Regulation of Copper and Iron Homeostasis by Metal Chelators: A Possible Chemotherapy for Alzheimer’s Disease

Abstract

With the increase of life expectancy of humans in more than two-thirds of the countries in the World, aging diseases are becoming the frontline health problems. Alzheimer's disease (AD) is now one of the major challenges in drug discovery, since, with the exception of memantine in 2003, all clinical trials with drug candidates failed over the past decade. If we consider that the loss of neurons is due to a high level of oxidative stress produced by nonregulated redox active metal ions like copper linked to amyloids of different sizes, regulation of metal homeostasis is a key target. The difficulty for large copper-carrier proteins to directly extract copper ions from metalated amyloids might be considered as being at the origin of the rupture of the copper homeostasis regulation in AD brains. So, there is an urgent need for new specific metal chelators that should be able to regulate the homeostasis of metal ions, specially copper and iron, in AD brains. As a consequence of that concept, chelators promoting metal excretion from brain are not desired. One should favor ligands able to extract copper ions from sinks (amyloids being the major one) and to transfer these redox-active metal ions to copper-carrier proteins or copper-containing enzymes. Obviously, the affinity of these chelators for the metal ion should not be a sufficient criterion, but the metal specificity and the ability of the chelators to release the metal under specific biological conditions should be considered. Such an approach is still largely unexplored. The requirements for the chelators are very high (ability to cross the brain-blood barrier, lack of toxicity, etc.), few chemical series were proposed, and, among them, biochemical or biological data are scarce. As a matter of fact, the bioinorganic pharmacology of AD represents less than 1% of all articles dedicated to AD drug research. The major part of these articles deals with an old and rather toxic drug, clioquinol and related analogs, that do not efficiently extract copper from soluble amyloids. We have designed and developed new tetradendate ligands such as 21 and PA1637 based on bis(8-aminoquinolines) that are specific for copper chelation and are able to extract copper(II) from amyloids and then can release copper ion upon reduction with a biological reducing agent. These studies contribute to the understanding of the physicochemical properties of the tetradentate copper ligands compared with bidentate ligands like clioquinol. One of these copper ligands, PA1637, after selection with a nontransgenic mouse model that is able to efficiently monitor the loss of episodic memory, is currently under preclinical development.

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

“…A large number of metal chelators have been proposed as therapeutics for AD (e.g., Telpoukhovskaia and Orvig, 2013; Robert et al, 2015), while only a handful have been clinically trialed. The most widely promoted therapeutic chelators for AD therapy are CQ (PBT1) and PBT2, both of which are based upon old chemistry with diverse applications (Gholz and Arons, 1964; Stevenson and Freiser, 1967; Rajagopalan et al, 2001; Ding et al, 2005).…”

Developing drugs targeting transition metal homeostasis

“…While ionophores and chelators may be considered opposite to each other in that the former is responsible for the delivery of metals and the latter for the removal of metals; ultimately they both act as metal-binding compounds. Several recent, comprehensive reviews detail the current state of research into chelators and ionophores [1,2] and the broader application of this class of metal-binding molecules to cancer [3,4] and neurodegenerative diseases [5,6•]. …”

Multitarget trehalose-carnosine conjugates inhibit Aβ aggregation, tune copper(II) activity and decrease acrolein toxicity

“…[68] These "multitarget" directed ligands (MTDL) are intended to prevent AD symptoms as well as disease progression as opposed to traditional therapies that were solely based on cholinesterase inhibition. [69,70] Reviews of MTDL classify the new molecules based on one chemical lead and list the modifications that might be introduced to maximize the pharmacological parameters measured for a given compound. [ 71 ] The newly synthesized Car derivative falls in this class of compounds as it may cope with: i) Aβ fibril formation, including also metal-assisted fibril formation; ii) alteration of metal homeostasis; iii) ROS activities and iv) ACR toxicity.…”