Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses.
Small molecule-mediated protein stabilization inside or outside of the cell is a promising strategy to treat protein misfolding/misassembly diseases. Herein we focus on the transthyretin (TTR) amyloidoses and demonstrate that preferential ligand binding to and stabilization of the native state over the dissociative transition state raises the kinetic barrier of dissociation (rate-limiting for amyloidogenesis), slowing and in many cases preventing TTR amyloid fibril formation. Since T119M-TTR subunit incorporation into tetramers otherwise composed of disease-associated subunits also imparts kinetic stability on the tetramer and ameliorates amyloidosis in humans, it is likely that small molecule-mediated native state kinetic stabilization will also alleviate TTR amyloidoses.
Johnson
Steven M
SM
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
Wiseman
R Luke
RL
Sekijima
Yoshiki
Y
Green
Nora S
NS
Adamski-Werner
Sara L
SL
Kelly
Jeffery W
JW
D000686:Amyloidosis / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship; D013974:Thyroxine / Q000378:metabolism
D011228:Prealbumin; D013974:Thyroxine