategies... 

Natural products are generally complex chemical structures, whether they are cyclic peptides like cyclosporin A, or complex diterpenes like paclitaxel. Inspection of the structures that are discussed in Section IV is usually enough to convince any skeptic that few of them would have been discovered without application of natural products chemistry. Recognition of this structural diversity has certainly made an impact on the design of combinatorial strategies, as exemplified by the 2 million plus compound library that was recently assembled by the Schreiber group using natural product-like structures as the initial scaffolds. 

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