肽基脯氨酸异构酶（PPIase）：天然产物和天然产物启发化合物的靶标,Journal of Medicinal Chemistry

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肽基脯氨酸异构酶（PPIase）：天然产物和天然产物启发化合物的靶标
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-07-25 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00411
Bryan M. Dunyak _{1,

2} , Jason E. Gestwicki ₂

Affiliation

肽基脯氨酸异构酶（PPIase）是一种伴侣蛋白超家族，包含FK506结合蛋白（FKBPs），亲环蛋白和小白蛋白。PPIases催化脯氨酸的顺式/反式异构化，在许多蛋白质的折叠，活化和/或降解过程中充当调节开关。这些“客户”包括在癌症，神经退行性疾病和精神疾病中起关键作用的蛋白质，这表明PPIase抑制剂可能是重要的治疗方法。但是，PPIase的活性位点较浅，暴露于溶剂中且在家族成员之间非常保守，这使得选择性抑制剂的设计具有挑战性。尽管存在这些障碍，但包括FK506，雷帕霉素和环孢菌素在内的大环天然产物仍能以纳摩尔或更好的亲和力结合PPIase。从头尝试衍生出新型抑制剂的尝试不太成功，通常会展示PPIase的“非消耗性”特征。有趣的是，这些下一代分子中最有力的趋向于整合天然产物的功能，包括大环化或脯氨酸模拟策略。在这里，我们回顾了PPIase抑制的最新进展和挑战，重点关注天然产物如何为有效和选择性抑制剂的产生提供信息。

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Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

Peptidyl-proline isomerases (PPIases) are a chaperone superfamily comprising the FK506-binding proteins (FKBPs), cyclophilins, and parvulins. PPIases catalyze the cis/trans isomerization of proline, acting as a regulatory switch during folding, activation, and/or degradation of many proteins. These “clients” include proteins with key roles in cancer, neurodegeneration, and psychiatric disorders, suggesting that PPIase inhibitors could be important therapeutics. However, the active site of PPIases is shallow, solvent-exposed, and well conserved between family members, making selective inhibitor design challenging. Despite these hurdles, macrocyclic natural products, including FK506, rapamycin, and cyclosporin, bind PPIases with nanomolar or better affinity. De novo attempts to derive new classes of inhibitors have been somewhat less successful, often showcasing the “undruggable” features of PPIases. Interestingly, the most potent of these next-generation molecules tend to integrate features of the natural products, including macrocyclization or proline mimicry strategies. Here, we review recent developments and ongoing challenges in the inhibition of PPIases, with a focus on how natural products might inform the creation of potent and selective inhibitors.

更新日期：2016-07-25

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