Inhibition of aggregate formation as therapeutic target in protein misfolding diseases: effect of tetracycline and trehalose.
BACKGROUND
The identification of molecules that inhibit protein deposition or reverse fibril formation could open new strategies for therapeutic intervention in misfolding diseases. Numerous compounds have been shown to inhibit amyloid fibril formation in vitro. Among these compounds, tetracycline and the disaccharide trehalose have been reported to inhibit or reverse amyloid aggregation but their efficiency as potential drugs is controversial.


METHODS
The results obtained using tetracycline and trehalose, reported in the last 15 years, are described and discussed.


RESULTS
The conclusions have important implications for the development of therapeutic agents for protein deposition diseases. If fibrillar proteins contribute to cell degeneration, then the disassembly of fibrils may reverse or slow down disease progression; however, if the action of therapeutic agents produces intermediates of fibrillation and/or products of fibril disaggregation, then their accumulation could be harmful.


CONCLUSIONS
Care should be taken to ensure that strategies aimed at inhibiting fibril formation do not cause a corresponding increase in the concentration of toxic oligomeric species.
Dipartimento di Biochimica e Biofisica, Seconda Universita` degli Studi di Napoli, Napoli, Italy. ivana.sirangelo@unina2.it
Ivana
I
Sirangelo
Gaetano
G
Irace
D000682:Amyloid / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D011500:Protein Synthesis Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000503:physiopathology; D013752:Tetracycline / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D014199:Trehalose / Q000378:metabolism / Q000494:pharmacology*
D000682:Amyloid; D058227:Amyloidogenic Proteins; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D014199:Trehalose; D013752:Tetracycline