Small molecule inhibitors of lysozyme amyloid aggregation.

Protein amyloid aggregation is associated with a number of important human pathologies, but the precise mechanisms underlying the toxicity of amyloid aggregates are still incompletely understood. In this context, drugs capable of blocking or interfering with the aggregation of amyloidogenic proteins should be considered in strategies aimed at the development of novel therapeutic agents. Human lysozyme variants have been shown to form massive amyloid deposits in the livers and kidneys of individuals affected by hereditary systemic amyloidosis. Currently, there are no clinical treatments available to prevent or reverse formation of such amyloid deposits. We have recently described a number of di- and trisubstituted aromatic compounds that block the formation of soluble oligomers and amyloid fibrils of the beta-amyloid peptide (Abeta) and protect hippocampal neurons in culture from Abeta-induced toxicity. Here, we show that some of those compounds inhibit the formation and disrupt preformed amyloid fibrils from both human and hen egg white lysozyme. These results suggest that these small molecule compounds may serve as prototypes for the development of drugs for the prevention or treatment of different types of amyloidoses.

Isolation and structural determination of xerophytolic acid A, a 3-geranyl-4-hydroxybenzoate derivative from Xerophyta plicata.

A novel compound of a rare class of secondary metabolites, 3-geranyl-4-hydroxybenzoic acid derivative, methyl xerophytolate A (2), was isolated from the crude extract of Xerophyta plicata (Velloziaceae) collected in Rio de Janeiro, Brazil. The structure of 2 was elucidated using spectroscopic methods.

Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Abeta oligomerization.

In the past two decades, a large body of evidence has established a causative role for the beta-amyloid peptide (Abeta) in Alzheimer's disease (AD). However, recent debate has focused on whether amyloid fibrils or soluble oligomers of Abeta are the main neurotoxic species that contribute to neurodegeneration and dementia. Considerable early evidence has indicated that amyloid fibrils are toxic, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. While this crucial aspect of AD pathogenesis remains controversial, effective therapeutic strategies should ideally target both oligomeric and fibrillar species of Abeta. Here, we describe the anti-amyloidogenic and neuroprotective actions of some di- and tri-substituted aromatic compounds. Inhibition of the formation of soluble Abeta oligomers was monitored using a specific antibody-based assay that discriminates between Abeta oligomers and monomers. Thioflavin T and electron microscopy were used to screen for inhibitors of fibril formation. Taken together, these results led to the identification of compounds that more effectively block Abeta oligomerization than fibrillization. It is significant that such compounds completely blocked the neurotoxicity of Abeta to rat hippocampal neurons in culture. These findings provide a basis for the development of novel small molecule Abeta inhibitors with potential applications in AD.

On the limits of highest-occupied molecular orbital driven reactions: the frontier effective-for-reaction molecular orbital concept.

We carried out Hartree-Fock (HF) and density functional theory calculations for 61 compounds, the conjugated bases of carboxylic acids, phenols, and alcohols, and analyzed their acid-base behavior using molecular orbital (MO) energies and their dependence on solvent effects. Despite the well-known correlation between highest-occupied MO (HOMO) energies and pKa, we observed that HOMO energies are inadequate to describe the acid-base behavior of these compounds. Therefore, we established a criterion to identify the best frontier MO for describing pKa values and also to understand why the HOMO approach fails. The MO that fits our criterion provided very good correlations with pKa values, much better than those obtained by HOMO energies. Since they are the frontier molecular orbitals that drive the acid-base reactions in each compound, they were called frontier effective-for-reaction MOs, or FERMOs. By use of the FERMO concept, the reactions that are HOMO driven, and those that are not, can be better explained, independently from the calculation method used, as both HF and Kohn-Sham methodologies lead to the same FERMO.