The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD.

Background: Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer's disease (AD). Thus, modulating the neuroinflammatory response represents a potential therapeutic strategy for treating neurodegenerative diseases. Several recent studies have shown that dopamine (DA) and its receptors are expressed in immune cells and are involved in the neuroinflammatory response.

Noncovalent, Electrostatic Interactions Induce Positively Cooperative Binding of Small Molecules to Alzheimer's and Parkinson's Disease-Related Amyloids.

Amyloids are self-assembled protein aggregates that represent a major hallmark of many neurologic and systemic diseases. Among the common features of amyloids is the presence of a high density of multiple binding sites for small molecule ligands, making them an attractive target for design of multimeric binding agents. Here, we demonstrate that noncovalent, intermolecular interactions between a 1:1 mixture of oppositely charged benzothiazole molecules enhances their binding to two different amyloid aggregates: Alzheimer's-related amyloid-β (Aβ) peptides or Parkinson's-related α-synuclein (αS) proteins.

Hexa (ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1-Ras dependent pathway.

Our recent study demonstrated that an amyloid-β binding molecule, BTA-EG4, increases dendritic spine number via Ras-mediated signaling. To potentially optimize the potency of the BTA compounds, we synthesized and evaluated an amyloid-β binding analog of BTA-EG4 with increased solubility in aqueous solution, BTA-EG6. We initially examined the effects of BTA-EG6 on dendritic spine formation and found that BTA-EG6-treated primary hippocampal neurons had significantly increased dendritic spine number compared to control treatment.

A tetra(ethylene glycol) derivative of benzothiazole aniline enhances Ras-mediated spinogenesis.

The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aβ-induced toxicity. However, the effects of Aβ-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aβ levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice.

Enzyme-linked immunosorbent assay-based method to quantify the association of small molecules with aggregated amyloid peptides.

This paper describes a simple enzyme linked immunosorbent assay (ELISA) protocol for quantifying the binding of small molecules to aggregated β-amyloid (Aβ) peptides. Amyloid-targeting small molecules have attracted wide interest as potential agents for the treatment or diagnosis of neurodegenerative disorders such as Alzheimer's disease. The lack of general methods to evaluate small molecule-amyloid binding interactions, however, has significantly limited the number of amyloid-targeting molecules that have been studied to date.

Oligovalent amyloid-binding agents reduce SEVI-mediated enhancement of HIV-1 infection.

This paper evaluates the use of oligovalent amyloid-binding molecules as potential agents that can reduce the enhancement of human immunodeficiency virus-1 (HIV-1) infection in cells by semen-derived enhancer of virus infection (SEVI) fibrils. These naturally occurring amyloid fibrils found in semen have been implicated as mediators that can facilitate the attachment and internalization of HIV-1 virions to immune cells. Molecules that are capable of reducing the role of SEVI in HIV-1 infection may, therefore, represent a novel strategy to reduce the rate of sexual transmission of HIV-1 in humans.

ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue.

A new family of fluorescent markers containing an Amino Naphthalenyl-2-Cyano-Acrylate (ANCA) motif has been synthesized and evaluated for its capability to associate with aggregated β-amyloid (Aβ) peptides. These fluorescent probes contain a nitrogen donor group that is connected via a naphthalene unit to an electron acceptor motif containing Water Solubilizing Groups (WSG). Chemical modifications were introduced to explore their effect on the capability of the ANCA-based probes to fluorescently label aggregated Aβ peptides.

Amyloid-binding small molecules efficiently block SEVI (semen-derived enhancer of virus infection)- and semen-mediated enhancement of HIV-1 infection.

Semen was recently shown to contain amyloid fibrils formed from a self-assembling peptide fragment of the protein prostatic acid phosphatase. These amyloid fibrils, termed semen-derived enhancer of virus infection, or SEVI, have been shown to strongly enhance HIV infectivity and may play an important role in sexual transmission of HIV, making them a potential microbicide target. One novel approach to target these fibrils is the use of small molecules known to intercalate into the structure of amyloid fibrils, such as derivatives of thioflavin-T.

Rational design of amyloid binding agents based on the molecular rotor motif.

Alzheimer’s disease (AD) is characterized by a progressive loss of cognitive function and constitutes the most common and fatal neurodegenerative disorder.[1] Genetic and clinical evidence supports the hypothesis that accumulation of amyloid deposits in the brain plays an important role in the pathology of the disease. This event is associated with perturbations of biological functions in the surrounding tissue leading to neuronal cell death, thus contributing to the disease process.

Surprisingly low aqueous acidity at the alpha-positions of pyridiniums and pyrimidinium: the role of solvation.

The p K(a)'s of the 6-CH groups of N-methyl-2-methoxypyridinium, N-methyl-4-methoxypyridinium, and 1-methyl-2,4-dimethoxypyrimidinium ions in aqueous solution were determined to be about 33. The p K(a) values were nearly identical to each other and surprisingly similar to those reported for the neutral pyridones and uracil. Further determination of the enthalpies and entropies of the H-D exchange reactions revealed the role of solvation.

Carbanions from decarboxylation of orotate analogs: stability and mechanistic implications.

The pKa's of the 6-CH groups of 1,3-dimethyluracil, N-methyl-2-pyridone, and N-methyl-4-pyridone were determined through their reactions with bases derived from carbon acids with known pKa and the reactions of their corresponding carbanions with the carbon acids. No correlation between the stability of the carbanions and the rate of decarboxylation of corresponding carboxylic acids was found.

Stability of the 6-carbanion of uracil analogues: mechanistic implications for model reactions of orotidine-5'-monophosphate decarboxylase.

[Structure: see text] The pKa's of the 6-CH groups of N-methyl-2-pyridone and N-methyl-4-pyridone in aqueous solution were determined. No correlation between the stability of the carbanions and the rate of decarboxylation of the corresponding carboxylic acids was found.