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Techniques for monitoring protein misfolding and aggregation in vitro and in living cells
Simpson Gregoire,권인찬,Jacob Irwin 한국화학공학회 2012 Korean Journal of Chemical Engineering Vol.29 No.6
Protein misfolding and aggregation have been considered important in understanding many neurodegenerative diseases and recombinant biopharmaceutical production. Various traditional and modern techniques have been utilized to monitor protein aggregation in vitro and in living cells. Fibril formation, morphology and secondary structure content of amyloidogenic proteins in vitro have been monitored by molecular probes, TEM/AFM, and CD/FTIR analyses,respectively. Protein aggregation in living cells has been qualitatively or quantitatively monitored by numerous molecular folding reporters based on either fluorescent protein or enzyme. Aggregation of a target protein is directly correlated to the changes in fluorescence or enzyme activity of the folding reporter fused to the target protein, which allows non-invasive monitoring aggregation of the target protein in living cells. Advances in the techniques used to monitor protein aggregation in vitro and in living cells have greatly facilitated the understanding of the molecular mechanism of amyloidogenic protein aggregation associated with neurodegenerative diseases, optimizing culture conditions to reduce aggregation of biopharmaceuticals expressed in living cells, and screening of small molecule libraries in the search for protein aggregation inhibitors.
Getter, Tamar,Zaks, Ilana,Barhum, Yael,Ben-Zur, Tali,Bö,selt, Sebastian,Gregoire, Simpson,Viskind, Olga,Shani, Tom,Gottlieb, Hugo,Green, Omer,Shubely, Moran,Senderowitz, Hanoch,Israelson, Adrian,K Wiley (John WileySons) 2015 ChemMedChem Vol.10 No.5
<P>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons and skeletal muscle atrophy. The majority of ALS cases are acquired spontaneously, with inherited disease accounting for only 10?% of all cases. Recent studies provide compelling evidence that aggregates of misfolded proteins underlie both types of ALS. Small molecules such as artificial chaperones can prevent or even reverse the aggregation of proteins associated with various human diseases. However, their very high active concentration (micromolar range) severely limits their utility as drugs. We synthesized several ester and amide derivatives of chemical chaperones. The lead compound 14, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N-dimethylpropan-1-amine oxide shows, in the micromolar concentration range, both neuronal and astrocyte protective effects in vitro; at daily doses of 10?mg?kg(-1) 14 improved the neurological functions and delayed body weight loss in ALS mice. Members of this new chemical chaperone derivative class are strong candidates for the development of new drugs for ALS patients.</P>