An Apoptosis‐Inducing Peptidic Heptad That Efficiently Clusters Death Receptor 5

Valldorf, Bernhard; Fittler, Heiko; Deweid, Lukas; Ebenig, Aileen; Dickgießer, Stephan; Sellmann, Carolin; Becker, J.W.; Zielonka, Stefan; Empting, Martin; Avrutina, Olga; Kolmar, Harald

doi:10.1002/anie.201511894

Cited by 28 publications

(23 citation statements)

References 32 publications

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“…Another experimental approach is to use no TRAIL itself but multivalent synthetic peptide agonists of TRAIL using different coupling agents such as adamantane cores [118], adamantane-based dendrons [119], or biomolecular scaffolds of peptidic nature [120]. These multivalent synthetic peptides show an improved affinity for DR5, inducing an enhanced cytotoxic activity due to an increased formation of high-order peptide: receptor complexes (dimeric, trimeric, and hexameric forms).…”

Section: Implication Of Trail Receptors Oligomerization In Cancer mentioning

confidence: 99%

Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy

Naval

Miguel

Gallego-Lleyda

et al. 2019

Cancers

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(TNF)-related apoptosis-inducing ligand (TRAIL) is able to activate the extrinsic apoptotic pathway upon binding to DR4/TRAIL-R1 and/or DR5/TRAIL-R2 receptors. Structural data indicate that TRAIL functions as a trimer that can engage three receptor molecules simultaneously, resulting in receptor trimerization and leading to conformational changes in TRAIL receptors. However, receptor conformational changes induced by the binding of TRAIL depend on the molecular form of this death ligand, and not always properly trigger the apoptotic cascade. In fact, TRAIL exhibits a much stronger pro-apoptotic activity when is found as a transmembrane protein than when it occurs as a soluble form and this enhanced biological activity is directly linked to its ability to cluster TRAIL receptors in supra-molecular structures. In this regard, cells involved in tumor immunosurveillance, such as activated human T cells, secrete endogenous TRAIL as a transmembrane protein associated with lipid microvesicles called exosomes upon T-cell reactivation. Consequently, it seems clear that a proper oligomerization of TRAIL receptors, which leads to a strong apoptotic signaling, is crucial for inducing apoptosis in cancer cells upon TRAIL treatment. In this review, the current knowledge of oligomerization status of TRAIL receptors is discussed as well as the implications for cancer treatment when using TRAIL-based therapies.

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Section: Implication Of Trail Receptors Oligomerization In Cancer mentioning

confidence: 99%

Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy

Naval

Miguel

Gallego-Lleyda

et al. 2019

Cancers

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“…In particular, they described an octameric TRAILR2 binder with >100 fold higher specific activity than soluble TRAIL in vitro and potent anti-cancer activity in vivo [146,147]. Similarly, it has been found that a TRAILR2-binding peptide elicits strong agonism when fused to a hepatemeric C4b scaffold [148].…”

Section: Next Generation Trail Death Receptor Agonists Based On Anmentioning

confidence: 99%

Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation

Wajant

2019

Cancers

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.

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“…AMG655 and Death Receptor 5 (DR5)), which is thought to be as a result of weak receptor activation [84]. For instance, DR5 requires cross-linking or receptor clustering for activation and therefore recent DR5-targeted therapeutic design has progressed towards multivalent agents, whereas first-generation DR5-targeting antibodies were bivalent [85][86][87]. Alternatively however, through the use of a multi-functional antibody-conjugated nanoparticle, a high number of antibody molecules can be conjugated per particle, resulting in a sufficient density of antibody paratopes to induce apoptosis via effective DR5 clustering, unlike free antibody alone [66,88,89].…”

Section: Targeting Moietiesmentioning

confidence: 99%

Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface

Tracey

Smyth

Barelle³

et al. 2021

Biochemical Society Transactions

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Interest in nanomedicines has grown rapidly over the past two decades, owing to the promising therapeutic applications they may provide, particularly for the treatment of cancer. Personalised medicine and ‘smart’ actively targeted nanoparticles represent an opportunity to deliver therapies directly to cancer cells and provide sustained drug release, in turn providing overall lower off-target toxicity and increased therapeutic efficacy. However, the successful translation of nanomedicines from encouraging pre-clinical findings to the clinic has, to date, proven arduous. In this review, we will discuss the use of nanomedicines for the treatment of cancer, with a specific focus on the use of polymeric and lipid nanoparticle delivery systems. In particular, we examine approaches exploring the surface functionalisation of nanomedicines to elicit active targeting and therapeutic effects as well as challenges and future directions for nanoparticles in cancer treatment.

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An Apoptosis‐Inducing Peptidic Heptad That Efficiently Clusters Death Receptor 5

Cited by 28 publications

References 32 publications

Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy

Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy

Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation

Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface

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