Title:Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases
Volume: 25
Issue: 4
Author(s): Valeria Lanza, Danilo Milardi, Giuseppe Di Natale and Giuseppe Pappalardo*
Affiliation:
- Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Catania,Italy
Keywords:
Clioquinol, metformin, copper, neurodegenerative diseases, drug repurposing, metallostasis, cyclodipeptides.
Abstract: Background: There is mounting urgency to find new drugs for the treatment of
neurodegenerative disorders. A large number of reviews have exhaustively described either
the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's
(AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for
other diseases can also be effective as therapeutic agents in neurodegenerative diseases
are less reported. This review focuses on the current uses of some copper(II) chelating
molecules as potential drug candidates in neurodegeneration.
Methods: Starting from the well-known harmful relationships existing between the dyshomeostasis
and mis-management of metals and AD onset, we surveyed the experimental
work reported in the literature, which deals with the repositioning of metal-chelating
drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from
common literature and their selection was limited to those describing the biomolecular
aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination
abilities of the selected drugs.
Results: Copper, together with zinc and iron, are known to play a key role in regulating
neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative
disorders. The studies included in this review may provide an overview on the current
strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative
disorders. Starting from the exemplary case of clioquinol repurposing, we discuss
the challenge and the opportunities that repurposing of other metal-chelating drugs
may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative
disease.
Conclusions: In order to improve the success rate of drug repositioning, comprehensive
studies on the molecular mechanism and therapeutic efficacy are still required. The present
review upholds that drug repurposing makes significant advantages over drug discovery
since repositioned drugs had already passed the safety and toxicity tests. Promising
drug candidates in neurodegenerative diseases may be represented by copper chelating
classes of drugs, provided that sufficient details on their mechanism of action are
available to encourage further investigations and clinical trials.