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Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-09-18 , DOI: 10.1021/acschembio.8b00705
Zuni I Bassi 1 , Martin C Fillmore 2 , Afjal H Miah 1 , Trevor D Chapman 3 , Claire Maller 3 , Emma J Roberts 3 , Lauren C Davis 3 , Darcy E Lewis 3 , Nicholas W Galwey 4 , Kirsty E Waddington , Valentino Parravicini , Abigail L Macmillan-Jones 1 , Celine Gongora 5 , Philip G Humphreys 3 , Ian Churcher , Rab K Prinjha 3 , David F Tough 3
Affiliation  

P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are closely related epigenetic proteins, each containing an acetyltransferase domain and a bromodomain. Consistent with reported roles for these proteins in immune function, we find that PCAF-deficient macrophages exhibit a markedly reduced ability to produce cytokines upon stimulation with lipopolysaccharide (LPS). Investigating the potential to target this pathway pharmacologically, we show that chemical inhibition of the PCAF/GCN5 bromodomains is insufficient to recapitulate the diminished inflammatory response of PCAF-deficient immune cells. However, by generating the first PCAF/GCN5 proteolysis targeting chimera (PROTAC), we identify small molecules able to degrade PCAF/GCN5 and to potently modulate the expression of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells. Our data illustrate the power of the PROTAC approach in the context of multidomain proteins, revealing a novel anti-inflammatory therapeutic opportunity for targeting PCAF/GCN5.

中文翻译:

通过PROTAC方法调节PCAF / GCN5免疫细胞功能。

P300 / CBP相关因子(PCAF)和一般对照不可抑制5(GCN5)是密切相关的表观遗传蛋白,每个蛋白都包含一个乙酰基转移酶结构域和一个溴结构域。与这些蛋白质在免疫功能中的作用报道一致,我们发现PCAF缺陷型巨噬细胞在脂多糖(LPS)刺激下产生细胞因子的能力明显降低。药理研究靶向此途径的潜力,我们表明对PCAF / GCN5溴结构域的化学抑制作用不足以概括PCAF缺陷免疫细胞减弱的炎症反应。但是,通过生成第一个针对嵌合体的PCAF / GCN5蛋白水解(PROTAC),我们鉴定出能够降解PCAF / GCN5并有效调节LPS刺激的巨噬细胞和树突状细胞中多种炎症介质表达的小分子。我们的数据说明了PROTAC方法在多结构域蛋白中的作用,揭示了靶向PCAF / GCN5的新型抗炎治疗机会。
更新日期:2018-09-10
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