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Multi-target-directed ligands to combat neurodegenerative diseases — Past, present and future

Abstract: Neurodegenerative diseases are some of the most pressing medical and societal challenges faced by the global population. Although molecular mechanisms are not fully understood, it is widely accepted that their pathogenesis involves a complex array of concomitant, intertwined processes. Thus, it may be unlikely that drugs acting on single targets can effectively control them. In 2008, attracted by the potential of polypharmacology, we proposed the development of single molecule able to simultaneously modulate multiple targets responsible for the complex neurodegeneration cascade. We coined for them the term of Multi-target- directed ligands (MTDLs). In the years we have developed various MTDLs differing in their intrinsic molecular features and design concepts: i.e. fragments, hybrids and conjugates. Here, we will examine differences between them and discuss the benefits and disadvantages of each for further clinical translation.

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