TY - JOUR
T1 - Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors
T2 - Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity
AU - Marcyk, Paul T.
AU - Leblanc, Emmanuelle V.
AU - Kuntz, Douglas A.
AU - Xue, Alice
AU - Ortiz, Francisco
AU - Trilles, Richard
AU - Bengtson, Stephen
AU - Kenney, Tristan M.G.
AU - Huang, David S.
AU - Robbins, Nicole
AU - Williams, Noelle S.
AU - Krysan, Damian J.
AU - Privé, Gilbert G.
AU - Whitesell, Luke
AU - Cowen, Leah E.
AU - Brown, Lauren E.
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/1/28
Y1 - 2021/1/28
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.0c01777
DO - 10.1021/acs.jmedchem.0c01777
M3 - Article
C2 - 33444025
AN - SCOPUS:85099952898
SN - 0022-2623
VL - 64
SP - 1139
EP - 1169
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -