“Metal-based compounds in antiviral and Antiparasitic research: Mechanistic insights from HIV NCp7 and leishmaniasis case studies”

Metallodrugs have long occupied a significant position in medicinal chemistry, yet their application to infectious diseases has historically lagged the extensive development observed in cancer therapy. The COVID-19 pandemic, together with the increased spread of parasitic diseases driven by climate change and human migration, has renewed interest in metal-based compounds as antiviral and antiparasitic agents. These efforts have been further enabled by advances in computational modeling and mechanistic analysis, allowing rational design strategies that extend beyond in vitro drug screening. This focused review traces a coherent body of work, including studies developed by our research group, illustrating how fundamental coordination chemistry principles can be progressively integrated to address infectious disease challenges. Viral molecular targets, exemplified by the HIV-1 nucleocapsid protein NCp7, a zinc finger protein essential for multiple stages of retroviral replication, demonstrate how combined spectroscopic, mass-spectrometric, and computational approaches enable molecular-level understanding of metal-mediated zinc finger inhibition. Similar principles have been extended to neglected and emerging viral pathogens, including arboviruses such as Zika and chikungunya, where metal-based compounds can be modulated to interfere with different steps of replication cycle. In contrast, kinetoplastids such as Leishmania spp. present a complex intracellular environment in which the biological activity of metal complexes is governed predominantly by redox perturbation, disruption of thiol-dependent metabolism, and mitochondrial dysfunction. By following a continuous methodological and conceptual progression from drug-screening to mechanistic approach and in vivo models, this review highlights this transition and underscores the potential of metallodrugs in infectious disease agents.