Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design

Li, Xiang; Tolbert, W.D.; Hu, Honggang; Gohain, Neelakshi; Zou, Yan; Niu, F.; He, Wangxiao; Yuan, Weirong; Su, Jiacan; Pazgier, Marzena; Li, Xiang

doi:10.1039/c8sc03275k

Cited by 53 publications

(47 citation statements)

References 63 publications

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“…Peptides are superior as therapeutics to small molecules in interacting with β-catenin but still suffer from the poor membrane permeability and protease stability 10 . Peptide stapling chemistry developed by Verdine and coworkers, takes advantage of ruthenium-catalyzed metathesis to crosslink the side chains of paired anchoring residues at suitable positions, and has been successfully applied to design various peptide inhibitors with improved proteolytic stability, membrane permeability, and thus biological activity 11,12 .…”

Section: Introductionmentioning

confidence: 99%

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

Liao

Zhao

et al. 2020

Cell Discov

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Aberrant activation of Wnt/β-catenin signaling has been associated with the onset and progression of many types of tumors and thus β-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to β-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/ β-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient β-catenin degradation. The obtained xStAx-VHLL sustained β-catenin degradation and manifested strong inhibition of Wnt signaling in cancer cells and in APC −/− organoids. Furthermore, xStAx-VHLL could effectively restrain tumor formation in BALB/C nude mice, and diminish the existing tumors in APC min/+ mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patientderived organoids. These findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of β-catenin degrader PROTACs as a new class of promising anticancer agent.

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Section: Introductionmentioning

confidence: 99%

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

Liao

Zhao

et al. 2020

Cell Discov

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“…Pairwise alanine-tolerated positions prompt sites amenable to further modifications, i.e., stapling. Side chain stapling is used for reinforcing helical structure and improving peptide stability toward proteases [30][31][32] . To leverage the pharmacological properties of the identified MDM2 binders, a hexafluorobenzene-mediated cysteine arylation reaction was employed to generate (i, i+4) stapled PMI analogs (peptides 9-16) 33 .…”

Section: Pairwise Sar Validationmentioning

confidence: 99%

Deep Alanine Scanning Reveals Potent Multi-alanine-substituted Protein–protein Interaction Inhibitors

Ye¹,

Lee²,

Gates³

et al. 2021

Preprint

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Establishing structure–activity relationships is crucial to understand and optimize the activity of peptide-based inhibitors of protein–protein interactions. Single alanine mutagenesis provides limited information toward this goal. To guide multiple simultaneous peptide modifications with retention of biological activity, we used synthetic combinatorial alanine-scanning libraries—in which each position was varied with either the wild type residue or alanine—with an affinity selection platform to study the mutational tolerance of protein–ligand interactions. Applying this platform to a peptide binder to the oncogenic protein MDM2, several multi-alanine-substituted analogs that retained low nanomolar affinity were discovered, including a 13-mer binder with seven alanine substitutions at non-hotspot positions. These binders served as templates for further modifications, generating cysteine-substituted, perfluoroaryl-stapled peptides with sub-nanomolar affinity and ten-fold improved proteolytic stability. The alanine substitution tolerances for peptide ligands of the 12ca5 antibody and 14-3-3 regulatory protein were also reported, demonstrating the general applicability of this new platform. We envision that deep combinatorial alanine scanning will be a powerful tool for structure–activity optimization of potential peptide therapeutics.

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“…The hydrocarbon-stapling technique pioneered by Verdine and colleagues enables side-chain cross-linked and conformationally stabilized helical peptides to traverse the cell membrane with improved proteolytic stability and enhanced biological activity [61,62]. Of note, a hydrocarbon-or dithiocarbamatestapled PMI has been shown to be a potent p53 activator in vitro and in vivo [63][64][65].…”

Section: Small Molecule and Peptide Versus Protein Activators Of P53mentioning

confidence: 99%

A tetrameric protein scaffold as a nano-carrier of antitumor peptides for cancer therapy

Niu

et al. 2019

Biomaterials

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A major pharmacological barrier to peptide therapeutics is their susceptibility to proteolytic degradation and poor membrane permeability, which, in principle, can be overcome by nanoparticle-based delivery technologies. Proteins, by definition, are nano materials and have been clinically proven as an efficient delivery vehicle for small molecule drugs. Here we describe the design of a protein-based peptide drug carrier derived from the tetramerization domain of the chimeric oncogenic protein Bcr/Abl of chronic myeloid leukemia. A dodecameric peptide inhibitor of the p53-MDM2/MDMX interaction, termed PMI, was grafted to the N-terminal helical region of Bcr/Abl tetramer. To antagonize intracellular MDM2/MDMX for p53 activation, we extended this protein, PMI Bcr/Abl, by a C-terminal Arg-repeating hexapeptide to facilitate its cellular uptake. The resultant tetrameric protein PMI Bcr/Abl-R6 adopted an alpha-helical conformation in solution and bound to MDM2 at an affinity of 32 nM. PMI Bcr/Abl-R6 effectively induced apoptosis of HCT116 p53 +/+ cells in vitro in a p53-dependent manner and potently inhibited tumor growth in a nude mouse xenograft model by stabilizing p53 in vivo. Our proteinbased delivery strategy thus provides a clinically viable solution to p53-inspired anticancer therapy *

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Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design

Abstract: A novel peptide stapling strategy based on the dithiocarbamate chemistry linking the side chains of residues Lys(i) and Cys(i + 4) of unprotected peptides is developed.

Cited by 53 publications

References 63 publications

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

Deep Alanine Scanning Reveals Potent Multi-alanine-substituted Protein–protein Interaction Inhibitors

A tetrameric protein scaffold as a nano-carrier of antitumor peptides for cancer therapy

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