Over the past 2 decades, solid evidence has emerged to suggest that the mode of action of certain classes of metal-based anti-cancer drugs (e.g., several ruthenium and gold compounds) is largely mediated by their interaction with cellular proteins rather than direct binding to DNA. This has sparked interest in studying the molecular mechanisms of protein metalation by anti-cancer metallodrugs in greater detail, mainly through combining ESI-MS and XRD measurements. Our integrated studies on small model proteins began in 2013, and this approach was later consolidated and summarised in two comprehensive publications in 2017, outlining the general investigative protocol, its development, and future perspectives. These studies have provided a deeper understanding of protein metalation processes at a molecular level. Based on an extensive collection of examples, we determined the main features of the metalation of several small model proteins (such as lysozyme and RNase A) by various classes of anti-cancer metallodrugs (e.g., platinum-, ruthenium- and gold-based) and identified the general rules of protein binding. Subsequently, the focus shifted towards analysing the metalation of larger proteins of great biological interest, such as human ferritin and serum albumin. Examples of these studies are provided and discussed. Finally, we offer a critical review of the issues that remain unresolved in the field of protein metalation by metal-based drugs, outlining prospects for future work.
Merlino et al. (Wed,) studied this question.