2019
DOI: 10.1016/j.csbj.2019.01.012
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Stapled Peptides Inhibitors: A New Window for Target Drug Discovery

Abstract: Protein-protein interaction (PPI) is a hot topic in clinical research as protein networking has a major impact in human disease. Such PPIs are potential drugs targets, leading to the need to inhibit/block specific PPIs. While small molecule inhibitors have had some success and reached clinical trials, they have generally failed to address the flat and large nature of PPI surfaces. As a result, larger biologics were developed for PPI surfaces and they have successfully targeted PPIs located outside the cell. Ho… Show more

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Cited by 140 publications
(130 citation statements)
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“…The stitched peptide displayed the highest helicity (52%) while the double stapled peptide remained unchanged at 20%, similar to that adopted by the linear peptide. Nevertheless, both these peptides displayed increased binding to Mdm2, suggesting that the binding 16 mechanism of these peptides are different from each other. However only the stitched peptide displayed increased cellular activity, probably resulting from increased cell permeability; the double stapled peptide appears unable to cross the cell membrane.…”
Section: Discussionmentioning
confidence: 92%
See 1 more Smart Citation
“…The stitched peptide displayed the highest helicity (52%) while the double stapled peptide remained unchanged at 20%, similar to that adopted by the linear peptide. Nevertheless, both these peptides displayed increased binding to Mdm2, suggesting that the binding 16 mechanism of these peptides are different from each other. However only the stitched peptide displayed increased cellular activity, probably resulting from increased cell permeability; the double stapled peptide appears unable to cross the cell membrane.…”
Section: Discussionmentioning
confidence: 92%
“…Thirdly, macrocyclization may enhance cell permeability, such as through increased stability of intramolecular hydrogen bonding to reduce the desolvation penalty otherwise incurred in the transport of peptides across an apolar cell membrane. Amongst the several cyclization techniques described, stapling via olefin metathesis using a non-proteogenic amino acid such as alpha-methyl alkenyl side chains has proven to be very effective [13][14][15][16][17][18], particularly when the desired secondary structure of the peptide macrocycle is helical. Stapling requires incorporation of the appropriate unnatural amino acid precursors to be placed at appropriate locations along the peptide sequence such that they do not interfere with the binding face of the helix.…”
Section: Introductionmentioning
confidence: 99%
“…In original PDB-format data, the experimentally determined atomic coordinates are presented in the ATOM records. Chances are that they do not exactly match the sequence (consisting of nucleic and/or amino acid residues) of the experimental sample per se, be it protein, DNA, RNA or their complexes with drugs and/or other small molecules [35][36][37]. In fact, this misalignment arises from the uncharted territories (i.e., missing residues) of MP experimental structures deposited in PDB.…”
Section: Motivationmentioning
confidence: 99%
“…[200][201][202] On the other hand, switching to other forms of cyclic bonds such as lactamisation, olefin metathesis, ruthenium-catalysed ring closure metathesis, Cu(I)-catalysed azide-alkyne cycloaddition, and thioether formation would also be beneficial for the therapeutic use of these peptides. [203][204][205][206][207][208][209]…”
Section: Figure 2 Chemical Structures Of Tb Drugs Currently Undergoinmentioning
confidence: 99%