Dataset Information

Structure-Based Peptide Inhibitor Design of Amyloid-? Aggregation.

ABSTRACT: Many human neurodegenerative diseases are associated with amyloid fibril formation. Inhibition of amyloid formation is of importance for therapeutics of the related diseases. However, the development of selective potent amyloid inhibitors remains challenging. Here based on the structures of amyloid ? (A?) fibrils and their amyloid-forming segments, we designed a series of peptide inhibitors using RosettaDesign. We further utilized a chemical scaffold to constrain the designed peptides into ?-strand conformation, which significantly improves the potency of the inhibitors against A? aggregation and toxicity. Furthermore, we show that by targeting different A? segments, the designed peptide inhibitors can selectively recognize different species of A?. Our study developed an approach that combines the structure-based rational design with chemical modification for the development of amyloid inhibitors, which could be applied to the development of therapeutics for different amyloid-related diseases.

SUBMITTER: Lu J

PROVIDER: S-EPMC6409328 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation.

Lu Jinxia J Cao Qin Q Wang Chuchu C Zheng Jing J Luo Feng F Xie Jingfei J Li Yichen Y Ma Xiaojuan X He Lin L Eisenberg David D Nowick James J Jiang Lin L Li Dan D

Frontiers in molecular neuroscience 20190304

Many human neurodegenerative diseases are associated with amyloid fibril formation. Inhibition of amyloid formation is of importance for therapeutics of the related diseases. However, the development of selective potent amyloid inhibitors remains challenging. Here based on the structures of amyloid β (Aβ) fibrils and their amyloid-forming segments, we designed a series of peptide inhibitors using RosettaDesign. We further utilized a chemical scaffold to constrain the designed peptides into β-str ...[more]

PMID: 30886570

Similar Datasets

Project description:The misfolding and aggregation of amyloid-? (A?) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of A?1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against A?-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent A? peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic ?-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-A? and TS2-A? systems also interpret different inhibitory effects on A? aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of A? inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

Structure-Based Peptide Inhibitor Design of Amyloid-? Aggregation.

Publications

Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure