Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides

Jamieson, A. G. , Boutard, N., Beauregard, K., Bodas, M. S., Ong, H., Quiniou, C., Chemtob, S. and Lubell, W. D. (2009) Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides. Journal of the American Chemical Society, 131(22), pp. 7917-7927. (doi: 10.1021/ja9010628) (PMID:19453183)

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Abstract

Incorporation of amino lactams into biologically active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection strategy has been developed for the systematic synthesis of peptides containing configurationally defined α- and β-amino γ-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates 9 and 8 minimized bis-alkylation and provided N-alkyl peptides, which underwent lactam annulation under microwave heating. Employing this solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 lactam derivatives and validated the effectiveness of this approach on peptides bearing aliphatic, aromatic, branched, charged, and heteroatomic side chains. The binding affinity IC50 values of the GHRP-6 lactam analogues on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogues. In these cases, lactam analogues were prepared exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biological activity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jamieson, Professor Andrew
Authors: Jamieson, A. G., Boutard, N., Beauregard, K., Bodas, M. S., Ong, H., Quiniou, C., Chemtob, S., and Lubell, W. D.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Journal of the American Chemical Society
Publisher:American Chemical Society
ISSN:0002-7863
ISSN (Online):1520-5126
Published Online:19 May 2009

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