Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions

• Published in: Biochimica et biophysica acta. Proteins and proteomics 2022-05, Vol.1870 (5), p.140772-140772, Article 140772
• Main Authors: García-Viñuales, Sara, Ilie, Ioana M., Santoro, Anna Maria, Romanucci, Valeria, Zarrelli, Armando, Di Fabio, Giovanni, Caflisch, Amedeo, Milardi, Danilo
• Format: Article
• Language: English
• Subjects: Aggregation; Amyloid - chemistry; Diabetes; Diabetes Mellitus, Type 2; Humans; Inhibitors; Insulin-Secreting Cells; Islet Amyloid Polypeptide - chemistry; Molecular dynamics; Peptide; Silybin - pharmacology
• ISSN: 1570-9639; 1878-1454
• DOI: 10.1016/j.bbapap.2022.140772

Type 2 Diabetes is a major public health threat, and its prevalence is increasing worldwide. The abnormal accumulation of islet amyloid polypeptide (IAPP) in pancreatic β-cells is associated with the onset of the disease. Therefore, the design of small molecules able to inhibit IAPP aggregation represents a promising strategy in the development of new therapies. Here we employ in vitro, biophysical, and computational methods to inspect the ability of Silybin A and Silybin B, two natural diastereoisomers extracted from milk thistle, to interfere with the toxic self-assembly of human IAPP (hIAPP). We show that Silybin B inhibits amyloid aggregation and protects INS-1 cells from hIAPP toxicity more than Silybin A. Molecular dynamics simulations revealed that the higher efficiency of Silybin B is ascribable to its interactions with precise hIAPP regions that are notoriously involved in hIAPP self-assembly i.e., the S20-S29 amyloidogenic core, H18, the N-terminal domain, and N35. These results highlight the importance of stereospecific ligand-peptide interactions in regulating amyloid aggregation and provide a blueprint for future studies aimed at designing Silybin derivatives with enhanced drug-like properties. [Display omitted] •Silybin A and Silybin B interfere with the toxic self-assembly of human islet amyloid polypeptide.•Silybin B inhibits amyloid aggregation and protects INS-1 cells from hIAPP toxicity more than Silybin A.•The higher efficiency of Silybin B is ascribable to its interactions with hIAPP regions involved in hIAPP self-assembly.