具有改善代谢稳定性的格皮那辛骨架糖基磷脂酰肌醇锚定生物合成抑制剂的抗真菌活性
Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability.
作者信息
Liston Sean D, Whitesell Luke, McLellan Catherine A, Mazitschek Ralph, Petraitis Vidmantas, Petraitiene Ruta, Kavaliauskas Povilas, Walsh Thomas J, Cowen Leah E
机构信息
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Whitehead Institute, Cambridge, Massachusetts, USA.
出版信息
Antimicrob Agents Chemother. 2020 Sep 21;64(10). doi: 10.1128/AAC.00899-20.
Abstract
The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. The stability and bioactivity of 39 analogs were tested to identify LCUT-8, a stabilized lead with increased potency and promising single-dose pharmacokinetics. Unfortunately, no antifungal activity was seen at the maximum dosing achievable in a neutropenic rabbit model. Nevertheless, structure-activity relationships identified here suggest strategies to further improve compound potency, solubility, and stability.
摘要
糖基磷脂酰肌醇锚定生物合成抑制剂格帕纳辛在培养物中表现出广谱抗真菌活性，且对哺乳动物的毒性可忽略不计，但在代谢上不稳定。对39种类似物的稳定性和生物活性进行了测试，以鉴定LCUT-8，一种具有增强效力和有前景的单剂量药代动力学的稳定先导化合物。不幸的是，在中性粒细胞减少兔模型中所能达到的最大给药剂量下未观察到抗真菌活性。然而，此处确定的构效关系提示了进一步提高化合物效力、溶解度和稳定性的策略。
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