Anti-Amyloid Drugs

Abstract

The requirements for amyloidogenesis, as it is currently understood, include an adequate amyloid precursor pool, a nidus for fibrillogenesis, interactions with a set of common components (most of which are involved in basement membrane structure) and amyloid turnover. These factors serve as the basis for therapeutic attack. General strategies focusing on each of these factors are presented with examples from the experimental and clinical literature. These include reducing the amyloid precursor protein pool in familial amyloid polyneuropathy by liver transplantation, inhibiting nidus formation in familial Mediterranean fever by the use of colchicine, inhibiting amyloid precursor protein/heparan sulphate interaction in experimental inflammation-associated amyloidosis by the use of novel small molecule anionic sulphates and sulphonates, and the use of new analogues of doxorubicin in light chain amyloidosis to accelerate amyloid removal. The potential significance of local and systemic amyloid deposits is discussed in the light of new information on the genetics of Alzheimer's disease, observations made in patients receiving long term dialysis for renal failure, and the potential involvement of amyloid deposits in the pathogenesis of non-insulin-dependent diabetes mellitus.

In situ atomic force microscopy study of Alzheimer’s β-amyloid peptide on different substrates: New insights into mechanism of β-sheet formation

“…Thus, there have been considerable efforts to understand the mechanism leading to A␤ deposition (1,18). The primary motivation of these efforts is the expectation that they may aid in the development of a treatment of Alzheimer's disease based on inhibition of amyloid formation (19)(20)(21). Extensive x-ray diffraction and electron microscopy studies revealed that A␤ forms characteristic, ␤-sheet-rich fibrils, 6-8 nm in diameter, in which the direction of peptide chains is perpendicular to the axis of a fibril (22)(23)(24).…”

Oligopeptide-Mediated Stabilization of the α-Helix of a Prion Protein Peptide

“…The amyloid fibrils are considered to be produced by the conformational changes from the α-helix to β-sheet rich structures . Thus, although there may be various therapautic strategies, stabilizing the α-helical conformation of the specific protein that inhibits its conversion into β-sheets appears to be the most fundamental therapeutic strategy. , Stabilizing the native fold of an amyloidogenic protein by a small molecule is also useful for preventing the conformational changes 1 The amino acid sequence of the Syrian hamster prion protein …”