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Congo red: a universal therapy for prionic diseases?
Jump to graphic of therapy model
Anthracycline slows prion disease in Syrian hamsters
Fatal cardiac failure after a single dose of anthracycline
Congo red prolongs the incubation period in scrapie-infected hamsters

Congo red: a universal therapy for prionic diseases?

18 July 1997 commentary -- webmaster
It seemed last year that yeast prions only provided a superficial analogy and a band-wagoning opportunity for grants, but now they turn out to have the same disease architecture -- Congophilic beta seed fibers -- just like AD, PD, CJD, and the other dozen disorders in this class. There's some reason for optimism that unmodified Congo red, upon beta intercalation, may slow the course of all these diseases.

This property of Congo red would be due to an induced conformational change that makes the residual boundary nucleation sites unsuitable for occupation. Remembering that Kurt Vonnegut proposed the ice IX disease mechanism long before Griffith, let's call this a classic Catch-22 situation: if a new unit fit before the Congo red, it won't fit now; if it fits now, the polymer couldn't still bind Congo red.

So even though CR can't cap that last site, one still gets the desired edge effect. The beta-binding may be an unevolved docking site, but it is an 'instinctual' one for many polypeptides, plus beta-binding may be highly cooperative across a long range of subunits, surely from a delocalization resonance of the hydrogen and peptide pi bonds into a large volume of phase space. Most of the participating peptide species seem clipped or somewhat denatured so that their native state is no longer a competitive alternative. The universal inter-subunit beta structure is in essence the default configuration.

It's the cooperativity of this extended beta sheet from different strands that is the driving force (ie, contributes the enthalpy) for creating the 'same' disease architecture out of all these unrelated peptides -- and you read it here first. It has been suggested by Perutz that this subclass of susceptible proteins might be predicted by the presence of chameleon peptide domains. Still puzzling is why they show up so often in the brain and why they trigger a cascade of toxicity when they would seem to be rather inert.

So there may something scientifically amusing about prionic disorders: if medicine can knock off a whole set of stubborn diseases with a single public-domain pharmaceutical, that would be some kind of a first. Congo red itself is moderately toxic [LD 50 intra-venously is 190mg/kg in rats], there may be problems with the blood-brain barrier, and perhaps some derivative might be more effective.

The alternative, anthracycline 4'-iodo-4'-deoxydoxorubicin or IDX, also seems to bind beta fiber quite specifically (but in some unknown manner) and could have scientific uses in unravelling structures even if it is too toxic. The graphic below of its structure at the bottom shows no obvious similarities to Congo red and lacks its symmetry.


Effectiveness of anthracycline against experimental prion disease in Syrian hamsters.

Science 1997 May 16; 276(5315):1119-1122 
Tagliavini F, McArthur RA,... Cervini MA, Lansen J, Salmona M, Post C
Prion diseases are transmissible neurodegenerative conditions characterized by the accumulation of protease-resistant forms of the prion protein (PrP), termed PrPres, in the brain. Insoluble PrPres tends to aggregate into amyloid fibrils. The anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDX) binds to amyloid fibrils and induces amyloid resorption in patients with systemic amyloidosis. To test IDX in an experimental model of prion disease, Syrian hamsters were inoculated intracerebrally either with scrapie-infected brain homogenate or with infected homogenate coincubated with IDX. In IDX-treated hamsters, clinical signs of disease were delayed and survival time was prolonged. Neuropathological examination showed a parallel delay in the appearance of brain changes and in the accumulation of PrPres and PrP amyloid.

Prion diseases, such as scrapie of sheep, spongiform encephalopathy of cattle, and Creutzfeldt-Jakob disease of humans, are transmissible neurodegenerative conditions characterized by the accumulation of protease-resistant forms of the prion protein (PrP), termed PrPres, in the brain (1). Unlike the normal PrP, PrPres has a large amount of -sheet secondary structure and a strong tendency to aggregate into amyloid fibrils (2). Deposition of PrPres and PrP amyloid is accompanied by nerve cell degeneration and glial cell proliferation, leading to the clinical signs of disease (3). In scrapie-infected hamsters, survival time is prolonged by the amyloid-binding dye Congo red (4). Congo red inhibits the accumulation of PrPres in scrapie-infected neuroblastoma cells without affecting the metabolism of normal PrP (5).

The anthracycline 4-iodo-4-deoxy-doxorubicin (IDX) (Fig. 1A) is a recently developed derivative of doxorubicin, a drug of proven efficacy in a large number of malignancies (6). The administration of IDX to eight patients with plasma cell dyscrasias complicated by immunoglobulin light-chain amyloidosis resulted in the partial resorption of amyloid deposits in three cases. In addition, four of the eight patients exhibited discernible clinical improvement, two patients showed reduced symptoms of the disease, and the other two patients were rendered stable (7). This unexpected activity of the compound was confirmed by further studies showing that IDX binds strongly to amyloid fibrils of different chemical composition, inhibits in vitro assembly of insulin into amyloid fibrils, and reduces amyloid deposits in a murine model of reactive amyloidosis (8). Thus, IDX can be regarded as a prototype of a class of drugs that are able to inhibit amyloidogenesis, reverse tissue deposition of amyloid fibrils, or both.

A wide variety of compounds has been tested in the treatment of prion diseases (14). A few of these compounds, particularly amphotericin B and sulfated polyanions, were effective in retarding the appearance of clinical symptoms and prolonging the survival of animals experimentally infected with scrapie (15). These compounds are structurally dissimilar and have diverse activity. Amphotericin B, for example, is an antifungal agent, whereas heteropolyanions such as HPA-23 are antivirals. Although these molecules are known to be active at the cell membrane, their mechanism of action in experimental scrapie is still unknown. Other antiviral compounds such as amantadine, vidarabine, and acyclovir have been used in patients with Creutzfeldt-Jakob disease with inconclusive results (14).

Fatal cardiac failure after a single dose of doxorubicin in myeloma-associated cardiac amyloid.

Postgrad Med J 1992 Jan;68(795):69  [LETTER]
Devoy MA, Tomson CR

Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis.

Proc Natl Acad Sci U S A 1995 Mar 28;92(7):2959-2963 
Merlini G, Ascari E, Amboldi N, ... Garini P, et al
All types of amyloidosis are structurally characterized by the cross beta-pleated sheet conformation of the fibrils, irrespective of their biochemical composition. The clinical observation that the anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDOX) can induce amyloid resorption in patients with immunoglobulin light chain amyloidosis was the starting point for this investigation of its possible mechanism of action. IDOX binds strongly to all five types of natural amyloid fibrils tested: immunoglobulin light chains, amyloid A, transthyretin (methionine-30 variant), beta-protein (Alzheimer), and beta 2-microglobulin. Quantitative binding studies showed that IDOX, but not doxorubicin, binds strongly to amyloid fibrils. This binding is saturable and involves two apparently distinct binding sites with Kd values of 5.9 x 10(-11) M and 3.4 x 10(-9) M. IDOX inhibited in vitro insulin amyloid fibrillogenesis. In vivo studies using the experimental amyloid murine model confirmed the specific targeting of IDOX to amyloid deposits. Preincubation of amyloid enhancing factor with IDOX significantly reduced the formation of amyloid deposits. It is hypothesized that IDOX exerts its beneficial effects through the inhibition of fibril growth, thus increasing the solubility of existing amyloid deposits and facilitating their clearance. IDOX may represent the progenitor of a class of amyloid-binding agents that could have both diagnostic and therapeutic potential in all types of amyloidoses.

New drug therapy of amyloidoses: resorption of AL-type deposits with 4'-iodo-4'-deoxydoxorubicin.

Gianni L, Bellotti V, Gianni AM, Merlini G
Blood 1995 Aug 1;86(3):855-861
Amyloidosis caused by monoclonal Ig light chains (AL) is characterized by the tissue deposition of paraproteins as insoluble fibrils that leads to organ dysfunction and death. After serendipitous observation of its efficacy, the new anthracycline 4'-iodo-4'-deoxydoxorubicin (I-DOX) was evaluated in eight patients with biopsy-proven A. .. I-DOX caused short-lived granulocytopenia and minimal extra-hematologic side effects. The pharmacokinetics of I-DOX presented features exploitable for diagnosis in amyloidotic patients and documented the active metabolite in the cerebrospinal fluid. We conclude that I-DOX represents an important treatment option for subjects with AL amyloidosis and could be the prototype of a new class of drugs that interfere with and reverse the process of all types of amyloid deposition.

Congo red prolongs the incubation period in scrapie-infected hamsters

J Virol 1995 Jan;69(1):506-508 
Ingrosso L, Ladogana A, Pocchiari M
In scrapie-infected cells, Congo red inhibits both the replication of the infectious agent and accumulation of the protease-resistant form of PrP (PrP-res). In this report, we show that Congo red prolongs the incubation periods of hamsters experimentally infected with two different strains of scrapie.

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