Quinone-based small molecules as a novel therapy for Alzheimer's disease and Amyloidosis

The Technology
Disease modifying drugs for Alzheimer's disease (AD) and the related Mild Cognitive Impairment (MCI), based on rationally-designed quinone-based small molecules. Results so far resulted in significant reversal of AD symptoms while causing no apparent adverse effects.

The Need
Alzheimer’s disease (AD) is a progressive, irreversible brain disorder with an unclear etiology and no cure. It is characterized by an extracellular accumulation of plaques that composed mainly from 42-amino acid peptide terms amyloid-b peptide (Ab). Another character of AD is the accumulation of intracellular neurofibrillary tangles. In the past two decades, several biochemical and genetic studies have suggested that the formation of amyloid fibrils by Ab protein play a central role in the pathogenesis of AD. Early studies suggested that the insoluble fibrillar aggregates of Ab are the neurotoxic agents, however recent studies indicate that the most neurotoxic forms of Aβ are the soluble oligomeric species of the polypeptide, in particularly the 56kDa (56*) specie.

Despite a significant increase in our understanding of the pathogenesis of AD, therapeutic options are still very limited and aim only at amelioration of symptoms. It may be advantageous to target the earliest stages of Ab recognition and oligomerization, thus removing all potential toxic species of Ab. In fact, it has been shown by our group and others that targeting the early process of Ab molecular recognition is a very promising approach for the treatment of AD. Moreover, Mild Cognitive Impairment (MCI) a much common phenomenon frequently observed as a prodromal stage of Alzheimer's disease is also associated with the formation of 56* species.

Potential Application

• A novel Disease modifying drug for Alzheimer's disease (AD)
• Possible effective drugs for other aggregation-associated diseases, e.g. Parkinson's, Type II diabetes.

Stage of development
Our previous studies have implicated aromatic residues in a-beta aggregation, suggesting that novel small molecules comprising an aromatic core and a moiety that will confer steric hindrance could be effective inhibitors of a beta aggregation. We have synthesized two novel tryptophan-modified naphthoquinones, NQTrp and Cl-NQTrp), which have shown marked inhibition of a-beta aggregation and fibrilization in vitro; protected cultured neuronal cells from the toxic effect of a-beta and alleviated remarkably AD-related symptoms in transgenic Drosophila flies expressing a-beta in their brains. This was accompanied by reduction of a-beta aggregates in their brains. Cl-NQTrp showed similar effects in small scale experiment in model AD mice. No apparent adverse effects were observed in this small scale experiment. Thus, NQTrp and Cl-NQTrp are promising novel candidate AD drugs. Bioavailability and pharmacokinetic studies demonstrated excellent absorption either by oral (PO) or injection (IP) and remarkable stability of the compound. Moreover, toxicity studies (acute and chronic) revealed the safety of the compounds.

Patent
Worldwide patent application (WO2010026592, Priority date – Sep 2008)

Supporting Publications
Scherzer-Attali R, Shaltiel-Karyo R, Adalist YH, Segal D, Gazit E (2012). Generic inhibition of amyloidogenic proteins by two naphthoquinone-tryptophan hybrid molecules. Proteins. 80(8):1962-73.

Scherzer-Attali, R., Farfara, D., Ben-Romano, T., Trudler, D., Vientrov, M., Shaltiel-Karyo, R., Shalev, D.E., Gazit, E., Segal, D., and Frenkel, D. (2012). Naphthoquinone-tyrptophan reduces neurotoxic Ab*56 level and improves cognition in Alzheimer's disease animal model Neurobiol Dis. 46(3):663-72.

Scherzer-Attali R, Shaltiel-Karyo R, Adalist YH, Segal D, Gazit E. Scherzer-Attali, R, Pellarin, R., Marino Convertino, M., Frydman-Marom, A., Egoz-Matia, N., Peled, S., Levy-Sakin, M., Shalev, DE., Caflisch, A., Gazit, E., and Segal, D. (2010). Complete Phenotypic Recovery of Alzheimer's Disease Model by a Quinone-Tryptophan Hybrid Aggregation Inhibitor. PLoS One 5: e11101.

Project manager

Elisha Natan
Director BD

Project researchers

Ehud Gazit
T.A.U Tel Aviv University, Life Sciences
Molecular Microbiology-Biotechnology

Daniel Segal
T.A.U Tel Aviv University, Life Sciences
Molecular Microbiology-Biotechnology