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Peptide-based Identification of Functional Motifs and their Binding Partners
Published on: June 30, 2013
Synthetic constrained peptide selectively binds and antagonizes death receptor 5
Johanna Vrielink1, Mariette S Heins, Rita Setroikromo
1Department of Pharmaceutical Biology, University of Groningen, the Netherlands.
The FEBS Journal
|February 17, 2010
Summary
Researchers identified a peptide that specifically binds to death receptor 5 (DR5), inhibiting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binding. This peptide may serve as a therapeutic lead for diseases involving dysregulated TRAIL signaling.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Apoptosis, or programmed cell death, is crucial for multicellular organism development and homeostasis.
- Dysregulation of apoptosis is linked to diseases like cancer, neurodegenerative disorders, and autoimmune conditions.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via death receptors DR4 and DR5, presenting a therapeutic target.
Purpose of the Study:
- To identify peptides that specifically bind to death receptor 5 (DR5).
- To investigate the potential of these peptides as inhibitors of TRAIL binding to DR5.
- To explore their utility as research tools or therapeutic leads for TRAIL-related diseases.
Main Methods:
- Screening of a disulfide-constrained phage display peptide library against DR5.
- Synthesis and characterization of identified peptides (YCKVILTHRCY) in monomeric and dimeric forms.
- Binding affinity studies using Surface Plasmon Resonance (SPR) and flow cytometry on cell lines.
Main Results:
- A peptide, YCKVILTHRCY, was identified that specifically binds DR5, not DR4 or decoy receptors.
- Both monomeric and dimeric forms of the peptide inhibited TRAIL binding to DR5.
- The dimeric form exhibited higher affinity (K(d) = 40 nm) than the monomeric form (K(d) = 272 nm).
- The peptide reduced TRAIL-induced cell death in Colo205 colon carcinoma cells.
Conclusions:
- The peptide YCKVILTHRCY specifically targets DR5 and inhibits TRAIL binding.
- This peptide can be a valuable tool for studying DR5 signaling pathways.
- It holds potential as a lead for developing therapeutics for diseases with aberrant TRAIL signaling.
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