Malattia di Alzheimer, nuove strategie di Drug Discovery

Alzheimer\u2019s disease (AD) is a complex neurodegenerative disorder resulting from multiple molecular abnormalities, and not from a single target/gene defect. This may explain why the currently available drugs and mostly of the candidates in the pipeline, developed according to the classic drug discovery paradigm of \u201cone-molecule-one-target\u201d, have turned out to be palliative or have failed in achieving any curative effect. This has led to a new paradigm in medicinal chemistry, the \u201cmulti-target-directed ligand\u201d design strategy, which has already been exploited at both academic and industrial levels [1]. Multi-target-directed ligands (MTDLs) are small molecules rationally designed to simultaneously modulate multiple targets involved in the neurotoxic cascade. Thus, they should be well-suited to addressing the multifactorial etiopathogenesis of AD. In parallel, there has been a shift in interest from a target-centric approach, which attempts to limit drug action to the level of individual genes and single proteins, to a system approach, which is better suited to the complexity of the disease. The early signs of this paradigm shift are now being registered, as AD is increasingly studied at multiple levels, and new scientific advances are providing insights into the functioning of interacting biomolecules within cells or organisms [2]. In particular, since a significant number of therapeutic targets reside inside cells and intracellular organelles, subcellular targeting strategies for drug design and delivery now represent a considerable drug discovery challenge [3]. Herein, we present our research efforts that, moving on from classic drug discovery approaches, have produced innovative molecular probes and promising drug candidates for AD treatment. [1] A. Cavalli, M. L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, M. Recanatini, C. Melchiorre. J. Med. Chem. 2008, 51, 347-72. [2] M. L. Bolognesi, R. Matera, A. Minarini, M. Rosini, V. Tumiatti, C. Melchiorre. Curr. Opin. Chem. Biol. 2009, 13, 303-8. [3] L. Rajendran, H. J. Kn\uf6lker, K. Simons. Nature Rev. Drug Discov. 2010, 9, 29-42