Multi-target-directed drugs for neurodegeneration

MULTI-TARGET-DIRECTED DRUGS FOR NEURODEGENERATION Carlo Melchiorre Alma Mater Studiorum – University of Bologna, Department of Pharmaceutical Sciences Via Belmeloro 6, 40126 Bologna, Italy Drug discovery began as an entirely human-phenotype-based endeavor and, as the understanding of disease pathogenesis advanced, moved to disease models of decreasing complexity (the reductionist approach). From mouse models to protein models via cellular models, these disease models had decreasing relevance for the human condition. As a consequence, drug research has, for decades, been based mainly on a single-target-directed compound strategy; that is, the discovery of a single molecule that is able to modulate the biological profile of a single protein target. This strategy has led to many successful drugs. However, a highly selective ligand for a given target does not always result in a clinically efficacious drug, whether because (a) the ligand does not recognize the target in vivo, (b) the ligand does not reach the site of action, or, (c) the interaction with that particular target is not sufficient enough to efficaciously treat a given disease. Drawbacks a and b can be solved by rationally modifying the ligand. Issue c, however, may not be so easily addressed. This lecture will focus on issue c. In particular, we will consider a new emerging paradigm in drug discovery (‘multi-target-directed ligands’) as a way of potentially overcoming the problems that arise from drugs that hit a single target, drugs that may therefore be inadequate for the treatment of diseases that have multiple pathogenic factors – for example, neurodegenerative diseases.