Harnessing chaperones to generate small-molecule inhibitors of amyloid beta aggregation.

Protein aggregation is involved in the pathogenesis of neurodegenerative diseases and hence is considered an attractive target for therapeutic intervention. However, protein-protein interactions are exceedingly difficult to inhibit. Small molecules lack sufficient steric bulk to prevent interactions between large peptide surfaces. To yield potent inhibitors of beta-amyloid (Abeta) aggregation, we synthesized small molecules that increase their steric bulk by binding to chaperones but also have a moiety available for interaction with Abeta. This strategy yields potent inhibitors of Abeta aggregation and could lead to therapeutics for Alzheimer's disease and other forms of neurodegeneration.

Synthesis of analogues of Congo red and evaluation of their anti-prion activity.

No cure as of yet exists for any of the transmissible spongiform encephalopathies. In this paper, we describe the synthesis of analogues of Congo red and evaluation against a cellular model of infection, the SMB (scrapie mouse brain) persistently infected cell line, for their ability to inhibit the infectivity of the abnormal form of prion protein (PrP-res). The compounds have also been tested for their ability to inhibit the polymerization of PrPC by PrP-res. A number of analogues showed inhibition of PrP-res infectivity at nanomolar concentrations. Several analogues show promise; the most active compound, 2a, inhibits the formation of PrP-res in SMB cells with an EC50 of 25-50 nM.

Pharmacokinetics and distribution of sodium 3,4-diaminonaphthalene-1-sulfonate, a Congo Red derivative active in inhibiting PrP(res) replication.

Sodium 3,4-diaminonaphthalene-1-sulfonate (CRA) is a compound, synthesised by our group from Congo Red (CR), that is active in preventing the pathological conversion of normal prion protein (PrP). As the precise mechanisms controlling the ways in which prions are distributed and infect the brain and other organs are not fully understood, studying the pharmacokinetics of drugs that are active against prions may clarify their targets and their means of inhibiting prion infection. This paper describes the pharmacokinetics of CRA in plasma, spleen and brain after single or repeated intraperitoneal or subcutaneous administration, as determined by means of specific and sensitive fluorimetric HPLC. A single intraperitoneal administration led to peak plasma CRA concentrations after 15 min, followed by biphasic decay with an apparent half-life of 4.3 h. After subcutaneous administration, T(max) was reached after 30 min, and was followed by a similar process of decay: Cmax and the AUC0-last were 25% those recorded after intraperitoneal administration. The mean peak concentrations and AUCs of CRA after a single intraperitoneal or subcutaneous administration in peripheral tissue (spleen) were similar to those observed in blood, whereas brain concentrations were about 2% those in plasma. After repeated intraperitoneal or subcutaneous doses, the Cmax values in plasma, brain and spleen were similar to those observed at the same times after a single dose. After repeated intraperitoneal doses, CRA was also found in the ventricular cerebrospinal fluid at concentrations of 1.8 +/- 0.2 microg(-1) mL, which is similar to, or slightly higher than, those found in brain. Brain concentrations may be sufficient to explain the activity of CRA on PrP reproduction in the CNS. However, peripheral involvement cannot be excluded because the effects of CRA are more pronounced after intraperitoneal than after intracerebral infection.

Synthesis and evaluation of analogues of Congo red as potential compounds against transmissible spongiform encephalopathies.

The synthesis of analogues of the amyloid stain Congo red (1) as potential compounds against transmissible spongiform encephalopathies (TSEs) is reported. Using the direct method, aniline (2) or diamines such as 4,4'-diaminodiphenylsulfone (dapsone, 9), 3,3'-diaminodiphenylsulfone (10), benzidine (11), 3,3'-dimethoxybenzidine (12) or 3,3'-dichlorobenzidine (13) were diazotised to afford the corresponding diazonium salts, which without isolation, were directly used for coupling with a range of aromatic sulfonic or carboxylic acids to provide the corresponding truncated dyes analogues of Congo red, 4, 6, 8, and the symmetrical bis azoic dyes 14-19, 21-22, 24 and 26-29 as their sodium salts. Compounds were assayed in a cellular model of scrapie, a sheep TSE. Some of the compounds were shown to have similar activity to the lead compound Congo red. Molecular modelling was carried out to investigate potential structure-activity relationships (SARs) relating to the size and shape of Congo Red analogues. Within the range of compounds tested no discernible SARs were found.