Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics

Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloido...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2003-01, Vol.299 (5607), p.713-716
Main Authors: Hammarström, Per, Wiseman, R. Luke, Powers, Evan T., Kelly, Jeffery W.
Format: Article
Language:English
Subjects:
Amyloidosis
Amyloidosis - metabolism
Amyloidosis - prevention & control
Amyloids
Biochemistry
Biological and medical sciences
Chemical inhibitors
Denaturation
Genetics
Humans
Hydrogen-Ion Concentration
Inhibition
Kinetics
Medical sciences
Metabolic diseases
Molecules
Monomers
Other metabolic disorders
Prealbumin - antagonists & inhibitors
Prealbumin - chemistry
Prealbumin - genetics
Prealbumin - metabolism
Prevention
Preventive medicine
Protein Denaturation
Protein Folding
Protein Structure, Quaternary
Protein Subunits
Proteins
Proteostasis deficiencies
Solar fibrils
Stoichiometry
Suppression, Genetic
Thermodynamics
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Summary:Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation, threonine 119 → methionine 119, which is known to ameliorate familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1079589