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From the theory to the bench in multitarget drugs for Alzheimer’s disease therapy

Abstract: Multitarget approach strategy is a new emergent paradigm in drug design that is gaining stage in the pharmacotherapy of complex diseases. Among them, neurodegenerative pathologies, characterized by their unknown etiology, their intricate molecular pathology, and their multifactorial nature, are being benefited from the multitarget drug design. These new drug candidates show balanced activity in more than one relevant pharmacological target showing multiple additives or synergic pharmacodynamic activities in a single molecule. Alzheimer’s disease (AD) is a highly prevalent dementia associated with the aging increase.  Despite the great efforts to find an effective drug, it still presents high clinical failure. Moreover, the complexity of the molecular pathology suggests that traditional drugs will not be able to produce a therapeutic effect. Specifically, neurodegeneration, protein aggregation, and brain inflammation are the main pathological processes in AD. Amyloid plaques and neurofibrillary tangles are the main pathological hallmarks of AD. They are composed of aggregated beta-amyloid and hyperphosphorylated tau, respectively. However, other proteinopathy has been recently described for AD such as the case of the nuclear TDP-43. The design of multitarget compounds able to interfere simultaneously with three different targets involved in AD: BACE1, the secretase of beta-amyloid production, and, at least, two different protein kinases able to phosphorylate tau protein and/or TDP-43, will be here shown. In the synthesis of these molecules, click chemistry and protein-templated synthesis using BACE1 as a scaffold has been used as versatile tools. Finally, different cellular assays confirmed the polypharmacology and applicability of our multitarget drugs. Altogether, and since kinase inhibitors are also involved in the reduction of neuroinflammation and beta-amyloid is emerging as a risk factor for many other diseases associated with aging, the combination of all the biological activities in a single molecule has created potential future powerful drugs not only for AD but also for other dementias associated to frailty and aging.

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