Cyclic hexapeptides derived from the human thymopoietin III

Kessler, Horst; Haase, Burkhard

doi:10.1111/j.1399-3011.1992.tb01553.x

Cited by 37 publications

(11 citation statements)

References 8 publications

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“…Interestingly, the use of D-amino acids in promoting cyclization of 12-membered peptides has been studied. 28 The present observation validates such a use and indicates that D-serine could be used as a design element that could force the stevastelins to adopt a specific dominant conformation in solution. Further synthetic manipulations could provide insight on this hypothesis.…”

Section: Discussionsupporting

confidence: 83%

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

Jogalekar

2010

Biopolymers

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The stevastelins are depsipeptide natural products that show valuable immunomodulatory and phosphatase inhibitory activity. A previous report described the synthesis, conformational analysis, and biological activity of modified diastereomeric C3 analogs (1) of these molecules and deduced a single dominant conformational scaffold for each of the six benzylated stevastelin diastereomers in solution. In this study, we report a combined computational and experimental approach (NAMFIS) of these analogs based on geometric variables from the NMR data and extensive conformational searching that suggests a more subtle and complex distribution of conformations in solution. Although the results indicate some conformations to be similar to those previously proposed, they include novel motifs not observed earlier such as gamma turns. In addition, the NAMFIS analysis confirms dramatic changes in conformations accompanying a chirality change at the C3 center and also establishes the conformational homogeneity of the D-serine diastereomers. The NAMFIS analysis thus suggests the use of D-serine as a possible constraining element in peptide design and derives a set of experimental solution conformers that could shed light on the bioactive conformation of the stevastelins. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 968-976, 2010.

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Section: Discussionsupporting

confidence: 83%

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

Jogalekar

2010

Biopolymers

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“…Indeed this strategy has been employed to improve the yields of various peptide cyclizations 32,33 . For two diastereomeric short peptide sequences that differ only in α-carbon configuration at the terminal residues, cyclization is favoured for the diastereomer that contains both a d-and an l-residue at its termini 34 .…”

Section: Conformational Elements That Help Bring the Ends Togethermentioning

confidence: 99%

Contemporary strategies for peptide macrocyclization

2011

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Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis.

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“…NMR studies have shown that including a D -amino acid in short cyclic pentapeptides or hexapeptides can stabilize a characteristic backbone conformation by inducing a bII’ turn motif with the D -amino acid in the i+1 position [10, 12, 14]. Thus, this class of cyclic peptides is thought to provide a defined backbone scaffold for presenting different short peptide binding motifs.…”

Section: Discussionmentioning

confidence: 99%

“…A number of such small cyclic peptides ligands have been developed to bind to diverse target proteins. These include RGD (Arg-Gly-Asp)-containing integrin ligands [11, 12, 15], analogues of the Leu-Asp-Thr sequence of mucosal addressin cell adhesion molecule-1 (alpha(4)beta(7) integrin antagonists) [3], somatostatin receptor agonists [26], human thymopoietin III analogs [14], and CXCR4-chemokine antagonists [9]. Motivated by these previous successes for this class of cyclic peptides, we have synthesized and tested cyclic hexapeptides with a single D -amino acid that contain the secretin receptor endogenous agonist WD motif.…”

Section: Discussionmentioning

confidence: 99%

Refinement of the pharmacophore of an agonist ligand of the secretin receptor using conformationally constrained cyclic hexapeptides

et al. 2010

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There is a compelling need for the development of small molecule agonists acting at family B G protein-coupled receptors. A possible lead for the development of such drugs was reported when it was recognized that sequences endogenous to the amino terminus of the secretin receptor and certain other receptors in this family possess weak full agonist activity (Dong et al., Mol Pharmacol 2006). In the current report, we extended those observations by building the active dipeptide motif found in the secretin receptor (WD) into each position around a conformationally-constrained D-amino acid-containing cyclic hexapeptide, and determining the biological activity of each peptide at the secretin receptor. Indeed, only two positions for WD around this constrained ring resulted in biological activity at the receptor, providing further insights into the structural specificity of this phenomenon. Molecular modeling supported the presence of a unique WD backbone conformation shared only by these active peptides, and provided a more constrained template for future receptoractive agonist drug development.

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Cyclic hexapeptides derived from the human thymopoietin III

Abstract: Six diastereoisomeric cyclic hexapeptides of the partial sequence 39‐44 of human thymopoietin III in which each residue was replaced with the d‐amino acid were synthesized. In contrast to expectations, the yields from cyclization were not influenced by the location of the d‐residue.

Cited by 37 publications

References 8 publications

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

Contemporary strategies for peptide macrocyclization

Refinement of the pharmacophore of an agonist ligand of the secretin receptor using conformationally constrained cyclic hexapeptides

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