The art of building multifunctional metal-binding agents from basic molecular scaffolds for the potential application in neurodegenerative diseases

Metal-ion homeostasis in the brain is critical for many physiological functions, particularly in the central nervous system where metals are essential in complex signaling pathways. Most common neurological diseases such as Alzheimer's (AD), Parkinson's (PD) and prion diseases, despite having distinct etiological bases, share similarities associated with metalloprotein misfolding and aggregation. In the last few years, several studies have provided evidence that abnormal concentrations of Cu(II), Zn(II) and/or Fe(III) specifically impair protein deposition and/or cause oxidative damage. This apparently critical role played by metal imbalance makes chelation therapy an attractive and challenging strategy to alleviate the development and progression of neurological disorders. Due to the multiple factors closely involved in the pathogenesis of these diseases, the classic drug discovery paradigm of “one molecule, one target” is limited in its ability to combat such complex diseases. Therefore, significant effort has been devoted to designing multifunctional metal-chelators aiming at multiple targets that must be addressed in these neurodegenerative diseases. In this review, the state-of-the-art in this latest strategy for designing metal-ion chelators as potential therapeutic agents in neurodegenerative diseases will be discussed, with special emphasis on AD and additional coverage of PD and prion diseases.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (310 K)Download as PowerPoint slideHighlights► Survey creative pathways to improve metal-binding agents according to the multifunctional concept. ► Tuning a basic scaffold with binding properties to coordinate metal ions and comprises other functionalities. ► Classification according to common molecular structures.