Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides

Nielsen, Daniel S.; Lohman, Rink-Jan; Hoang, Huy N.; Hill, Timothy A.; Jones, Alun; Lucke, Andrew J.; Fairlie, David P.

doi:10.1002/cbic.201500441

Cited by 61 publications

(67 citation statements)

References 24 publications

(12 reference statements)

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“…The occurrence of intramolecular hydrogen bonds in cyclic peptides also depends on the overall backbone conformation of the peptide. Nielsen et al (39) studied cyclic hexapeptides with different number of proline residues in the peptide sequence. Their study suggested that cyclic hexapeptides without a proline have relatively flexible backbone conformations in solution compared with cyclic peptide with prolines.…”

Section: Discussionmentioning

confidence: 99%

Peptide ligands for targeting the extracellular domain of EGFR: Comparison between linear and cyclic peptides

et al. 2017

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Colorectal cancer (CRC) is the third most common solid internal malignancy among cancers. Early detection of cancer is key to increasing the survival rate of colorectal cancer patients. Overexpression of the EGFR protein is associated with CRC. We have designed a series of peptides that are highly specific for the extracellular domain of EGFR, based on our earlier studies on linear peptides. The previously reported linear peptide LARLLT, known to bind to EGFR, was modified with the goals of increasing its stability and its specificity toward EGFR. Peptide modifications, including D-amino acid substitution, cyclization, and chain reversal, were investigated. In addition, to facilitate labeling of the peptide with a fluorescent dye, an additional lysine residue was introduced onto the linear (KLARLLT) and cyclic peptides cyclo(KLARLLT) (Cyclo.L1). The lysine residue was also converted into an azide group in both a linear and reversed cyclic peptide sequences cyclo(K(N3)larllt) (Cyclo.L1.1) to allow for subsequent "click" conjugation. The cyclic peptides showed enhanced binding to EGFR by SPR. NMR and molecular modeling studies suggest that the peptides acquire a β-turn structure in solution. In vitro stability studies in human serum show that the cyclic peptide is more stable than the linear peptide.

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Section: Discussionmentioning

confidence: 99%

Peptide ligands for targeting the extracellular domain of EGFR: Comparison between linear and cyclic peptides

et al. 2017

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“…Their findings suggested that membrane permeability of cyclic peptides due to passive transport might be governed by intramolecular hydrogen bonding, steric protection of the amide NH group from solvation, and conformational flexibility allowing the peptide to assume a conformation in a hydrophobic environment, such as the center of a lipid bilayer, different from that in water. However, a more recent study by Fairlie's group showed that conformational rigidity rather than flexibility results in higher membrane permeability . Kessler's group synthesized a collection of cyclo[ d ‐ala‐(Ala) 5 ] with different N‐methylation patterns.…”

Section: Introductionmentioning

confidence: 99%

Highly Conformationally Restricted Cyclopropane Tethers with Three‐Dimensional Structural Diversity Drastically Enhance the Cell Permeability of Cyclic Peptides

Matsui,

Kido,

Watari

et al. 2016

Chemistry A European J

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What is the most significant result of this study? This study demonstrates that by introducing ah ighly constrained cyclopropane tether,c ell-membrane-permeable cyclic peptides can be obtained amino acid sequence-independently,b ut conforma-tion-dependently.T his strategy would be applicable for getting permeable cyclic peptides with ad esired bioactive amino acid sequence , which allow us to address undruggable targets, such as protein-protein interactions, that are difficult to regulate by typical "Rule of Five" small molecules. This allows the use of the cyclic peptides as potential drugs. How did the collaborationo nt his project start? Shuto group in Hokkaido University have developed "3D structural diversity-oriented strategy", which provides as eries of peptidomi-metics with the same functional groups, but with various 3D structures by introducing the key highly constrained cyclopropane units to identify peptidomimetics regulating at arget biomolecule. Shio-nogi group suggested that 3D structural diversity-oriented strategy would provide cell-membrane-permeable cyclic peptides, and thus, the collaboration started. To wards ag oal, the original theoretical aspect in university and the high-quality technical aspect in industry complementarily worked in as ynergistic manner to provide the remarkable results. Invited for the cover of this issue is the group of Kouhei Matsui and Satoshi Shuto at Shionogi &C o.,Ltd. and at Hokkaido University.T he image depicts the cyclopropane tethers with three-dimensional structural diversity that are able to remarkably change the conformation and physicochemical properties of cyclic peptides due to the characteristic steric feature of cy-clopropane. Read the fulltext of the article at

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“…However, a drawback often associated with peptides is a short half‐life due to a lack of proteolytic stability. One way to improve the stability of a peptide is through backbone or side chain cyclization, as this reduces susceptibility to proteases and, in some cases, improves activity (Clark et al, ) and potentiates orally delivered activity (Clark et al, ; Nielsen et al, ; Wang et al, ). One class of peptides that has gained particular interest is venom‐derived disulfide‐rich peptides due to their inherent stability (brought about by the high number of cysteine residues) and ability to selectively and potently inhibit voltage‐gated potassium (K V ), calcium (Ca V ), and sodium (Na V ) channels.…”

Section: Introductionmentioning

confidence: 99%

Efficient enzymatic cyclization of an inhibitory cystine knot‐containing peptide

Kwon

Bosmans²,

Kaas

et al. 2016

Biotech & Bioengineering

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Disulfide-rich peptides isolated from cone snails are of great interest as drug leads due to their high specificity and potency toward therapeutically relevant ion channels and receptors. They commonly contain the inhibitor cystine knot (ICK) motif comprising three disulfide bonds forming a knotted core. Here we report the successful enzymatic backbone cyclization of an ICK-containing peptide κ-PVIIA, a 27-amino acid conopeptide from Conus purpurascens, using a mutated version of the bacterial transpeptidase, sortase A. Although a slight loss of activity was observed compared to native κ-PVIIA, cyclic κ-PVIIA is a functional peptide that inhibits the Shaker voltage-gated potassium (Kv) channel. Molecular modeling suggests that the decrease in potency may be related to the loss of crucial, but previously unidentified electrostatic interactions between the N-terminus of the peptide and the Shaker channel. This hypothesis was confirmed by testing an N-terminally acetylated κ-PVIIA, which shows a similar decrease in activity. We also investigated the conformational dynamics and hydrogen bond network of cyc-PVIIA, both of which are important factors to be considered for successful cyclization of peptides. We found that cyc-PVIIA has the same conformational dynamics, but different hydrogen bond network compared to those of κ-PVIIA. The ability to efficiently cyclize ICK peptides using sortase A will enable future protein engineering for this class of peptides and may help in the development of novel therapeutic molecules.

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Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides

Cited by 61 publications

References 24 publications

Peptide ligands for targeting the extracellular domain of EGFR: Comparison between linear and cyclic peptides

Peptide ligands for targeting the extracellular domain of EGFR: Comparison between linear and cyclic peptides

Highly Conformationally Restricted Cyclopropane Tethers with Three‐Dimensional Structural Diversity Drastically Enhance the Cell Permeability of Cyclic Peptides

Efficient enzymatic cyclization of an inhibitory cystine knot‐containing peptide

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