The significance of copper chelators in clinical and experimental application

The essentiality and redox-activity of copper make it indispensable in the mammalian system. However, a comprehensive understanding of copper metabolism and function has not been achieved. Copper chelators have been used as an approach to provide insights into copper acquisition, distribution, and disposition at both the cellular and organism level. Unfortunately, the understanding of effective copper chelators is predominantly based upon their chemical structures and their reactions with copper. The understanding of the efficacy of copper chelators in the biological system has been equivocal, thereby leading to under- or misleading-utilization of these agents in clinical and experimental approaches. Current use of copper chelators in vivo almost exclusively either limits the availability or focuses on the removal of copper in mammalian organ system. There are at least two aspects of copper chelators that are yet to be explored. First, copper chelators preferentially bind either cuprous or cupric. As a result, they potentially modulate copper redox-activity without removing copper from the system. Second, copper chelators are characterized as either membrane-permeable or -impermeable, thus would serve as an organ-selective copper delivery or deprivation system to manipulate the biological function of copper. Here we review clinically relevant copper chelators that have been experimentally or clinically studied for their role in manipulation of copper metabolism and function, paying critical attention to potentially more valuable usage of these agents.