- Switching substitution groups on the in-tether chiral centre influences backbone peptides' permeability and target binding affinity
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Different substitution groups on the in-tether chiral centre of chirality-induced helical peptides (CIH peptides) showed distinguishable effects on the peptides' cellular uptakes and binding affinities with the estrogen receptor α(ER-α). This study proves that in-tether chiral centres are a valuable modification site for constructing peptide ligands with preferable biophysical properties.
- Jiang, Yixiang,Hu, Kuan,Shi, Xiaodong,Tang, Qingzhuang,Wang, ZiChen,Ye, Xiyang,Li, Zigang
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- Mono-Substituted Hydrocarbon Diastereomer Combinations Reveal Stapled Peptides with High Structural Fidelity
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Modified peptides, such as stapled peptides, which replicate the structure of α-helical protein segments, represent a potential therapeutic advance. However, the 3D solution structure of these stapled peptides is rarely explored beyond the acquisition of circular dichroism (CD) data to quantify bulk peptide helicity; the detailed backbone structure, which underlies this, is typically undefined. Diastereomeric stapled peptides based on helical sections of three proteins (αSyn, Cks1 and CK1α) were generated; their overall helicity was quantified by CD; and the most helical peptide from each series was selected for structural analysis. Solution-phase models for the optimised peptides were generated using NMR-derived restraints and a modified CHARMM22 force field. Comparing these models with PDB structures allowed deviation between the stapled peptides and critical helical regions to be evaluated. These studies demonstrate that CD alone is not sufficient to assess the structural fidelity of a stapled peptide.
- McWhinnie, Fergus S.,Sepp, Kristel,Wilson, Charlotte,Kunath, Tilo,Hupp, Ted R.,Baker, Terry S.,Houston, Douglas R.,Hulme, Alison N.
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- Novel potent apoA-I peptide mimetics that stimulate cholesterol efflux and pre-β particle formation in vitro
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Reverse cholesterol transport (RCT) is believed to be the primary mechanism by which HDL and its major protein apoA-I protect against atherosclerosis. Starting from the inactive 22-amino acid peptide representing the consensus sequence of the class A amphipathic helical repeats of apoA-I, we designed novel peptides able to mobilize cholesterol from macrophages in vitro, and to stimulate the formation of 'nascent HDL' particles, with potency comparable to the entire apoA-I protein.
- Ingenito, Raffaele,Burton, Charlotte,Langella, Annunziata,Chen, Xun,Zytko, Karolina,Pessi, Antonello,Wang, Jun,Bianchi, Elisabetta
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supporting information; experimental part
p. 236 - 239
(2010/04/05)
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