Synthesis and Conformational Analysis of Cyclotetrapeptide Mimetic β-Turn Templates and Validation as 3D Scaffolds (original) (raw)
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We extend to you a warm and sunny Aloha in celebration of the 23 rd American Peptide Symposium and the 6 th International Symposium. The meeting theme, Peptides Across the Pacific, embraced the spirit of the scientific and social program. Peptides Across the Pacific encompassed the important role that peptide science currently plays in so many disciplines and explored the potential impact peptides can make in scientific fields that have yet to realize the utility of these wonderful molecules. The scientific program for 2013 was framed by distinguished lectures delivered by two renowned peptide chemists.
Mimicking reverse turns with cyclic tetrapeptides
2008
OF THE DISSERTATION 10 INTRODUCTION 1 1.1 Secondary Protein Structure 3 1.2 Importance of Reverse Turns 7 1.3 The Entropic Cost of Binding and Conformational Flexibility 16 1.5 Computational Drug Design 19 1.6 Reverse-Turn Mimics 24 1.7 Thesis Outline 29 CHAPTER TWO EXPLORING AMINO ACID EFFECT ON CONFORMATIONS OF CYCLIC TETRAPEPTIDE REVERSE TURN MIMICS 31 2.1 Conformational Searches 38 2.2 Cyclic Peptide Synthesis 38 2.3 NMR Structural Analysis 44 2.4 Overlap of NMR structures with reverse-turn classes from PDB 56 CONFORMATIONAL PREDICTION OF CYCLIC TETRAPEPTIDE LIBRARY THAT MIMICS 54% OF REVERSE TURNS IN THE PDB 62 3.1 Validation of CTP Conformational Prediction 63
Journal of Computer-Aided Molecular Design, 2009
Reverse turns are often recognition sites for protein/protein interactions and, therefore, valuable potential targets for determining recognition motifs in development of potential therapeutics. A virtual combinatorial library of cyclic tetrapeptides (CTPs) was generated and the bonds in the low-energy structures were overlapped with canonical reverse-turn Ca-Cb bonds (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005) to determine the utility of CTPs as reverse-turn peptidomimetics. All reverse turns in the Protein Data Bank (PDB) with a crystal structures resolution B3.0 Å were classified into the same known canonical reverse-turn Ca-Cb bond clusters (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005). CTP reverse-turn mimics were compiled that mimicked both the relative orientations of three of the four as well as all four Ca-Cb bonds in the reverse turns of the PDB. 54% of reverse turns represented in the PDB had eight or more CTPs structures that mimicked the orientation of all four of the Ca-Cb bonds in the reverse turn.
Constraining cyclic peptides to mimic protein structure motifs
Angewandte Chemie (International ed. in English), 2014
Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well-defined three-dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein-like structures in water. However, short peptides can be induced to fold into protein-like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine-tune three-dimensional structure. Such constrained cyclic peptides can have protein-like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic pep...
Cyclopentapeptides as Flexible Conformational Templates
Journal of the American Chemical Society, 2000
Studies of 3D models for cyclopentapeptides (CPP's) employing only NMR spectroscopy encounter a serious problem. Because of conformer averaging, 3D structure(s) derived directly from NMR data may not correspond to the energy minimum (minima) with low relative conformational energy. At the same time, independent energy calculations can determine all low-energy conformers for the CPP backbone. The two approaches are compared in this study by results obtained for cyclo(D-Pro 1 -Ala 2 -Ala 3 -Ala 4 -Ala 5 ). Contrary to the conclusion (predominance of the II′γ type conformer) of earlier NMR studies, independent energy calculations found a different family of low-energy 3D structures that are consistent both with the NMR data in DMSO and with the known X-ray data on CPP's. The preferable Ala 4 conformations were found in the R R /R L regions suggesting studies of cyclo(D-Pro 1 -Ala 2 -Ala 3 -Aib 4 -Ala 5 ) which was synthesized. Further NMR studies confirmed the results of the independent energy calculations. The independent energy calculations have been applied also to cyclo(Arg 1 -Gly 2 -Asp 3 -D-Phe 4 -Val 5 ) and cyclo(Arg 1 -Gly 2 -Asp 3 -Phe 4 -D-Val 5 ). Both peptides are almost equally potent inhibitors of binding of R IIb 3 integrins to fibrinogen and of R V 3 integrins to vitronectin. If both of them possess a NMR-predicted conformer of the II′γ type, however, the conformations of the active sequence, Arg 1 -Gly 2 -Asp 3 , should be dissimilar in these two peptides. This discrepancy is eliminated in the 3D pharmacophore model proposed by independent energy calculations. The model is also in good agreement with the model by other authors that was confirmed by X-ray studies. Appel, J.; Blondelle, S.; Dooley, C.; Dorner, B.; Eichler, J.; Ostresh, J.; Houghten, R. Rothemund, S.; Brudel, M.; Beyermann, M.; Carpino, L. A.; Bienert, M. In Peptides. Chemistry, Structure and Biology; Proceedings of the Thirteenth American Peptide Symposium; Hodges, R. S., Smith, J. A., Eds.; ESCOM: Leiden, 1995; pp 95-96. (7) Ehrlich, A.; Brudel, M.; Beyermann, M.; Winter, R.; Carpino, L. A.; Bienert, M.
Synthesis of All-l Cyclic Tetrapeptides Using Pseudoprolines as Removable Turn Inducers
Organic Letters, 2010
Cyclic tetrapeptides have generated great interest because of their broad-ranging biological properties. In order to synthesize these highly strained 12-membered cyclic compounds, a cyclization strategy using pseudoprolines as removable turn inducers has been developed. The pseudoproline derivatives induce a cisoid amide bond in the linear peptide backbone which facilitates cyclization. After cyclization, the turn inducers can be readily removed to afford cyclic tetrapeptides containing serine or threonine residues.