De novo design of potent and selective mimics of IL-2 and IL-15
De novo design of potent and selective mimics of IL-2 and IL-15
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DOI：
10.1038/s41586-018-0830-7
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发表时间：
2019-01-10
期刊：
影响因子：
64.8
通讯作者：
Baker, David
中科院分区：
文献类型：
--
作者：
Silva, Daniel-Adriano;Yu, Shawn;Baker, David
我们描述了一种从头计算的方法来设计蛋白质，概括天然细胞因子的结合位点，但在拓扑结构或氨基酸序列无关。我们使用这种策略来设计中枢免疫细胞因子白细胞介素-2（IL-2）的模拟物，其结合IL-2受体β γ c异源二聚体（IL-2 R β γ c），但没有IL-2 R α（也称为CD 25）或IL-15 R α（也称为CD 215）的结合位点。该设计是超稳定的，以比天然细胞因子更高的亲和力结合人和小鼠IL-2 R β γ c，并独立于IL-2 R α和IL-15 R α引发下游细胞信号传导。优化设计的新白细胞介素-2/15（Neo-2/15）的晶体结构，无论是单独的还是与IL-2 R β γ c复合的，都与设计的模型非常相似。Neo-2/15在小鼠黑色素瘤和结肠癌模型中具有优于IL-2的上级治疗活性，具有降低的毒性和不可检测的免疫原性。我们构建超稳定从头模拟物的策略可普遍应用于信号传导蛋白，从而能够产生上级治疗候选物。
We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor beta gamma c heterodimer (IL-2R beta gamma c) but have no binding site for IL-2R alpha (also called CD25) or IL-15R alpha (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2R beta gamma c with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2R alpha and IL-15R alpha. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2R beta gamma c, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyperstable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.