Structural Insights into Selectively Targeting Candida albicans Hsp90

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Rising threat of drug-resistant pathogens necessitates novel antimicrobial and antifungal strategies.
• Heat-shock protein 90 (Hsp90) is a validated therapeutic target in human cancers and is also present in microbial pathogens.
• Pathogenic fungi, such as *Candida albicans*, possess Hsp90 orthologs that are essential for their survival and virulence.

Purpose of the Study:

• To investigate the potency and selectivity of human Hsp90 ligands against *Candida albicans* Hsp90 (CaHsp90).
• To define the key chemical features responsible for effective binding to CaHsp90.
• To provide structural insights into CaHsp90 inhibition for the development of new antifungal agents.

Main Methods:

• Biochemical assays to assess ligand binding affinity and potency.
• X-ray crystallography to determine the structures of CaHsp90 in complex with human Hsp90 ligands.
• Fragment-based and *in silico* screening to identify and optimize CaHsp90 binders.
• Structural analysis of CaHsp90 with a non-hydrolyzable ATP analog.

Main Results:

• Several human Hsp90 ligands demonstrated potent binding to CaHsp90.
• Key chemical features contributing to effective CaHsp90 binding were identified.
• Crystal structures revealed the binding modes of diverse ligands within the CaHsp90 nucleotide-binding domain.
• The structural basis for the selective inhibition of CaHsp90 by TAS116 was elucidated.

Conclusions:

• Human Hsp90 ligands can be adapted to target CaHsp90, presenting a viable strategy for antifungal drug development.
• Structural information provides a foundation for designing more potent and selective CaHsp90 inhibitors.
• Targeting CaHsp90 offers a promising avenue to combat infections caused by drug-resistant *Candida albicans*.