Fungal heat shock protein 90 (Hsp90)

Fungal heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that plays a central role in the survival, environmental adaptation, and virulence of pathogenic fungi such as Candida albicans and Aspergillus fumigatus (Islam et al., 2020; Lu et al., 2025). It functions by assisting in the folding and stabilization of various "client" proteins, including key signaling molecules like calcineurin and protein kinase C, which are essential for stress response and the development of antifungal resistance (Wirk, 2011; Lamoth et al., 2014). By inhibiting Hsp90, drugs can abrogate these protective pathways, rendering fungi more susceptible to traditional antifungal agents and potentially reversing drug resistance (Costa-de-Oliveira et al., 2022; Islam et al., 2020). This synergistic effect is particularly valuable in treating invasive fungal infections where resistance to azoles or echinocandins has emerged (Islam et al., 2020; Wirk, 2011). However, the high degree of structural similarity between fungal and human Hsp90 presents a major challenge for drug development, as off-target inhibition of the host protein can lead to significant toxicity (Lu et al., 2025; The Molecular Mechanic, 2021). Clinical candidates like Efungumab (Mycograb) have been investigated as adjunctive therapies, though safety and efficacy concerns have hindered their widespread adoption (Matthews et al., 2003; Sutherland & Ellis, 2008). Current research focuses on identifying fungal-specific inhibitors or targeting extracellular Hsp90 to minimize these safety concerns and improve therapeutic outcomes (Lu et al., 2025; The Molecular Mechanic, 2021).

Other names

Heat shock protein 90HSP9090 kDa heat shock proteinHsp90pHsp82Hsc82

Fungal Hsp90 inhibitors typically bind to the N-terminal ATP-binding pocket, inhibiting its ATPase activity. This prevents the chaperone from undergoing the conformational changes necessary to fold and stabilize its client proteins, such as calcineurin and protein kinase C. The loss of these client proteins compromises the fungus's ability to respond to stress, maintain cell wall integrity, and develop resistance to other antifungal agents (Wirk, 2011; Islam et al., 2020; Matthews et al., 2003).