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

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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 of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-14 , DOI: 10.1021/acs.jmedchem.0c01777
Paul T Marcyk ₁ , Emmanuelle V LeBlanc ₂ , Douglas A Kuntz ₃ , Alice Xue ₂ , Francisco Ortiz ₄ , Richard Trilles ₁ , Stephen Bengtson ₁ , Tristan M G Kenney ₅ , David S Huang ₁ , Nicole Robbins ₂ , Noelle S Williams ₄ , Damian J Krysan ₆ , Gilbert G Privé _{3,

5,

7} , Luke Whitesell ₂ , Leah E Cowen ₂ , Lauren E Brown ₁

Affiliation

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.

中文翻译：

真菌选择性间苯二酚氨基吡唑 Hsp90 抑制剂：全细胞抗隐球菌活性的优化以及隐球菌选择性结构起源的见解

重要的真核分子伴侣 Hsp90 调节多种客户蛋白的形式和功能，其中许多蛋白控制真菌物种的耐热性、毒力和耐药性。然而，由于人类宿主毒性和免疫反应抑制，Hsp90 抑制剂作为抗真菌疗法的使用已被排除。我们最近将间苯二酚氨基吡唑 (RAP) 描述为第一类 Hsp90 抑制剂，能够在生化检测中区分真菌（新型隐球菌、白色念珠菌）和人类 Hsp90 亚型。在这里，我们报告了针对能够抑制培养中新型隐球菌生长的 RAP 的迭代结构-性能优化。此外，我们报告了第一个新型隐球菌Hsp90 核苷酸结合域 (NBD) 的 X 射线晶体结构，作为脱辅基蛋白，并与非物种选择性 Hsp90 抑制剂 NVP-AUY922 和三个 RAP 形成复合物，揭示了独特的配体诱导构象重排，这再次证实了这样的假设：蛋白质灵活性的内在差异可以选择性地抑制真菌与人类 Hsp90 亚型。

更新日期：2021-01-28

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