Antifungal metallacarboranes modulate Hsp90 activity

Aims Despite growing interest in metallacarborane biological activity, the molecular targets underlying their antifungal activity remain unknown. This study aimed to identify protein targets of antifungal metallacarborane derivatives in Candida albicans and to characterize their interaction with the molecular chaperone Hsp90.Experimental Affinity chromatography using chromatographic beads bearing immobilized [CoSAN-I]− was employed to pull down proteins from C. albicans cell lysate. Captured proteins were identified by MALDI-TOF mass spectrometry. Direct binding of [CoSAN]−, [CoSAN-I]−, and its derivatives to recombinant Hsp90 was confirmed by affinity chromatography and surface plasmon resonance. The effect of compounds on Hsp90 ATPase activity was assessed using a malachite green phosphate release assay. Molecular docking and DFT (Density Functional Theory) calculations were performed to rationalize binding mechanisms.Results MALDI-TOF analysis identified 72 interacting proteins, of which 14 are established antifungal targets; Hsp90 showed the highest sequence coverage (82.7%). SPR confirmed direct, multivalent binding of all metallacarborane derivatives to Hsp90. The compounds modulated Hsp90 activity in a biphasic, dose-dependent manner, with maximal activation of 82–107% at 50–75 µM.Conclusions Metallacarboranes directly engage and functionally modulate Candida albicans Hsp90, establishing a novel mechanistic basis for their antifungal activity and providing a rational framework for the development of boron-cluster-based therapeutics.