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  • Review Article
  • Published:

Therapeutic strategies for human amyloid diseases

Nature Reviews Drug Discovery volume 1, pages 267–275 (2002)Cite this article

Key Points

  • A relatively large and diverse set of human proteins are known to form fibrils that accumulate in tissue in association with several different diseases. It is widely accepted that these fibrils — called amyloid — are the causative agent of the related diseases. Another common attribute of amyloid diseases is that beyond the age of forty, the risk of developing an amyloid disease greatly increases. This is true for all known amyloid diseases with the exception of the familial type.

  • On a molecular level, amyloid fibrils resemble an aircraft cable, with 3–6 filaments wrapped around one another to form the fibril. All amyloid fibrils studied to date are composed of individual filaments that are made of a lamellar cross-?-sheet, which contains thousands of non-covalently associated protein subunits.

  • The most common strategy that is being pursued in the development of small-molecule amyloid inhibitors involves finding molecules that prevent the initiation of the conformational changes or endoproteolytic processing that lead to amyloid formation. A more difficult approach might be to discover compounds that prevent amyloid formation by intercepting the misfolded protein.

  • Intermediates in amyloid assembly might be responsible for some, if not all, of the pathology. Therefore, 'amyloid-fibril inhibitors' could, in theory, lead to more pronounced pathology owing to the accumulation of soluble disease-associated quaternary structures.

  • Small-molecule inhibitors that stabilize the native conformation of transthyretin (TTR) have been discovered using functional screens and structure-based methods. Several of these small-molecule inhibitors efficiently prevent TTR amyloid fibril formation in vitro, and are being tested for their in vivo activity.

Abstract

Amyloid diseases are a large group of a much larger family of misfolding diseases. This group includes pathologies as diverse as Alzheimer's disease, immunoglobulin-light-chain disease, reactive amyloid disease and the familial amyloid polyneuropathies. These diseases are generally incurable at present, although some drugs are known to transiently slow the progression of Alzheimer's disease. As we increase our understanding of the causative mechanisms of these disorders, the likelihood of success for a given therapeutic strategy will become clearer. This review will look at small-molecule and macromolecular approaches for intervention in amyloid diseases other than Alzheimer's disease, although select examples from Alzheimer's disease will be discussed.

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Figure 1: The structure of amyloid fibrils.
Figure 2: Free-energy-reaction coordinate diagram.
Figure 3: Small-molecule TTR amyloid-fibril inhibitors.
Figure 4: Interallelic trans-suppression of misfolding.

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Acknowledgements

J.W.K. thanks the members of his laboratory, who made the discoveries outlined in this review possible, and appreciates the financial support from the National Institutes of Health, The Skaggs Institute of Chemical Biology and the Lita Annenberg Hazen Foundation. J.C.S. thanks his laboratory and the Robert A. Welch Foundation for financial support.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Texas A&M University, 2128 TAMU, College Station, Texas, 77843-2128, USA

    James C. Sacchettini

  2. Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92075, California, USA

    Jeffery W. Kelly

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DATABASES

LocusLink

ABri

amyloid-P component

ANF

α1-antichymotrypsin

APOE

apolipoprotein A1

APP

calcitonin

cystatin C

fibrinogen

furin

gelsolin

huntingtin

IAPP

insulin

lactotransferrin

lysozyme

β2-microglobulin

prion protein

prolactin

β-secretase

serum amyloid A

superoxide dismutase

α-synuclein

TTR

OMIM

Alzheimer's disease

Down syndrome

familial amyloidosis of Finnish

familial amyotrophic lateral sclerosis

familial British dementia

gelsolin-based disease

haemodialysis-related amyloidosis

hereditary cerebral amyloid angiopathy

hereditary renal amyloidosis

Huntington's disease

Parkinson's disease

prion disease

transthyretin-based amyloid diseases

type II diabetes

FURTHER INFORMATION

Encyclopedia of Life Sciences

Alzheimer's disease

amyloidosis

prion diseases

LINKS

Neurochem

Glossary

EXTRACELLULAR MATRIX

A network of polysaccharides and proteoglycans that templates an assembly of cells to assist in function and impart strength.

ENDOPROTEOLYTIC PROCESSING

Refers to proteolytic cleavage of internal amide bonds in a protein — that is, all amides except those that connect the carboxy- and amino-terminal residues.

AMYLOIDOGENIC

Refers to a property of a protein that allows it to form amyloid fibrils in a human.

TRANSTHYRETIN

(TTR.) An amyloidogenic plasma protein that normally transports the retinol-binding protein–vitamin A complex and thyroxine.

MULTIGENIC DISEASE

A disease with a course that is influenced by the expression of more than one gene.

DENATURATION STRESS

A change in the aqueous environment of a protein, such as the pH or the dielectric constant, that causes it to denature.

QUATERNARY STRUCTURE

The association of proteins in a geometrically specific manner through non-covalent interactions.

FREE-ENERGY MINIMUM

Refers to the most stable conformation of a macromolecule.

ENDOCYTIC PATHWAY

The vesicular pathway by which molecules are taken into a cell.

ANALYTICAL ULTRACENTRIFUGATION

A method for determining quaternary structure that uses a centrifuge fitted with a UV detector to quantify concentration gradients.

STOICHIOMETRY

Refers to molar proportions in a reaction or assembly.

MULTIDENTATE

A binding interaction in which one partner can bind to two or more sites on another partner.

HYDROPHOBIC INTERACTION

A favourable interaction between nonpolar substructures or surfaces in aqueous solution that is characterized by a large change in heat capacity.

ELECTROSTATIC INTERACTION

A non-covalent dipole–dipole or induced dipole–dipole interaction that can be stabilizing or destabilizing.

SEEDED POLYMERIZATION

A mechanism of polymerization in which the quaternary structure or seed is formed in a rate-determining fashion. This is followed by rapid addition of monomer to afford a high-molecular-weight assembly such as an amyloid fibril.

MIMETIC

A molecule that mimics another.

SULPHONATED AROMATICS

An aromatic ring that is functionalized with a sulphonate functional group.

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Sacchettini, J., Kelly, J. Therapeutic strategies for human amyloid diseases. Nat Rev Drug Discov 1, 267–275 (2002). https://doi.org/10.1038/nrd769

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