TRAIL-Inspired Multivalent Dextran Conjugates Efficiently Induce Apoptosis upon DR5 Receptor Clustering

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Targeting tumor cells for apoptosis induction is a long-standing goal in cancer research.
• Death receptor 5 (DR5) is overexpressed on many cancer cells and its clustering initiates the death-inducing signaling cascade (DISC).

Purpose of the Study:

• To develop potent apoptosis-inducing conjugates by covalently multimerizing a DR5-targeting peptide (DR5TP) on a dextran scaffold.
• To investigate the impact of scaffold flexibility on DR5 clustering and apoptosis induction.
• To assess the feasibility of conjugating these DR5-targeting molecules to Fc receptors for improved in vivo properties.

Main Methods:

• Covalent multimerization of DR5TP onto a dextran scaffold.
• Enzyme-catalyzed ligation of the dextran conjugate to a human fragment crystallizable (Fc) receptor.
• Assessment of apoptosis-inducing potency using EC50 values.

Main Results:

• The dextran-based DR5TP conjugates demonstrated potent apoptosis induction with EC50 values in the nanomolar range (2-20 nM).
• The flexible polysaccharide framework of dextran facilitated effective DR5 clustering, overcoming limitations of previous methods requiring defined ligand orientation.
• Conjugation to an Fc receptor maintained high potency (EC50 = 2-7 nM), suggesting potential for enhanced in vivo half-life and bispecific targeting applications.

Conclusions:

• Dextran-based multimerization of DR5-targeting peptides offers a novel and effective strategy for inducing tumor cell apoptosis.
• This approach provides enhanced conformational flexibility, leading to potent receptor clustering and apoptosis induction.
• Fc-conjugation presents a promising avenue for developing advanced cancer therapeutics with improved pharmacokinetics and targeting capabilities.