Macrocyclic RGD-peptides with high selectivity for α_vβ₃ integrin in cancer imaging and therapy

Area of Science:

• Biochemistry and Molecular Biology
• Oncology
• Drug Discovery

Background:

• Integrins, especially α_vβ₃, are key regulators of cell behavior implicated in cancer progression.
• Developing selective integrin ligands for α_vβ₃ over other subtypes (e.g., α_vβ₅) remains a therapeutic challenge.

Purpose of the Study:

• To synthesize and identify highly selective α_vβ₃-targeting macrocyclic peptides.
• To establish a novel platform for developing integrin-targeted cancer diagnostics and therapeutics.

Main Methods:

• One-pot sortase A-mediated on-resin peptide cleavage and in situ cyclization.
• Synthesis of two generations of macrocyclic RGD-peptide libraries.
• Screening using surface plasmon resonance and cell-based competition assays.

Main Results:

• Identification of the lead compound c-(G5RGDKcLPET) with high affinity and selectivity for α_vβ₃.
• Functionalization of the lead peptide with Cy5 for imaging and monomethyl auristatin E (MMAE) for targeted therapy.
• Demonstration of enhanced potential for cancer imaging and therapy.

Conclusions:

• The study presents a novel method for synthesizing selective integrin-targeting macrocyclic peptides.
• The lead compound and its functionalized derivatives show promise for α_vβ₃-targeted cancer diagnostics and therapeutics.
• Macrocyclic peptides offer a valuable strategy for advancing cancer treatment.