Protein-Protein Interactions : Fungal Hsp90
Fungal diseases result in approximately 11 million life-threatening infections annually. Current treatment strategies for these infections are limited by antifungal resistance, toxicity and drug interactions.
Fungal Hsp90 chaperone is a major regulator of cell wall integrity and virulence. Genetic impairment of Hsp90 function reduces tolerance to stress and abrogates drug resistance to the two main classes of antifungals (azoles and echinocandins). Inhibition of Hsp90 by geldanamycin restores susceptibility of C. albicans strains resistant to azoles and echinocandins but such ATP inhibitors appear to have limited therapeutic potential on their own as they exhibit in vivo toxicity because of their non-selectivity.
This project proposes an innovative and original strategy in medical mycology to selectively inhibit yeast Hsp90 by targeting its interactions with associated proteins. The aim is to identify in silico and in vitro small molecules or hits able to disrupt the protein-protein interactions (PPIs).
This approach will be carried out thanks to an interdisciplinary consortium, gathering biologists, organic and computational chemists. Therefore, the goal of the fundamental and multidisciplinary project will be the identification of new drug candidates with selective antifungal activity and being able to bypass resistance to the most widely used antifungal drugs.
The involved members/partners are P Le Pape (Biology), A. Laurent (Molecular modeling), P. Marchand and MA Bazin (Organic chemistry). Support from the IMPACT plateforme.