Seminario: Inhibitors of amyloid aggregation

Mercoledì 16 ottobre 2013 ore 15:00, Edificio Chimica, Aula I0.2 (ex. Aula PT1 - Piano terra)

Relatore: Prof.ssa Zuzana Gazova (Institute of Biophysics, Slovak Academy of Sciences, Kosice)

Abstract: Interest in the phenomenon of amyloid formation by polypeptides has developed rapidly in recent years because of links between amyloid formation and a range of disorders, including Alzheimer’s disease and type II diabetes. Accordingly, there is a considerable world-wide interest to identify entities that can influence the aggregation processes in order to speed-up the drug development process for the above mentioned diseases.
The precise mechanism of toxicity of amyloid aggregates is not fully elucidated; however, there are evidences that prevention or reversion of the amyloid aggregation is beneficial. Recently, the increasing attention is focused on searching for agents able to intervene against amyloid aggregates.
The promising group of aggregation inhibitors is small molecules. We screened a group of about hundred compounds for their ability to interfere with amyloidal aggregation of poly/peptides. We found several derivatives of acridine, phytoalexin and polyphenols with significant inhibiting abilities (IC50 and DC50 values in micromolar range). Our results indicate important relationship between compound structure and anti-amyloidal activity.
In silico screening of 8000 tripeptides by docking and MM-PBSA methods was used to determine tripeptides with significant binding affinity to Abeta fibrils. Tripeptides containing amino acids with aromatic rings were shown as the most potent inhibitors revealed by the virtual screening; the tripeptides WWW, WWP, WPW and PWW were selected to be the top leads. The predicted ability of the best fit tripeptides to destroy amyloidal fibrils was confirmed experimentally.
The special attention was devoted to nanoparticles as novel agents able to affect amyloidal aggregation of poly/peptides. The obtain data suggest that anti amyloid activities of nanoparticles, namely their ability to inhibit amyloid fibrillization and/or to destroy amyloid fibrils, depended on the physical chemical properties (composition, size, surface charge, zeta potential, and modification) of studied nanoparticles.
The obtained findings favor the application of the selected active small molecules, tripeptides and nanoparticles as therapeutic agents targeting amyloidal related diseases.

Ospite: Fabio Biscarini

[Ultimo aggiornamento: 14/10/2013 18:44:51]