Discovery and Optimization of a TRAIL R2 Agonist for Cancer Therapy

Angell, Yvonne M.; Bhandari, Ashok; Chakrabarti, Anjan; Francisco, M. Nuria De; Duguay, Amy; Frederick, Brian; Leu, Karen; Leuther, Kerstin K.; Li, Xianfeng; Penta, Kalyani; Piplani, Sunila; Sana, Reuben; Whitehorn, Erik A.; Schatz, Pete J.; Yin, Kevin; Holmes, Christopher P.

doi:10.1007/978-0-387-26575-9_168

Cited by 2 publications

(3 citation statements)

References 7 publications

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“…Crude cyclic peptides were purified by preparative C 18 RP-HPLC and lyophilized. Divalent 1d-3d were prepared as described (30) by reaction of cyclic peptides (2.2 equiv) with the bis-succinimidyl carboxymethoxyacetate (1 equiv) in dimethylformamide in the presence of a tertiary base. The detailed synthesis of trivalent 1t-3t based on adamantane core will be reported elsewhere.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, small apoptogenic peptides that bind to specific TRAIL receptor interfaces have been reported (30,31). It is well established that death receptor oligomerization is important for DISC function/efficacy, and structural studies provide novel insight into this process (32).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, it has been shown that strategies that increase receptor oligomerization amplify TRAIL-induced apoptosis (33,34). Therefore, we used previously described sequences (30) to systematically study the effect of peptide dimerization and trimerization on DR5 binding and selective DR5-mediated death induction. By using two different stepwise tumorigenesis models (35), we revealed the tumor-selective activity of such TRAIL mimics (TRAIL mim ) in vitro and determined their capacity to synergize with resveratrol.…”

Section: Introductionmentioning

confidence: 99%

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Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

et al. 2010

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Ongoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5. In this study, we report on the selective apoptotic effects of multivalent DR5 binding peptides (TRAIL mim/DR5 ) on cancer cells in vitro and in vivo. Surface plasmon resonance revealed up to several thousand-fold increased affinities of TRAIL mim/DR5 -receptor complexes on generation of divalent and trivalent molecules, the latter of which was achieved with a conformationally restricted adamantane core. Notably, only multivalent molecules triggered a substantial DR5-dependent apoptotic response in vitro. In tumor models derived from human embryonic kidney cells or primary foreskin fibroblasts, TRAIL mim/DR5peptides exerted a cancer cell-selective action that could synergize with resveratrol in a manner independent of p53. In a xenograft model of human colon cancer, a divalent TRAIL mim/DR5 peptide inhibited tumor growth.Our results offer a proof-of-principle for the development of synthetic small molecules to trigger the TRAIL apoptosis pathway for cancer therapy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

et al. 2010

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Thioether Analogues of Disulfide‐Bridged Cyclic Peptides Targeting Death Receptor 5: Conformational Analysis, Dimerisation and Consequences for Receptor Activation

et al. 2014

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Cyclic peptides containing redox-stable thioether bridges might provide a useful alternative to disulfide-bridged bioactive peptides. We report the effect of replacing the disulfide bridge with a lanthionine linkage in a 16-mer cyclic peptide that binds to death receptor 5 (DR5, TRAIL-R2). Upon covalent oligomerisation, the disulfide-bridged peptide has previously shown similar behaviour to that of TNF-related apoptosis inducing ligand (TRAIL), by selectively triggering the DR5 cell death pathway. The structural and biological properties of the DR5-binding peptide and its desulfurised analogue were compared. Surface plasmon resonance (SPR) data suggest that these peptides bind DR5 with comparable affinities. The same holds true for dimeric versions of these peptides: the thioether is able to induce DR5-mediated apoptosis of BJAB lymphoma and tumorigenic BJELR cells, albeit to a slightly lower extent compared to its disulfide homologue. NMR analysis revealed subtle variation in the conformations of the two peptides and suggests that the thioether peptide is slightly less folded than its disulfide homologue. These observations could account for the different capability of the two dimers to cluster DR5 receptors on the cell surface and to trigger apoptosis. Nevertheless, our results suggest that the thioether peptide is a potential candidate for evaluation in animal models.

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Discovery and Optimization of a TRAIL R2 Agonist for Cancer Therapy

Cited by 2 publications

References 7 publications

Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Thioether Analogues of Disulfide‐Bridged Cyclic Peptides Targeting Death Receptor 5: Conformational Analysis, Dimerisation and Consequences for Receptor Activation

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