Rapamycin-inspired macrocycles with new target specificity
Rapamycin-inspired macrocycles with new target specificity
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DOI：
10.1038/s41557-018-0187-4
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发表时间：
2019-03-01
期刊：
影响因子：
21.8
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
--
作者：
Guo, Zufeng;Hong, Sam Y.;Liu, Jun O.
雷帕霉素和FK506是具有特殊作用模式的大环天然产物，它们先与FK506结合蛋白(FKBP)形成一个共同的FKBP结合域，然后分别与各自的靶标雷帕霉素(MTOR)和钙调神经磷酸酶(CaN)形成三元复合体。受此启发，我们试图建立一个雷帕霉素样的大分子文库，通过用低聚肽的组合文库取代雷帕霉素的效应结构域来靶向新的细胞蛋白。我们开发了一种基于闭环复分解的强健的大环化方法，并利用优化的FKBP结合结构域合成了一个含有45,000个化合物的杂化大环文库(命名为Rapafucins)。对人类细胞中的Rapafucin文库的筛选导致发现了Rapadocin，一种核苷摄取的抑制剂。雷帕多辛是一种有效的、异构体特异性的、依赖于FKBP的平衡核苷转运蛋白1的抑制剂，在肾脏缺血再灌注损伤的动物模型中有效。总之，这些结果表明，Rapafucins是一类新的化学探针和药物线索，可以扩大蛋白质靶标的范围，远远超出mTOR和钙调神经磷酸酶的范围。
Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action, in which they form binary complexes with FK506-binding protein (FKBP) through a shared FKBP-binding domain before forming ternary complexes with their respective targets, mechanistic target of rapamycin (mTOR) and calcineurin, respectively. Inspired by this, we sought to build a rapamycin-like macromolecule library to target new cellular proteins by replacing the effector domain of rapamycin with a combinatorial library of oligopeptides. We developed a robust macrocyclization method using ring-closing metathesis and synthesized a 45,000-compound library of hybrid macrocycles (named rapafucins) using optimized FKBP-binding domains. Screening of the rapafucin library in human cells led to the discovery of rapadocin, an inhibitor of nucleoside uptake. Rapadocin is a potent, isoform-specific and FKBP-dependent inhibitor of the equilibrative nucleoside transporter 1 and is efficacious in an animal model of kidney ischaemia reperfusion injury. Together, these results demonstrate that rapafucins are a new class of chemical probes and drug leads that can expand the repertoire of protein targets well beyond mTOR and calcineurin.