Protease Inhibitors in Fungal Pathogenesis

Proteases secreted by pathogenic fungi orchestrate key steps in host colonisation, including tissue invasion, immune evasion and biofilm formation. These enzymes—among them aspartic proteases, metalloproteases and serine proteases—degrade host proteins, modulate cell signalling and facilitate morphological transitions such as yeast-to-hypha switching. Inhibition of fungal proteases has emerged as an attractive therapeutic strategy to attenuate virulence without exerting the same selective pressure as fungicidal agents. Protease inhibitors originally developed for other indications, notably human immunodeficiency virus protease inhibitors (HIV-PIs), have demonstrated off-target activity against fungal aspartic proteases. In parallel, small-molecule inhibitors and metal-chelate complexes that bind catalytic metal ions can block metalloprotease activity. By impeding nutrient acquisition, cell-surface remodelling and extracellular matrix degradation, protease inhibitors reduce fungal adhesion, biofilm maturation and dissemination. Preclinical studies highlight synergistic potential when combining protease inhibitors with existing antifungals, offering hope for tackling multidrug-resistant species. Advances in structure-guided design and repurposing pipelines continue to expand the repertoire of compounds capable of targeting critical proteolytic pathways in fungi, paving the way for novel adjuvant therapies in systemic and superficial mycoses.

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Protease Inhibitors in Fungal Pathogenesis publication trend

The graph below shows the total number of articles in protease inhibitors in fungal pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Protease inhibitor: A compound that binds to a protease’s active site or regulatory region to prevent substrate cleavage.

Aspartic protease: An enzyme that utilises two aspartate residues to hydrolyse peptide bonds, often secreted by fungi as virulence factors.

Metalloprotease: A protease requiring a metal ion cofactor, typically zinc, for catalytic activity in host tissue degradation.

Biofilm: A structured community of microorganisms embedded in extracellular matrix that confers increased resistance to antifungal agents.

Repurposing: The application of an existing approved drug to a new therapeutic indication.

1,10-Phenanthroline complex: A chelating ligand that coordinates metal ions and can inhibit metalloprotease activity.

References

1. Silver(I) 1,10-Phenanthroline Complexes Are Active against Fonsecaea pedrosoi Viability and Negatively Modulate Its Potential Virulence Attributes. Journal of Fungi (2023).
2. Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans—In Silico, In Vitro and In Vivo Approaches. Journal of Fungi (2021).
3. Repurposing HIV Protease Inhibitors Atazanavir and Darunavir as Antifungal Treatments against Candida albicans Infections: An In Vitro and In Vivo Study. Current Issues in Molecular Biology (2022).