N-methylated cyclic pentaalanine peptides as template structures

Jayanta Chatterjee, Dale Mierke, Horst Kessler

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

The N-methylation of cyclic peptides can be used to modify the activity and/or selectivity of biologically active peptides. As N-methylation introduces different flexibility and lipophilicity, it can also improve the bioavailability (the ADMET profile). To search for conformationally constrained cyclic peptides, a library of 30 different N-methylated peptides with the basic sequence cyclo(-D-Ala-L-Ala4-) was synthesized. Based on the NMR analysis, seven of these peptides exhibited single conformations (>98%). The structural features of these peptides were determined by a combination of NMR and distance geometry and then further refined by molecular dynamics simulations in an explicit DMSO solvent box. The structures provided from these efforts can now serve as templates for the rational design of cyclic pentapeptides with a distinct backbone conformation or for "spatial screening" to explore the bioactive conformation of medically important peptide systems.

Original languageEnglish
Pages (from-to)15164-15172
Number of pages9
JournalJournal of the American Chemical Society
Volume128
Issue number47
DOIs
StatePublished - 29 Nov 2006

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