Authors: Lorenzi Ersilia D.; Giorgetti Sofia; Grossi Silvia; Merlini Giampaolo; Caccialanza Gabriele; Bellotti Vittorio

Source: Current Medicinal Chemistry, Volume 11, Number 8, April 2004 , pp. 1065-1084(20)

Publisher: Bentham Science Publishers

Abstract:

The group of diseases caused by abnormalities of the process of protein folding and unfolding is rapidly growing and includes diseases caused by loss of function as well as diseases caused by gain of function of misfolded proteins. Amyloidoses are caused by gain of function of certain proteins that lose their native structure and self-assemble into toxic insoluble, extracellular fibrils. This process requires the contribution of multiple factors of which only a few are established, namely the conformational modification of the amyloidogenic protein, protein's post-translational modifications and the co-deposition of glycosaminoglicans and of serum amyloid P component. In parallel with the exponential growth of biochemical data regarding the key events of the fibrillogenic process, several reports have shown that small molecules, through the interaction with either the amyloidogenic proteins or with the common constituents, can modify the kinetics of formation of amyloid fibrils or can facilitate amyloid reabsorption. These small molecules can be classified on the basis of their protein target and mechanism of action, according to the following properties. 1) molecules that stabilize the amyloidogenic protein precursor 2) molecules that prevent fibrillogenesis by acting on partially folded intermediates of the folding process as well as on low molecular weight oligomers populating the initial phase of fibril formation 3) molecules that interact with mature amyloid fibrils and weaken their structural stability 4) molecules that displace fundamental co-factors of the amyloid deposits like glycosaminoglycans and serum amyloid P component and favor the dissolution of the fibrillar aggregate.

Keywords: protein misfolding; protein targeting ligands; fibrillogenesis inhibitors; amyloid fibril disaggregation

Document Type: Review article

DOI: http://dx.doi.org/10.2174/0929867043455549

Affiliations: 1: Department of Biochemistry, University of Pavia, Via Taramelli 3 / b, 27100 Pavia, Italy.

Publication date: 2004-04-01

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• Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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