PDF(Pubmed)
Abstract：
Life-threatening systemic fungal infections occur in immunocompromised patients at an alarming rate. Current antifungal therapies face challenges like drug resistance and patient toxicity, emphasizing the need for new treatments. Membrane-bound enzymes account for a large proportion of current and potential antifungal targets, especially ones that contribute to cell wall and cell membrane biosynthesis. Moreover, structural biology has led to a better understanding of the mechanisms by which these enzymes synthesize their products, as well as the mechanism of action for some antifungals. This review summarizes the structures of several current and potential membrane-bound antifungal targets involved in cell wall and cell membrane biosynthesis and their interactions with known inhibitors or drugs. The proposed mechanisms of action for some molecules, gleaned from detailed inhibitor-protein studeis, are also described, which aids in further rational drug design. Furthermore, some potential membrane-bound antifungal targets with known inhibitors that lack solved structures are discussed, as these might be good enzymes for future structure interrogation.
摘要：
危及生命的系统性真菌感染在免疫功能低下的患者中以惊人的速度发生。目前的抗真菌治疗面临的挑战，如耐药性和患者的毒性，强调需要新的治疗方法。膜结合酶在当前和潜在的抗真菌靶标中占很大比例，特别是那些有助于细胞壁和细胞膜生物合成的物质。此外，结构生物学使人们对这些酶合成其产物的机制有了更好的理解，以及一些抗真菌药物的作用机制。这篇综述总结了与细胞壁和细胞膜生物合成有关的几种当前和潜在的膜结合抗真菌靶标的结构，以及它们与已知抑制剂或药物的相互作用。一些分子的作用机制，从详细的抑制剂蛋白研究中收集到，还描述了，这有助于进一步合理的药物设计。此外，一些潜在的膜结合抗真菌靶标与已知的抑制剂，缺乏解决的结构进行了讨论，因为这些可能是未来结构询问的好酶。
