True and apparent inhibition of amyloid fibril formation

Abstract

A possible therapeutic strategy for amyloid diseases involves the use of small molecule compounds to inhibit protein assembly into insoluble aggregates. According to the recently proposed Crystallization-Like Model, the kinetics of amyloid fibrillization can be retarded by decreasing the frequency of new fibril formation or by decreasing the elongation rate of existing fibrils. To the compounds that affect the nucleation and/or the growth steps we call true inhibitors. An apparent inhibition mechanism may however result from the alteration of thermodynamic properties such as the solubility of the amyloidogenic protein. Apparent inhibitors markedly influence protein aggregation kinetics measured in vitro, yet they are likely to lead to disappointing results when tested in vivo. This is because cells and tissues media are in general much more buffered against small variations in composition than the solutions prepared in lab. Here we show how to discriminate between true and apparent inhibition mechanisms from experimental data on protein aggregation kinetics. The goal is to be able to identify false positives much earlier during the drug development process.

Keywords: :

• amyloid
• aggregation
• inhibitors
• kinetics
• modeling

This article refers to:

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

I thank Rosa Crespo, Ana M. Damas and Fernando A. Rocha for helpful discussions. This work is funded by FEDER Funds through the Operational Competitiveness Programme, COMPETE and by National Funds through FCT, Fundação para a Ciência e a Tecnologia under the project FCOMP-01–0124-FEDER-009037 (PTDC/BIA-PRO/101260/2008).