Blondel S, Egesipe A-L, Picardi P, Jaskowiak A-L, Notarnicola M, Ragot J, Tournois J, Le Corf A, Brinon B, Poydenot P, Georges P, Navarro C, Pitrez P R, Ferreira L, Bollot G, Bauvais C, Laustriat D, Mejat A, De Sandre-Giovannoli A, Levy N, Bifulco M, Peschanski M, Nissan X
INSERM U861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
UEVE, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
Cell Death Dis. 2016 Feb 18;7(2):e2105. doi: 10.1038/cddis.2015.374.
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.
哈钦森-吉尔福德早衰综合征（HGPS）是一种罕见的遗传性疾病，其特征是明显呈现出早衰的外观。HGPS是由LMNA基因第11外显子中的单碱基替换（c.1824C>T）引起的，导致产生一种名为早老素的有毒形式的前层粘连蛋白A蛋白。由于法尼基化过程已被证明可控制早老素的毒性，在本研究中，我们开发了一种筛选方法，以鉴定新的法尼基化药理学抑制剂。为此，我们利用了多能干细胞的独特潜力，以获取无限且相关的生物资源，并测试了21608种小分子。这项研究鉴定出了几种化合物，称为单氨基嘧啶，它们靶向法尼基化过程的两种关键酶，法尼基焦磷酸合酶和法尼基转移酶，并挽救了与HGPS相关的体外表型。我们的研究结果通过鉴定一类新的蛋白质法尼基化抑制剂，为HGPS的治疗开辟了新的治疗可能性，并且这些抑制剂也可能适用于与涉及法尼基化蛋白的突变相关的癌症和疾病。
