N-methylated cyclic pentaalanine peptides as template structures.
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.
Chatterjee
Jayanta
J
Department Chemie, Lehrstuhl II für Organische Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching D-85747, Germany.
Mierke
Dale
D
Kessler
Horst
H
D000409:Alanine / Q000737:chemistry*; D008745:Methylation; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D010455:Peptides; D010456:Peptides, Cyclic; C019529:polyalanine; D000409:Alanine