Conformationally constrained macrocycles that mimic tripeptide beta-strands in water and aprotic solvents

Reid, RC, Kelso, MJ, Scanlon, MJ and Fairlie, DP (2002) Conformationally constrained macrocycles that mimic tripeptide beta-strands in water and aprotic solvents. Journal of The American Chemical Society, 124 20: 5673-5683. doi:10.1021/ja0256461

Author Reid, RC
Kelso, MJ
Scanlon, MJ
Fairlie, DP
Title Conformationally constrained macrocycles that mimic tripeptide beta-strands in water and aprotic solvents
Journal name Journal of The American Chemical Society   Check publisher's open access policy
ISSN 0002-7863
Publication date 2002
Sub-type Article (original research)
DOI 10.1021/ja0256461
Volume 124
Issue 20
Start page 5673
End page 5683
Total pages 11
Place of publication USA
Publisher American Chemical Society
Collection year 2002
Language eng
Subject C1
250204 Bioinorganic Chemistry
730102 Immune system and allergy
Abstract The beta-strand conformation is unknown for short peptides in aqueous solution, yet it is a fundamental building block in proteins and the crucial recognition motif for proteolytic enzymes that enable formation and turnover of all proteins. To create a generalized scaffold as a peptidomimetic that is preorganized in a beta-strand, we individually synthesized a series of 15-22-membered macrocyclic analogues of tripeptides and analyzed their structures. Each cycle is highly constrained by two trans amide bonds and a planar aromatic ring with a short nonpeptidic linker between them. A measure of this ring strain is the restricted rotation of the component tyrosinyl aromatic ring (DeltaG(rot) 76.7 kJ mol(-1) (16-membered ring), 46.1 kJ mol(-1) (17-membered ring)) evidenced by variable temperature proton NMR spectra (DMF-d(7), 200-400 K). Unusually large amide coupling constants ((3)J(NH-CHalpha) 9-10 Hz) corresponding to large dihedral angles were detected in both protic and aprotic solvents for these macrocycles, consistent with a high degree of structure in solution. The temperature dependence of all amide NH chemical shifts (Deltadelta/T7-12 ppb/deg) precluded the presence of transannular hydrogen bonds that define alternative turn structures. Whereas similar sized conventional cyclic peptides usually exist in solution as an equilibrium mixture of multiple conformers, these macrocycles adopt a well-defined beta-strand structure even in water as revealed by 2-D NMR spectral data and by a structure calculation for the smallest (15-membered) and most constrained macrocycle. Macrocycles that are sufficiently constrained to exclusively adopt a beta-strand-mimicking structure in water may be useful pre-organized and generic templates for the design of compounds that interfere with beta-strand recognition in biology.
Keyword Chemistry, Multidisciplinary
Nuclear Magnetic-resonance
Hiv-1 Protease
Peptidomimetic Inhibitors
Molecular Recognition
Peptide Conformation
Secondary Structure
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
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Created: Tue, 14 Aug 2007, 18:56:22 EST