Amyloid diseases

Small drugs lead the attack

Many human disorders — a well-known example being Alzheimer's disease — are characterized by the misfolding and aggregation of key proteins. New small-molecule drugs may help to destabilize these aggregates.

On page 254 of this issue, Pepys and colleagues1 describe a new pharmacological approach to treating human amyloid diseases. These often devastating disorders range from type II diabetes to Alzheimer's disease, and involve the abnormal folding of usually soluble proteins into an insoluble, tightly packed shape known as a β-sheet. This causes the proteins to be deposited outside cells and form aggregates called amyloid deposits that lead to tissue damage and, ultimately, to death of the patient. Several human proteins can undergo such a transformation; in Alzheimer's disease, for instance, the accumulation in the brain of insoluble aggregates of the amyloid-β (Aβ) peptide — also known as 'senile plaques' — is thought to be a key pathological event underlying the loss of brain cells2.

There is interest in a variety of approaches aimed at preventing or even reversing amyloid deposition, particularly in Alzheimer's disease. One tack involves vaccination, which has seen some success in mice that were genetically modified to overexpress the human amyloid precursor protein, from which the Aβ peptide is produced. When these mouse 'models' of Alzheimer's disease were immunized with the Aβ peptide itself, the formation of senile plaques in the brain and the associated behavioural deficits were reduced3. It was proposed that a small proportion of the antibody that the animals produced in response to the vaccine passed the barrier between blood and brain and 'decorated' the Aβ plaques, enabling them to be recognized and consumed by microglia (a type of white blood cell). The findings prompted clinical trials of this potential vaccine for treating Alzheimer's disease. But unfortunately, the trials had to be halted because some patients developed signs of inflammation of the central nervous system4. An alternative approach is 'passive' immunization, which involves injecting antibodies against the Aβ peptide (rather than the peptide itself); this has also proved effective in the mouse model5 but has yet to face clinical trials.

Another strategy involves using several low-molecular-weight substances, including dyes such as Congo red, the antibiotic rifampicin and the anthracycline 4′-iodo-4′-deoxydoxorubicin, to disrupt the aggregation of the Aβ peptide6. Screening for such compounds also identified other chemicals that are active against amyloid deposits6. In a related approach, short peptides that bind to the Aβ peptide and interfere with aggregation were synthesized7.

The discovery that Aβ deposition is accelerated by metals, notably copper and zinc, provided yet another angle of attack. The antibiotic iodochlorhydroxyquin (known by the trade name Clioquinol) chelates copper and zinc in vitro, and reduced Aβ deposition in a mouse model8. Moreover, interim results from a randomized, double-blind, placebo-controlled clinical trial in 32 patients with Alzheimer's disease suggested that this drug slows the rate of cognitive decline in the most severely affected group9.

Clinical trials are also under way with the small, sulphonated molecule NC-758 (trade name Alzhemed), which was designed to interfere with the binding of glycosaminoglycans to the Aβ peptide10. (Glycosaminoglycans are polysaccharides that may help to stabilize and protect brain amyloid deposits.) NC-758 had previously proved effective at reducing Aβ deposition in a mouse model11.

These are all imaginative strategies, but new approaches are, of course, always welcome. Pepys et al.1 have come up with just that: they reveal a different way of destabilizing amyloid deposits using small-molecule drugs. Specifically, these drugs target the protein serum amyloid P (SAP), which is universally present in amyloid deposits — both in Alzheimer's disease and in peripheral amyloid disorders (which affect tissues other than the brain). SAP binds to these deposits in a calcium-dependent manner and helps to protect them from degradation by protein-degrading enzymes or white blood cells. Pepys and colleagues suggested almost 20 years ago12 that drugs that promote the dissociation of SAP from amyloid deposits, making these deposits accessible to the body's normal removal mechanisms, might represent a new way of treating amyloid diseases. They now go a long way towards proving this concept.

The authors1 used a high-throughput screen to test a library of chemicals for those that inhibit the binding of SAP to Aβ deposits in vitro. This led to the discovery of a series of dimeric derivatives of the amino acid proline that are highly active both in vitro and in vivo. SAP normally exists as a pentamer13 (Fig. 1), and the proline derivatives link two pentamers together (see Fig. 2a on page 256). This has two important effects: SAP is prevented from binding to amyloid deposits; and the drug–SAP complex is rapidly removed from the blood circulation and degraded in the liver. Consequently, Pepys et al. found that levels of SAP in the blood serum of test animals were dramatically reduced. Moreover, in animal models of amyloid diseases, using the drug led to the removal of SAP from peripheral amyloid deposits, and a gradual reduction in the size of these deposits.

Figure 1: Structure of the pentamer of the serum amyloid P protein (SAP)13.

Pepys et al.1 have discovered some small-molecule drugs that prevent SAP from binding to amyloid deposits, and might therefore be useful in treating amyloid disorders such as Alzheimer's disease.

Pepys et al. also report the first results from studies in humans. One of the proline derivatives was given safely for up to nine and a half months to 19 patients with peripheral amyloid diseases. Levels of SAP in the blood plasma of these patients were markedly reduced and there was evidence that SAP levels in amyloid deposits also decreased.

So this new approach1 offers great promise for treating both peripheral amyloid disorders and, possibly, Alzheimer's disease. The blood–brain barrier often presents a stumbling block to new drugs, but it may not be necessary for the proline derivatives to cross this barrier: lowering circulating SAP levels may be enough to deplete SAP from the brain and other tissues. Moreover, the clinical-trial data suggest that the prolonged removal of circulating SAP has no obvious harmful effects, even though it is a normal component of blood plasma. But whether lowering SAP levels will be sufficient to facilitate the disaggregation and complete removal of long-standing amyloid deposits remains to be seen.

It may be possible to extend the use of low-molecular-weight organic drugs to other protein-folding diseases. For instance, acridines and phenothiazines inhibit the conversion of the prion protein PrPc to the disease-causing form, PrPSc, in cultured cells infected with prions14. Quinacrine and chlorpromazine have been used for many years to treat malaria and schizophrenia, and it has been proposed14 that these drugs be used in clinical trials for treating Creutzfeldt–Jakob disease. With all the activity in this research arena, we can perhaps be hopeful that drugs can be found to combat the abnormal protein deposits seen in so many distressing human diseases.


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Correspondence to Leslie Iversen.

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Iversen, L. Small drugs lead the attack. Nature 417, 231–233 (2002).

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