Paracoccidioidomycosis is a neglected disease that causes economic and social impacts, mainly affecting people of certain social segments, such as rural workers. The limitations of antifungals, such as toxicity, drug interactions, restricted routes of administration, and the reduced bioavailability in target tissues, have become evident in clinical settings. These factors, added to the fact that Paracoccidioidomycosis (PCM) therapy is a long process, lasting from months to years, emphasize the need for the research and development of new molecules. Researchers have concentrated efforts on the identification of new compounds using numerous tools and targeting important proteins from Paracoccidioides, with the emphasis on enzymatic pathways absent in humans. This review aims to discuss the aspects related to the identification of compounds, methodologies, and perspectives when proposing new antifungal agents against PCM.

Background: Systemic mycosis is a cause of death of immunocompromised subjects. The treatment directed to evade fungal pathogens shows severe limitations, such as time of drug exposure and side effects. The paracoccidioidomycosis (PCM) treatment depends on the severity of the infection and may last from months to years. Methods: To analyze the main interactions of Paracoccidioides lutzii isocitrate lyase (ICL) regarding the energetic metabolism through affinity chromatography, we performed blue native PAGE and co-immunoprecipitation to identify ICL interactions. We also performed in silico analysis by homology, docking, hot-spot prediction and contact preference analysis to identify the conformation of ICL complexes. Results: ICL interacted with 18 proteins in mycelium, 19 in mycelium-to-yeast transition, and 70 in yeast cells. Thirty complexes were predicted through docking and contact preference analysis. ICL has seven main regions of interaction with protein partners. Conclusions: ICL seems to interfere with energetic metabolism of P. lutzii, regulating aerobic and anaerobic metabolism as it interacts with proteins from glycolysis, gluconeogenesis, TCA and methylcitrate cycles, mainly through seven hot-spot residues.