In silico/in vitro screening and hit evaluation identified new phenothiazine anti-prion derivatives.

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of rare neurodegenerative disorders. TSEs are characterized by the accumulation of prions (PrPSc) that represent pathological isoforms of the physiological cellular prion protein PrPC. Although the conversion of PrPC to PrPSc is still not completely understood, blocking this process may lead to develop new therapies. Here, we have generated a pharmacophore model, based on anti-prion molecules reported in literature to be effective in phenotypic assay. The model was used to conduct a virtual screen of commercial compound databases that selected a small library of ten compounds. These molecules were then screened in mouse neuroblastoma cell line chronically infected with prions (ScN2a) after excluding neurotoxicity. 1 has been identified as the therapeutic hit on the basis of the following evidence: chronic treatments of ScN2a cells using 1 eliminate PrPSc loaded in both Western blotting analysis and Real-Time Quaking-Induced Conversion (RT-QuIC) assay. We also proposed the mechanism of action of 1 by which it has the ability to bind PrPC and consequentially blocks prion conversion. Herein we describe the results of these efforts.

Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3ß and Tau-Aggregation Inhibitors.

Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3ß and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3ß, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 µM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.

Therapeutic Approaches to Prion Diseases.

Therapy of prion diseases represents an extremely challenging effort for scientists working in the field. These challenges are epitomized by 20 years of failures in clinical trials and preclinical investigations. However, the discovery that misfolded proteins involved in other neurodegenerative diseases show a prion-like mechanism of spreading, is positively impacting the prion drug discovery field. Herein, we describe those efforts that have contributed to strengthen the drug discovery process in prion diseases. Accordingly, we analyze the historical course of clinical trials that have assessed the efficacy of several chemically unrelated repositioned drugs. Unfortunately, none of them resulted successful. Thus, alternative approaches aiming at identifying innovative drugs with a completely new mechanism of action, have been recently pursued. In this respect, the multifactorial nature of prion diseases provides a strong foundation to the development of small molecules directed to two or multiple pathological targets, critically involved in the intricate disease pathogenesis (i.e., multitarget compounds). Second, the fact that misfolded proteins can be considered not only as therapeutic target, but also as neuropathological hallmark, lends support to the development of theranostics, i.e., single molecules with concomitant therapeutic and diagnostic properties. Although nobody knows whether these innovative tools will be brought to clinical trials, and the process is certainly time-consuming and demanding, the rewards are well worth the effort.

Neuroregeneration versus neurodegeneration: toward a paradigm shift in Alzheimer's disease drug discovery.

Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease.