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Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions


García-Viñuales, Sara; Ilie, Ioana M; Santoro, Anna Maria; Romanucci, Valeria; Zarrelli, Armando; Di Fabio, Giovanni; Caflisch, Amedeo; Milardi, Danilo (2022). Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions. BBA - Proteins and Proteomics, 1870(5):140772.

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.

Keywords: Aggregation; Diabetes; Inhibitors; Molecular dynamics; Peptide

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.

Keywords: Aggregation; Diabetes; Inhibitors; Molecular dynamics; Peptide

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Physical Sciences > Analytical Chemistry
Life Sciences > Biophysics
Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Language:English
Date:1 May 2022
Deposited On:01 Nov 2022 16:24
Last Modified:28 May 2024 01:40
Publisher:Elsevier
ISSN:1570-9639
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.bbapap.2022.140772
PubMed ID:35307557
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)