Protein Misfolding Disorders and Rational Design of Antimisfolding Agents

Abstract

Compelling evidence strongly suggests that the conversion of a normal soluble protein into a beta-sheet-rich oligomeric structure and further fibril formation is the critical step in the pathogenesis of several human diseases, termed protein misfolding disorders. Therefore, a promising therapeutic strategy consists of the design of molecules that prevent the misfolding and aggregation of these proteins. In this chapter, we survey the mechanism of protein misfolding and some strategies to rationally produce inhibitors of this process.

Anti‐Misfolding and Anti‐Fibrillization Therapies for Protein Misfolding Disorders

“…Examples of small molecules that that have been reported to prevent the misfolded and aggregation of proteins involved in PMDs include Congo red and derivatives, curcumin and rosmarinic acid, small sulfonated anions, wine polyphenols and tannic acid, melatonin, nicotine, estrogen, hexadecyl-N-methylpiperidinium bromide, benzofuran-based compounds, amphiphilic surfactants such as di-C6-PC and di-C7-PC, the disaccharide trehalose, the anti-leprosy drugs dapsone and rifampicin, anthracyclines, thyroxine, flufenamic acid, N-substituted anthranilic acids, N-phenylphenoxazines, nitrophenols, diclofenac analog, inositol, nordihydroguaiaretic acid, b-cyclodextrins, apomorphine and analog, tetracyclines, quinacrine, branched polyamines, acridine and phenotiazine derivatives, porphyrins and phtalocyanines, 4u-iodo-4u-deoxydoxorubicin, pentosane polysulfate, amphotericin B, suramin, and ''chemical chaperones'' (e.g., glycerol, dimethyl sulfoxide, trimethylamine-N-oxide). (A more comprehensive list of compounds, including the specific references, may be found in [47][48][49].) These compounds result in a net reduction of misfolded aggregates but reach this goal acting through diverse mechanisms (Fig.…”

“…Peptide inhibitors based on similar principles have also been reported to prevent misfolding and aggregation of several proteins involved in other PMDs, including prion diseases, PD, HD, and type 2 diabetes [47]. The major advantage of the peptide approach is that highly potent and specific compounds can be produced which usually are not overly toxic.…”

In silico design of misfolding resistant proteins: the role of structural similarity of a competing conformational ensemble in the optimization of frustration

“…These increasingly common pathological conditions that arise due to aberrant folding are termed as Protein Misfolding Disorders (PMDs). [9][10][11][12][13] These diseases range from neurodegenerative to systemic diseases. Alzheimer's disease (AD), 14 Parkinson's disease (PD), 15 Huntington's disease (HD), 16 transmissible spongiform encephalopathies (TSE), 17 amyotrophic lateral sclerosis (ALS), 18 and type II diabetes (T2D) 19 are a few common diseases that fall under the category of PMDs, which are becoming more common in today's society.…”

Can Plant-Made Copper Chaperones Heal Early Alzheimer’s Disease?

“…The outcome of these pathological processes may lead to incurable chronically progressive neurodegenerative diseases such as Alzheimer's disease [1,2]. Several therapeutic strategies and nearly all medications used or suggested as Aβ inhibitors, including metal-chelating agents or radical scavengers, at present time, aim at the treatment of AD symptoms only and may either be toxic, lack specificity or have unknown mechanisms of action in vivo [2,3].…”