Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses
SM Johnson, RL Wiseman, Y Sekijima… - Accounts of chemical …, 2005 - ACS Publications
SM Johnson, RL Wiseman, Y Sekijima, NS Green, SL Adamski-Werner, JW Kelly
Accounts of chemical research, 2005•ACS PublicationsSmall 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 …
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 …
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.
ACS Publications