Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.
Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.
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DOI：
10.1038/cddis.2015.374
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发表时间：
2016-02-18
影响因子：
9
通讯作者：
Nissan X
中科院分区：
文献类型：
--
作者：
Blondel S;Egesipe AL;Picardi P;Jaskowiak AL;Notarnicola M;Ragot J;Tournois J;Le Corf A;Brinon B;Poydenot P;Georges P;Navarro C;Pitrez PR;Ferreira L;Bollot G;Bauvais C;Laustriat D;Mejat A;De Sandre-Giovannoli A;Levy N;Bifulco M;Peschanski M;Nissan X
Hutchinson-Gilford早衰综合征（HGPS）是一种罕见的遗传性疾病，其特征是戏剧性的过早衰老。HGPS是由于LMNA基因的外显子11中的单碱基取代（c.1824C>T）导致产生称为早老蛋白的核纤层蛋白A前体蛋白的毒性形式。由于法尼基化过程已被证明可以控制早老蛋白的毒性，因此在本研究中，我们开发了一种筛选方法，可以鉴定新的法尼基化药理学抑制剂。为此，我们利用多能干细胞的独特潜力，获得了无限的相关生物资源，并测试了21608个小分子。这项研究确定了几种称为单氨基嘧啶的化合物，它们靶向法尼基化过程的两个关键酶，法尼基焦磷酸合酶和法尼基转移酶，并拯救与HGPS相关的体外表型。我们的研究结果通过鉴定一个新的蛋白质法尼基化抑制剂家族为HGPS的治疗开辟了新的治疗可能性，并且也可能适用于与涉及法尼基化蛋白质的突变相关的癌症和疾病。
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21 608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.