Heat shock protein 90 (fungal) (Hsp90)

Heat shock protein 90 (Hsp90) is a highly conserved and essential molecular chaperone in fungi that plays a pivotal role in maintaining cellular proteostasis and orchestrating responses to environmental stress (4, 9). It functions as an ATPase-dependent chaperone that stabilizes a specific subset of 'client proteins,' including key signal transducers like calcineurin and protein kinase C (PKC), which are critical for fungal virulence, morphogenesis, and the development of drug resistance (2, 14). In major human pathogens such as Candida albicans and Aspergillus fumigatus, Hsp90 enables the emergence and maintenance of resistance to common antifungal classes like azoles and echinocandins by buffering the phenotypic effects of genetic variation (6, 13). Pharmacological inhibition of fungal Hsp90, often using repurposed anticancer agents like 17-AAG, can convert fungistatic drugs into fungicidal combinations and restore susceptibility in resistant strains (10, 11). However, the significant structural similarity between fungal and mammalian Hsp90 presents a major therapeutic challenge, as non-selective inhibition often leads to severe host toxicity and dose-limiting side effects (1, 19).

Other names

Hsp82Hsc8290 kDa heat shock proteinExtracellular Hsp90 (eHsp90)

Inhibition of the N-terminal ATPase activity of Hsp90, which prevents the chaperone cycle and leads to the destabilization and degradation of essential client proteins required for fungal survival and stress response.