An interdisciplinary team of ULB researchers has developed molecules that can transport copper ions across lipid membranes of cells. Together with colleagues of the Université Grenoble Alpes, they found that copper transport is an efficient way to kill cancer cells.
Disrupting copper homeostasis using small molecules
Copper ions are essential for life, because many enzymes need copper. For instance, without copper ions, we cannot transform food into energy. However, too much copper is often toxic. For this reason, cells and organisms carefully maintain the copper levels constant, for instance by storing the excess of copper in separate compartments. Molecules that undermine this storage system by transporting the copper ions out of these compartments, can thus lead to toxicity, which can be used to kill cancer cells.
Cuphoralix as copper transporter
Inspired by copper-binding motifs found in proteins, the ULB researchers have developed crab-like molecules with two binding arms able to efficiently grab copper ions that have a single positive charge (Cu+). This is important, as most copper ions inside cells have a single charge, whereas most reported molecules only bind copper ions that have a double charge (Cu2+). Furthermore, the researchers had to optimise the ability of the molecule to insert in the lipid membrane, for it to function as transmembrane transporter and be efficient in cells. The best molecule was named Cuphoralix, as it is a copper ionophore based on a calixarene macrocycle.
Interdisciplinary teamwork
Over the past 8 years, Hennie Valkenier (Engineering of Molecular NanoSystems, Ecole Polytechnique de Bruxelles) and Ivan Jabin (Laboratory of Organic Chemistry, Faculty of Science) and their researchers have worked on the synthesis of a series of small molecules for the transport of copper ions across cell membranes. The copper transport by these molecules was first studied in liposomes as model systems, using fluorescent probes that respond to copper ions. Then, they were tested on yeast cells with Anna Marini and Mélanie Boeckstaens (Biology of Membrane Transport laboratory, Faculty of Science) to demonstrate that they do not only work in model systems, but also in membranes of living cells.
Studies on cancer cells have been performed by Aurélien Deniaud and colleagues from the Université Grenoble Alpes (UGA), who found highly toxic effects on cancer cells. Advanced studies in the European Synchrotron Radiation Facility (ESRF) in Grenoble allowed to monitor the copper distribution in cells, which demonstrated that Cuphoralix acts as a copper transporter and redistributes copper ions inside liver cells, leading to toxicity.
This work has been patented by ULB and UGA and the results are now published in the Journal of the American Chemical Society: https://doi.org/10.1021/jacs.5c15335