Peptide combinatorial library cyclization

The appeal of cyclic peptides as a rich source of biologically active molecules makes the synthesis of combinatorial libraries of these compounds desirable. However, few avenues for the synthesis of large arrays of cyclic peptides exist. This is primarily caused by the difficult orthogonal deprotection requirements, which require a careful choice of synthetic strategy. For example, if a solution-phase head-to-tail cyclization is undertaken (15) (Fig. 2A), the peptide must be purified at each step of the synthesis (i.e., after synthesis of the linear, cyclized protected and after deprotection) (see Note 1). 

Initially, combinatorial libraries of peptides consisted primarily of products made from linear combinations of naturally occurring amino acids. Subsequently just about every devise employed in ordinary peptide work has been applied to combinatorial studies, leading to a persistent evolutionary drift away from collections of natural peptides. For example, to enhance the metabolic stability of such libraries, end capping of the amino end and the carboxy end and also cyclization have been employed to stabilize these substances. Before long, the incorporation of unusual amino acids also began (Fig. 1.10). These substances can be termed pseudopeptides... 

While in normal combinatorial peptide libraries (either chemical or phage display) each component has a unique sequence that is different from all others, in the cycloscan libraries all components have the same sequence, but differ in their conformation. This conformational diversity is generated in a dendrimeric hierarchy as shown exemplarily in Scheme 27 for the parent linear heptapeptide A-B-C-D-E-F-G. The diversity of the 1st order sublibrary (this nomenclature was adopted from Furka[468l) is based on the mode of cyclization. Excluding the head-to-tail cyclization there are seven different modes of cyclization that can be used for cycloscan three natural modes of cyclization and four modes of N-backbone cyclization. In addition there are five theoretical modes of C-backbone cyclization (see Scheme 1) which are not included in Scheme 27. 

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