Structurally Resilient Peptide Assembly Regulates Pathogenic Galectin-10 Crystallization To Mitigate Crystallopathy...

Area of Science:

• Biochemistry
• Immunology
• Nanotechnology

Background:

• Pathogenic protein crystallization in vivo causes inflammation and tissue damage, posing a therapeutic challenge.
• Galectin-10 (Gal-10) crystallization is a key driver of airway inflammation, activating IL-1β pathways and promoting neutrophilic inflammation.

Purpose of the Study:

• To develop and characterize ISQ, a novel self-assembling peptide targeting Gal-10 crystallization.
• To evaluate the therapeutic potential of ISQ in preclinical models of Gal-10 crystal-induced airway inflammation.

Main Methods:

• ISQ was designed to target and dissolve Gal-10 crystals.
• ISQ's binding affinity and self-assembly properties were assessed in vitro.
• Therapeutic efficacy was evaluated in a murine model and primary patient-derived airway epithelial cells.

Main Results:

• ISQ binds Gal-10 with nanomolar affinity (KD = 2.1 nM) and dissolves preformed crystals.
• ISQ self-assembles into stable nanostructures with high thermal resilience.
• Intratracheal ISQ administration significantly reduced airway inflammation, cytokine production, and neutrophil infiltration in a murine model.

Conclusions:

• ISQ is a first-in-class self-assembling peptide therapeutic that disrupts pathogenic protein crystallization.
• ISQ demonstrates significant therapeutic efficacy in preclinical models of Gal-10 crystallopathy.
• ISQ offers a promising new treatment strategy for inflammatory conditions driven by protein crystallization.