Synthesis and incorporation into cyclic peptides of tolan amino acids and their hydrogenated congeners: construction of an array of A–B-loop mimetics of the Cε3 domain of human IgE

Offermann, D. A., McKendrick, J. ORCID: https://orcid.org/0000-0003-2275-0569, Sejberg, J. J. P., Mot, B., Holdom, M. D., Helm, B. A., Leatherbarrow, R. J., Beavil, A. J., Sutton, B. J. and Spivey, A. C. (2012) Synthesis and incorporation into cyclic peptides of tolan amino acids and their hydrogenated congeners: construction of an array of A–B-loop mimetics of the Cε3 domain of human IgE. Journal of Organic Chemistry, 77 (12). pp. 3197-3214. ISSN 0022-3263 doi: 10.1021/jo202604q

Abstract/Summary

The disruption of the human immunolobulin E–high affinity receptor I (IgE–FcεRI) protein–protein interaction (PPI) is a validated strategy for the development of anti asthma therapeutics. Here, we describe the synthesis of an array of conformationally constrained cyclic peptides based on an epitope of the A–B loop within the Cε3 domain of IgE. The peptides contain various tolan (i.e., 1,2-biarylethyne) amino acids and their fully and partially hydrogenated congeners as conformational constraints. Modest antagonist activity (IC50 660 μM) is displayed by the peptide containing a 2,2′-tolan, which is the one predicted by molecular modeling to best mimic the conformation of the native A–B loop epitope in IgE.