Dataset Information

Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability.

ABSTRACT: Beta-peptides possess several features that are desirable in peptidomimetics; they are easily synthesized, fold into stable secondary structures in physiologic buffers, and resist proteolysis. They can also bind to a diverse array of proteins to inhibit their interactions with alpha-helical ligands. beta-peptides are usually not cell-permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg(8) sequence to a beta-peptide improves uptake but adds considerable mass. We previously reported that embedding a small cationic patch within a PPII, alpha-, or beta-peptide helix improves uptake without the addition of significant mass. In another mass-neutral strategy, Verdine, Walensky, and others have reported that insertion of a hydrocarbon bridge between the i and i + 4 positions of an alpha-helix also increases cell uptake. Here we describe a series of beta-peptides containing diether and hydrocarbon bridges and compare them on the basis of cell uptake and localization, affinities for hDM2, and 14-helix structure. Our results highlight the relative merits of the cationic-patch and hydrophobic-bridge strategies for improving beta-peptide uptake and identify a surprising correlation between uptake efficiency and hDM2 affinity.

SUBMITTER: Bautista AD

PROVIDER: S-EPMC2853015 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability.

Bautista Arjel D AD Appelbaum Jacob S JS Craig Cody J CJ Michel Julien J Schepartz Alanna A

Journal of the American Chemical Society 20100301 9

Beta-peptides possess several features that are desirable in peptidomimetics; they are easily synthesized, fold into stable secondary structures in physiologic buffers, and resist proteolysis. They can also bind to a diverse array of proteins to inhibit their interactions with alpha-helical ligands. beta-peptides are usually not cell-permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg(8) sequence to a beta-peptide improves upta ...[more]

PMID: 20158215

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Project description:BACKGROUND: Sunflower trypsin inhibitor-1 (SFTI-1) and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are potent protease inhibitors comprising a cyclic backbone. RESULTS: Elucidation of structure-activity relationships for SFTI-1 and MCoTI-II was used to design inhibitors with enhanced inhibitory activity. CONCLUSION: An analog of MCoTI-II is one of the most potent inhibitors of matriptase. SIGNIFICANCE: These results provide a solid basis for the design of selective peptide inhibitors of matriptase with therapeutic potential. The type II transmembrane serine protease matriptase is a key activator of multiple signaling pathways associated with cell proliferation and modification of the extracellular matrix. Deregulated matriptase activity correlates with a number of diseases, including cancer and hence highly selective matriptase inhibitors may have therapeutic potential. The plant-derived cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), is a promising drug scaffold with potent matriptase inhibitory activity. In the current study we have analyzed the structure-activity relationships of SFTI-1 and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II), a structurally divergent trypsin inhibitor from Momordica cochinchinensis that also contains a cyclic backbone. We show that MCoTI-II is a significantly more potent matriptase inhibitor than SFTI-1 and that all alanine mutants of both peptides, generated using positional scanning mutagenesis, have decreased trypsin affinity, whereas several mutations either maintain or result in enhanced matriptase inhibitory activity. These intriguing results were used to design one of the most potent matriptase inhibitors known to date with a 290 pm equilibrium dissociation constant, and provide the first indication on how to modulate affinity for matriptase over trypsin in cyclic peptides. This information might be useful for the design of more selective and therapeutically relevant inhibitors of matriptase.

Dataset Information

Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability.

Publications

Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability.

Similar Datasets

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