Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions
Title | Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | García-Viñuales S., Ilie I.M, Santoro A.M, Romanucci V., Zarrelli A., Di Fabio G., Caflisch A., Milardi D. |
Journal | Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics |
Volume | 1870 |
Issue | 5 |
Pagination | 140772 |
Date Published | 2022 Mar 17 |
Type of Article | Research Article |
ISSN | 1878-1454 |
Abstract | 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. |
DOI | 10.1016/j.bbapap.2022.140772 |
pubindex | 0275 |
Alternate Journal | Biochim. Biophys. Acta Proteins Proteom. |
PubMed ID | 35307557 |