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Studying Protein Function and the Role of Altered Protein Expression by Antibody Interference and Three-dimensional Reconstructions
11:57

Studying Protein Function and the Role of Altered Protein Expression by Antibody Interference and Three-dimensional Reconstructions

Published on: April 21, 2016

Prevention of transthyretin amyloid disease by changing protein misfolding energetics

Per Hammarström1, R Luke Wiseman, Evan T Powers

  • 1Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Science (New York, N.Y.)
|February 1, 2003
PubMed

Insights

Small molecules can treat amyloid diseases by stabilizing the native protein state, preventing harmful amyloid fibril formation. This kinetic stabilization strategy is effective for transthyretin amyloidosis and potentially other amyloid diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Amyloid diseases are linked to the formation of amyloid fibrils.
  • Current amyloid inhibitors shift aggregation equilibrium away from the amyloid state.
  • Genetic evidence suggests small molecule inhibition of amyloid fibril formation is a viable therapeutic strategy.

Purpose of the Study:

  • To describe novel transthyretin amyloidosis inhibitors.
  • To investigate the mechanism of action for these inhibitors.
  • To explore the potential of kinetic stabilization as a therapeutic strategy for amyloid diseases.

Main Methods:

  • Synthesis and characterization of small molecule inhibitors.
  • Assays to measure protein misfolding and amyloid formation.
  • Analysis of a known trans-suppressor mutation (T119M) in transthyretin.

Main Results:

  • Developed small molecules that inhibit transthyretin amyloidosis.
  • These inhibitors increase the kinetic barrier of protein misfolding.
  • Stabilization of the native protein state prevents amyloidogenesis.
  • The T119M mutation functions via kinetic stabilization, similar to the small molecules.

Conclusions:

  • Small molecules can prevent amyloid diseases by kinetically stabilizing the native protein state.
  • This strategy offers a new approach for treating transthyretin amyloidosis.
  • Kinetic stabilization is a promising therapeutic avenue for various amyloid diseases.

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