Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity

Paul T Marcyk; Emmanuelle V LeBlanc; Douglas A Kuntz; Alice Xue; Francisco Ortiz; Richard Trilles; Stephen Bengtson; Tristan M G Kenney; David S Huang; Nicole Robbins; Noelle S Williams; Damian J Krysan; Gilbert G Privé; Luke Whitesell; Leah E Cowen; Lauren E Brown

doi:10.1021/acs.jmedchem.0c01777

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Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity

Journal article

Open access

Peer reviewed

Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity

Paul T Marcyk, Emmanuelle V LeBlanc, Douglas A Kuntz, Alice Xue, Francisco Ortiz, Richard Trilles, Stephen Bengtson, Tristan M G Kenney, David S Huang, Nicole Robbins, …

Journal of medicinal chemistry, Vol.64(2), pp.1139-1169

01/28/2021

DOI: 10.1021/acs.jmedchem.0c01777

PMCID: PMC8493596

PMID: 33444025

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https://www.ncbi.nlm.nih.gov/pmc/articles/8493596View

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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 ( , ) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting growth in culture. In addition, we report the first X-ray crystal structures of 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.

Animals

Antifungal Agents - chemistry

Antifungal Agents - pharmacology

Cell Line

Cell Survival - drug effects

Cryptococcus neoformans - drug effects

Crystallography, X-Ray

Fungi - drug effects

HSP90 Heat-Shock Proteins - antagonists & inhibitors

Humans

Mice

Microbial Sensitivity Tests

Microsomes, Liver - metabolism

Protein Binding

Pyrazoles - chemistry

Pyrazoles - pharmacology

Species Specificity

Structure-Activity Relationship

Details

Title: Subtitle: Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity
Creators: Paul T Marcyk - Boston University
Emmanuelle V LeBlanc - University of Toronto
Douglas A Kuntz - Princess Margaret Cancer Centre
Alice Xue - University of Toronto
Francisco Ortiz - Southwestern Medical Center
Richard Trilles - Boston University
Stephen Bengtson - Boston University
Tristan M G Kenney - University of Toronto
David S Huang - Boston University
Nicole Robbins - University of Toronto
Noelle S Williams - Southwestern Medical Center
Damian J Krysan - University of Iowa
Gilbert G Privé - University of Toronto
Luke Whitesell - University of Toronto
Leah E Cowen - University of Toronto
Lauren E Brown - Boston University
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.64(2), pp.1139-1169
DOI: 10.1021/acs.jmedchem.0c01777
PMID: 33444025
PMCID: PMC8493596
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Grant note: R01 AI120958 / NIAID NIH HHS
Language: English
Date published: 01/28/2021
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984297318802771

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