Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation

Micewicz, Ewa D.; Sharma, Sanjai; Waring, Alan J.; Luong, Hai; McBride, William H.; Ruchala, Piotr

doi:10.1007/s10989-015-9487-3

Cited by 9 publications

(12 citation statements)

References 148 publications

(198 reference statements)

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“…Specifically, while ( i , i +3 ) staples of various chemistries have been reported, these reports do not examine the compatibility of helical structure with stapling of two d -amino acids at ( i , i +3 ) positions. 48,70−73 Another relevant feature of DD5-o is an extended hydrophobic surface of over 750 Å 2 which includes the staple and the required hot spot residues. This hydrophobic surface wraps around more than half of the helix (Figure 4c).…”

Section: Discussionmentioning

confidence: 99%

Diversity-Oriented Stapling Yields Intrinsically Cell-Penetrant Inducers of Autophagy

Zou²,

et al. 2017

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Autophagy is an essential pathway by which cellular and foreign material are degraded and recycled in eukaryotic cells. Induction of autophagy is a promising approach for treating diverse human diseases, including neurodegenerative disorders and infectious diseases. Here, we report the use of a diversity-oriented stapling approach to produce autophagy-inducing peptides that are intrinsically cell-penetrant. These peptides induce autophagy at micromolar concentrations in vitro, have aggregate-clearing activity in a cellular model of Huntington’s disease, and induce autophagy in vivo. Unexpectedly, the solution structure of the most potent stapled peptide, DD5-o, revealed an α-helical conformation in methanol, stabilized by an unusual (i,i+3) staple which cross-links two d-amino acids. We also developed a novel assay for cell penetration that reports exclusively on cytosolic access and used it to quantitatively compare the cell penetration of DD5-o and other autophagy-inducing peptides. These new, cell-penetrant autophagy inducers and their molecular details are critical advances in the effort to understand and control autophagy. More broadly, diversity-oriented stapling may provide a promising alternative to polycationic sequences as a means for rendering peptides more cell-penetrant.

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Section: Discussionmentioning

confidence: 99%

Diversity-Oriented Stapling Yields Intrinsically Cell-Penetrant Inducers of Autophagy

Zou²,

et al. 2017

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“…Recently, Micewicz et al have used a range of distinctive S ‐alkylation staplings, with cysteines at ( i , i + 3), ( i , i + 4), ( i , i + 5) or ( i , i + 6) positions, in combination with amino acid mutations to design a library of over sixty stapled peptides in a search for antagonists of the p53‐mdm2/mdmx interaction. The peptide ligand that showed greatest cell permeability and in vivo antitumor activity in mice at low dose (3 mg) was an ( i , i + 3) o ‐xylene crosslinked peptide (AbB14Co) equipped with multiple Arg residues (Figure ) …”

Section: Chemical Approaches For Cysteine Staplingmentioning

confidence: 99%

“… An o ‐xylene stapled peptide with in vivo anticancer activity in a mouse model of cancer (AbB14Co) derived from a linear phage‐display peptide epitope (PMI‐N84) ( d ‐residues are underlined, Pf5 = pentafluorophenylalanine, Nal = 1‐naphthylalanine) …”

Section: Chemical Approaches For Cysteine Staplingmentioning

confidence: 99%

“…Likewise, some interesting bis‐electrophilic linkers are not sufficiently activated to effect the crosslink via S ‐alkylation. For instance, simple alkyl halides such as dibromooctane, dibromoheptane and dibromobutane have been shown to fail to staple a pair of cysteines. In contrast, the crosslinking of identical linkers with an olefin instead of halide occur in high yields in a p53 sequence via the thiol‐ene coupling …”

Section: Chemical Approaches For Cysteine Staplingmentioning

confidence: 99%

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Stapling peptides using cysteine crosslinking

2016

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Stapled peptides are an emerging class of cyclic peptide molecules with enhanced biophysical properties such as conformational and proteolytic stability, cellular uptake and elevated binding affinity and specificity for their biological targets. Among the limited number of chemistries available for their synthesis, the cysteine-based stapling strategy has received considerable development in the last few years driven by facile access from cysteine-functionalized peptide precursors. Here we present some recent advances in peptide and protein stapling where the side-chains of cysteine residues are covalently connected with a range of different crosslinkers affording bisthioether macrocyclic peptides of varying topology and biophysical properties. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 843-852, 2016.

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“…Cysteine‐mediated macrocycle formation has also been an effective conformational constraint, due to the sulfhydryl reactivity profile and the encodability of this natural amino acid . Various methods have been employed for macrocyclization, including S‐alkylation with bis‐electrophiles, S N Ar, and thiol‐ene reactions to form thioethers. Determining what factors affect cell penetration of crosslinked peptides has recently been assessed by Walensky et al., who determined that hydrophobicity, α‐helicity, and pI are the driving factors of cellular uptake .…”

Section: Introductionmentioning

confidence: 99%

Tuning Sulfur Oxidation States on Thioether‐Bridged Peptide Macrocycles for Modulation of Protein Interactions

et al. 2017

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Thioethers, sulfoxides, and sulfonium ions, despite diverse physicochemical properties, all engage in noncovalent interactions with proteins. Thioether-containing macrocycles are also attracting attention as protein-protein interaction (PPI) inhibitors. Here, we used a model PPI between α-helical mixed lineage leukemia (MLL) protein and kinase-inducible domain interacting (KIX) domain to evaluate oxidation effects on sulfurcontaining macrocycle structure, stability, and protein affinity. Desolvation effects from various polarity states were evaluated computationally and experimentally at the side chain, amino acid, and peptide level. Sulfur-containing side chains spanned polarity ranges between all-hydrocarbon and lactam bridges for modulating solubility, cellular uptake, and affinity. Helical propensity studies showed that, although oxidized sulfur-containing side chains could be tolerated, conformational effects were sequence-dependent. In some cases, proteolytic stability, binding capacity with KIX, and increased helicity were obtained as first steps toward developing PPI inhibitors.

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Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation

Cited by 9 publications

References 148 publications

Diversity-Oriented Stapling Yields Intrinsically Cell-Penetrant Inducers of Autophagy

Diversity-Oriented Stapling Yields Intrinsically Cell-Penetrant Inducers of Autophagy

Stapling peptides using cysteine crosslinking

Tuning Sulfur Oxidation States on Thioether‐Bridged Peptide Macrocycles for Modulation of Protein Interactions

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