N-Methylated Cyclic Pentaalanine Peptides as Template Structures

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.

Improving Oral Bioavailability of Peptides by Multiple N‐Methylation: Somatostatin Analogues

“…This result gives an indication of the importance of the spatial orientation of Phe 11 . Although there is a loss in the bent conformation by Nmethylation of Phe 11 which results in the deep burying of the phenyl ring, it retains an activity comparable to the stem peptide. These results suggest that multiple N-methylation can also be useful in elucidating fine details of the bioactive conformation.…”

“…[17] In general, we observe an enhancement in the binding affinity when the molecule contains MeLys 9 and a reduction with Me-d-Trp 8 or MePhe 11 , this subtle modulation in the activity could be understood by analyzing the conformations of these analogues. Goodman et al suggested the bent conformation of the peptide as the bioactive conformation, which is stabilized by the two g turns about Phe 7 and Thr 10 .…”

“…[16] The cyclization yield was also dependent on the sequence of the linear precursor. As the conformation of the stem peptide cyclo-(-PFwKTF-) has a bII' turn about d-Trp 8 and Lys 9 and a bVI turn about Phe 11 and Pro 6[17] Lys 9 was chosen as the Cterminal amino acid to be linked to the tritylchloridepolystyrene (TCP) resin in all the cases where Thr 10 was non Nmethylated. Thus, during cyclization, though the linear peptide exhibits a dynamic nature in solution, it will always prefer a turn structure, this brings the N-terminal and Cterminal ends into close proximity to enhance cyclization.…”

“…Goodman et al suggested the bent conformation of the peptide as the bioactive conformation, which is stabilized by the two g turns about Phe 7 and Thr 10 . [31] This bent conformation results in the deep insertion of the analogue is less active than MePhe 11 . This result gives an indication of the importance of the spatial orientation of Phe 11 .…”

“…[31] This bent conformation results in the deep insertion of the analogue is less active than MePhe 11 . This result gives an indication of the importance of the spatial orientation of Phe 11 . Although there is a loss in the bent conformation by Nmethylation of Phe 11 which results in the deep burying of the phenyl ring, it retains an activity comparable to the stem peptide.…”