PEPTIDE INHIBITORS OF HUMAN ISLET AMYLOID POLYPEPTIDE AGGREGATION: FROM MOLECULAR DESIGN TO THERAPEUTIC POTENTIAL
DOI:
https://doi.org/10.65327/hsn.v10i3.2496Keywords:
hIAPP, amyloid aggregation, peptide inhibitors, β-cell toxicity, type 2 diabetesAbstract
Huge amounts of human islet amyloid polypeptide (hIAPP) aggregate in patients with type 2 diabetes mellitus (T2DM) and this aggregation pathway is an important therapeutic target. In this review, peptide-based inhibitors of hIAPP aggregation are discussed about their molecular design, inhibitory mechanisms, translational potential. Structural and biophysical evidence suggests that hIAPP aggregation occurs through nucleation, formation of oligomers, secondary nucleation, fibril elongation and mature fibril assembly with membrane associated intermediates playing a role in the cytotoxicity. Regions of hIAPP are amyloidogenic, and can be disrupted by sequence complementarity, conformational restriction, stereochemical inversion, cyclization, glycosylation, and peptidomimetic modification. Methods reported are mimics of β-hairpin conformation, D-peptides, rationally designed hexapeptides, cyclic peptides, anti-cross amyloid compounds, and O-glycosylated peptides. Peptides inhibits primary nucleation, by interfering with oligomer formation, by capping fibril ends, by remodelling preformed aggregates, by protecting lipid membranes and by preserving the β-cell viability. Peptide inhibitors provide more options in designing sequences that recognize specific targets and in rational optimization as compared to small molecules, natural compounds, chaperones, and nanomaterials. The clinical translation is hampered by proteolysis, fast clearance, delivery issues, structural heterogeneity and lack of validation in physiologically relevant models. The future should involve integration of computational design, chemical stabilization, targeted delivery, kinetic and structural characterization, membrane assays, β-cell models and in vivo testing to identify peptide candidates to inhibit toxic aggregation whilst preserving pancreatic function. Standardized comparative assays will be important to distinguish reductions in fibril burden from reductions of toxic intermediates and improvements in biological outcomes.
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