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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.
Marcyk, Paul T; LeBlanc, Emmanuelle V; Kuntz, Douglas A; Xue, Alice; Ortiz, Francisco; Trilles, Richard; Bengtson, Stephen; Kenney, Tristan M G; Huang, David S; Robbins, Nicole; Williams, Noelle S; Krysan, Damian J; Privé, Gilbert G; Whitesell, Luke; Cowen, Leah E; Brown, Lauren E.
Afiliación
  • Marcyk PT; Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.
  • LeBlanc EV; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada.
  • Kuntz DA; Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.
  • Xue A; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada.
  • Ortiz F; Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390-9038, United States.
  • Trilles R; Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.
  • Bengtson S; Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.
  • Kenney TMG; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Huang DS; Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.
  • Robbins N; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada.
  • Williams NS; Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390-9038, United States.
  • Krysan DJ; Departments of Pediatrics and Microbiology/Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United States.
  • Privé GG; Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.
  • Whitesell L; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Cowen LE; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • Brown LE; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada.
J Med Chem ; 64(2): 1139-1169, 2021 01 28.
Article en En | MEDLINE | ID: mdl-33444025
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Proteínas HSP90 de Choque Térmico / Cryptococcus neoformans / Hongos / Antifúngicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Proteínas HSP90 de Choque Térmico / Cryptococcus neoformans / Hongos / Antifúngicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos