Development of small-molecule libraries for neurodegenerative protein misfolding diseases

Protein misfolding diseases (PMDs) are chronic and progressively degenerative disorders, characterized by the accumulation of insoluble aggregates of misfolded proteins. Particularly, amyloid-\u3b2 and tau protein in Alzheimer\u2019s disease, prion protein in prion diseases, and \u3b1-synuclein in Parkinson disease are prototypical misfolded proteins that aggregate and accumulate in the brain, being responsible for the respective neurodegenerative disease. In the last decades, neurodegenerative PMDs have drawn public and scientific attention due to an increasing number of cases, becoming a critical issue in terms of healthcare and social costs. Moreover, while the list of neurodegenerative PMDs is long and growing, the pipeline of disease-modifying drugs is dry. In light of this clear unmet medical need, the present PhD thesis has been devoted to the development of three small-molecule libraries for neurodegenerative PMDs, through different and innovative strategies. First, we applied the multi-target directed ligand approach and we developed the first class of multi-target compounds able to hit the tau cascade at two different hubs. The synthesized 2,4-thiazolidinedione derivatives were able to concomitantly inhibit the phosphorylating tau kinase GSK-3\u3b2, as well as the tau aggregation process. Thus, these multi-target compounds could be promising tools for the validation of a completely new tau-centric approach as a disease-modifying strategy to treat Alzheimer\u2019s disease. Secondly, we applied the theranostic approach and we designed and synthesized a library of fluorescent bivalent derivatives. These bivalent compounds could be able, in principle, to stain A\u3b2 and tau protein aggregates and to inhibit the protein aggregation process. If we will be able to further demonstrate their theranostic profile in vitro and in vivo, these compounds could serve as innovative tools to potentially diagnose, deliver therapy, and monitor response to therapy in PMDs. Finally, we designed a focused library of compounds with the aim of optimizing the drug-like properties of a previously identified antiprion compound. Namely, we inserted on a position amenable to derivatization solubilizing groups, specifically tailored for CNS drug optimization. If our design strategy will be successful, we will have improved the pharmacokinetic properties of a promising antiprion compound, making possible its progression to further in vivo studies

From Companion Diagnostics to Theranostics:A New Avenue for Alzheimer's Disease?

The recent literature signals a growing paradigm shift toward integrating therapeutics and diagnostics rather than developing and deploying them separately. In this gradual move toward more effective and personalized medications, companion diagnostics are an intermediate stage. The next step may be "theranostics", in which single chemical entities are developed to deliver therapy and diagnosis simultaneously. This strategy has been successfully exploited in oncology and is now emerging as a possibility for Alzheimer's disease, where its feasibility has caught the attention of researchers from industry and academia. Medicinal chemists do not yet completely understand the nuances of theranostic action and consequently have not yet developed universally validated strategies for developing theranostic clinical applications against Alzheimer's disease. However, given the emerging indications of the potentially enormous benefits that theranostics may bring to the fight against this devastating disease, further rigorous research is warranted

Discovery of Dual Aβ/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer's Disease

Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aβ clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aβ and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells overexpressing Aβ42 and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood−brain barrier (BBB), together with the in vitro interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds 22 and 23 were tested in vivo, in a Drosophila melanogaster model of AD. The carbazole derivative 22 (20 μM) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of Aβ42 expressing flies and generating a better outcome than doxycycline (50 μM). Moreover, 22 proved to be able to decrease Aβ42 aggregates in the brains of the flies. We conclude that bivalent small molecules based on 22 deserve further attention as hits for dual Aβ/Tau aggregation inhibition in A

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

Drug Discovery Strategies for the Generation of Multitarget Ligands against Neglected Tropical Diseases

This chapter by choosing the field of neglected tropical diseases (NTDs) as the background therapeutic area describes efforts to develop multitarget drugs for solving the vexing medical problem. Among the various NTDs, the chapter focuses on three diseases most significant in terms of morbidity and mortality: human African trypanosomiasis (HAT), Chagas' disease, and leishmaniasis. A numerous class of hybrid anti‐trypanosomatid molecules is represented by the so‐called targeted drugs, which combine a framework with antiparasitic activity with a fragment recognized by a parasite transporter. A multitarget‐directed ligand (MTDL) is a single chemical entity that simultaneously recognizes different targets inside the parasite. The chapter then presents the report on the different approaches that are exploited to obtain innovative hybrid small molecules. Modern drug discovery for NTDs is carried out using both target‐based and phenotypic approaches. The target‐based approaches to NTDs are a widely used route for drug discovery programs aimed at identifying new lead compounds for diseases

Acupuncture and auricular cryotherapy for chronic headache in a patient with type III von Willebrand disease

[No abstract available

Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β 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-3β 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 IC50values toward GSK-3β, 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