Selective BET bromodomain inhibition as an antifungal therapeutic strategy.
Selective BET bromodomain inhibition as an antifungal therapeutic strategy.
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DOI：
10.1038/ncomms15482
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发表时间：
2017-05-18
影响因子：
16.6
通讯作者：
Petosa C
中科院分区：
文献类型：
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作者：
Mietton F;Ferri E;Champleboux M;Zala N;Maubon D;Zhou Y;Harbut M;Spittler D;Garnaud C;Courçon M;Chauvel M;d'Enfert C;Kashemirov BA;Hull M;Cornet M;McKenna CE;Govin J;Petosa C
侵袭性真菌感染在免疫功能低下的个体中造成显著的发病率和死亡率，迫切需要新的抗真菌治疗策略。在这里，我们研究了染色质相互作用模块，来自BET家族的溴域(BD)，作为白色念珠菌的潜在抗真菌靶点，白色念珠菌是人类主要的真菌病原体。我们证明了BET蛋白Bdf1在白色念珠菌中是必不可少的，突变使其两个BDS失活会导致体外活性的丧失和小鼠毒力的降低。我们报道了抑制白色念珠菌BDF1的小分子化合物，其选择性高于人的BDS。BDF1 BDS的晶体结构揭示了这些抑制剂的结合模式，这些模式与人类BET结合口袋空间不相容。此外，我们报告了一种二苯并噻吩酮化合物，该化合物表现出BDF1 BD失活突变对白色念珠菌活性的影响。这些发现确立了BET抑制作为一种有前景的抗真菌治疗策略，并确认BDF1是一个抗真菌药物靶点，可以在不对抗人类BET功能的情况下被选择性抑制。BET蛋白通过其溴结构域(BDS)与染色质结合，调节转录和染色质重塑。在这里，作者证明了BET蛋白Bdf1对真菌病原体白色念珠菌是必不可少的，并报告了抑制Bdf1 BDS的化合物，比人类BDS具有更高的选择性。
Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function. BET proteins bind chromatin through their bromodomains (BDs) to regulate transcription and chromatin remodelling. Here, the authors show that the BET protein Bdf1 is essential for the fungal pathogen Candida albicans, and report compounds that inhibit the Bdf1 BDs with high selectivity over human BDs.