Geometric diversity through permutation of backbone configuration in cyclic peptide libraries.
Cyclic peptides offer the possibility of varying both scaffold geometry and R-group functionality. For example, parameters such as ring size and the placement of D-amino acid and proline residues can have a dramatic effect on the conformations of cyclic peptides, allowing access to structurally diverse species based on simple modifications in their linear sequences. We synthesized a cyclic peptide library in which ring size, alpha-carbon stereochemistry, and proline placement were varied. Analysis of the products showed that heptapeptides in general cyclized more readily than hexapeptides, and within these groups the scaffolds with a greater number of pralines cyclized with markedly lower yields than scaffolds with fewer pralines. Split-pool libraries based on a sample set of these scaffolds showed that, in general, scaffold geometry outweighed side chains variation in determining cyclization efficiency. These concepts were applied to the synthesis of cyclodimeric variants of an inhibitor of actin assembly in Xenopus egg extracts, yielding side chain variants with improved potency over the original scaffold.
Perlman
Zachary E
ZE
Department of Systems Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115l, USA.
Bock
Jonathan E
JE
Peterson
Jeffrey R
JR
Lokey
R Scott
RS
D000199:Actins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002457:Cell Extracts / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014981:Xenopus
D000199:Actins; D002457:Cell Extracts; D009842:Oligopeptides; D019151:Peptide Library; D010456:Peptides, Cyclic