Flora Cozzolino

Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them to adjust the properties of molecules differently from organic molecules. Therefore, interest in the study of metal–drug complexes from different aspects has been aroused, and numerous approaches have been developed to characterize, activate, deliver, and clarify molecular mechanisms. The integration of these different approaches, ranging from chemoproteomics to nanoparticle systems and various activation strategies, enables the understanding of the cellular responses to metal drugs, which may form the basis for the development of new drugs and/or the modification of currently used drugs. The purpose of this review is to briefly summarize the recent advances in this field by describing the technological platforms and their potential applications for identifying protein targets for discovering the mechanisms of action of metallodrugs and improving their efficiency during delivery.

Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy.