Design Strategies and Medicinal Applications of Metal-Peptidic Bioconjugates

The conjugation of metal-based scaffolds to peptides, proteins, or antibodies allows the systemic targeting of these payloads to specific locations in the body, such as target cells/tissues (e.g., cancer) and subcellular compartments, for either therapy or imaging. This Topical Review includes an overview of the available chemical strategies to achieve metal-peptidic bioconjugates for biomedical applications, focusing on the types of chemical functionalities used to tether the drug to the peptide directly or indirectly. Central to all the possible approaches is the development of highly efficient and selective bioconjugation reactions that operate under mild, peptide-compatible conditions. For each strategy, selected examples are highlighted with particular emphasis to the studies reporting the therapeutic effects of the metal-peptidic conjugates in the treatment of cancer. Overall, some of the herewith discussed cases clearly hold promise for translation into clinically meaningful applications in the field of targeted therapeutics. Nevertheless, novel chemical approaches enabling the chemoselective metalation of specific residues in peptides under biologically friendly conditions, as well as the design of stimuli-responsive bioconjugates, are still expected to emerge. Certainly, the peculiar biorthogonal reactivity of metallodrugs provides an enlarged toolbox of opportunities for bioconjugation. Therefore, we outline a number of possible future directions and applications.