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Bioorg Med Chem. 2009 Feb 1;17(3):1018-25. doi: 10.1016/j.bmc.2008.01.045. Epub 2008 Jan 30.

On-bead cyclization in a combinatorial library of 15,625 octapeptides.

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Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, CH-3012 Berne, Switzerland.


Combinatorial peptide libraries prepared by split-and-mix synthesis on solid support can be decoded by amino acid analysis (AAA) using the TAGSFREE method, which assigns variable amino acids to 'unique pair' positions. The method was used here to investigate on-bead cyclization in a library of 15,625 octapeptides X(8)X(7)X(6)X(5)X(4)-Lys-X(2)-glu(beta-Ala-beta-Ala-TentaGel Macrobead)-OAllyl, anchored via the side-chain carboxylate of the d-glutamate. Cyclization was carried out by amide bond formation between the free N-terminus and the alpha-carboxyl group of d-glutamate after selective removal of the Fmoc and allyl protecting groups, and followed using the TNBS test for free amines. Fast-cyclizing sequences often contained a turn element, in particular Ala-(Asp/Thr)-Pro at X(8)-X(7)-X(6), and phenylalanine at X(2). Slow-cyclizing sequences contained predominantly basic and polar residues, in particular Arg-His-Ser at X(7)-X(6)-X(5) and threonine at X(8). Fast-cyclizing sequences gave higher preparative yields of cyclic peptides (22-26% purified yields) than slow-cyclizing sequences (6-8%), showing that fast reaction is associated with efficient cyclization. This experiment demonstrates the first use of a TAGSFREE library of cyclic peptides.

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