Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity
- 13 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (2), 1139-1169
- https://doi.org/10.1021/acs.jmedchem.0c01777
Abstract
The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal (Cryptococcus neoformans, Candida albicans) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting C. neoformans growth in culture. In addition, we report the first X-ray crystal structures of C. neoformans Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.Funding Information
- Samuel Waxman Cancer Research Foundation
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI120958)
- Natural Sciences and Engineering Research Council of Canada
This publication has 92 references indexed in Scilit:
- Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputsNature Reviews Microbiology, 2012
- Regulatory Circuitry Governing Fungal Development, Drug Resistance, and DiseaseMicrobiology and Molecular Biology Reviews, 2011
- Overview of theCCP4 suite and current developmentsActa crystallographica. Section D, Structural biology, 2011
- Analysis of protein-ligand interactions by fluorescence polarizationNature Protocols, 2011
- A Medicinal Chemist’s Guide to Molecular InteractionsJournal of Medicinal Chemistry, 2010
- Features and development of CootActa crystallographica. Section D, Structural biology, 2010
- XDSActa crystallographica. Section D, Structural biology, 2010
- Efflux-Mediated Antifungal Drug ResistanceClinical Microbiology Reviews, 2009
- Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious diseaseProceedings of the National Academy of Sciences of the United States of America, 2009
- Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug ResistanceEukaryotic Cell, 2008