Departamento de Química Orgánica, Facultad de Ciencias Químicas, Plaza de las Ciencias s/n, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Plaza de las Ciencias s/n, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
Bioorg Chem. 2024 Jan;142:106967. doi: 10.1016/j.bioorg.2023.106967. Epub 2023 Nov 11.
Hutchinson-Gilford progeria syndrome (HGPS) or progeria is a rare genetic disease that causes premature aging, leading to a drastic reduction in the life expectancy of patients. Progeria is mainly caused by the intracellular accumulation of a defective protein called progerin, generated from a mutation in the LMNA gene. Currently, there is only one approved drug for the treatment of progeria, which has limited efficacy. It is believed that progerin levels are the most important biomarker related to the severity of the disease. However, there is a lack of effective tools to directly visualize progerin in the native cellular models, since the commercially available antibodies are not well suited for the direct visualization of progerin in cells from the mouse model of the disease. In this context, an alternative option for the visualization of a protein relies on the use of fluorescent chemical probes, molecules with affinity and specificity towards a protein. In this work we report the synthesis and characterization of a new fluorescent probe (UCM-23079) that allows for the direct visualization of progerin in cells from the most widely used progeroid mouse model. Thus, UCM-23079 is a new tool compound that could help prioritize potential preclinical therapies towards the final goal of finding a definitive cure for progeria.
亨廷顿舞蹈病-早老综合征（HGPS）或早老症是一种罕见的遗传性疾病，可导致过早衰老，从而大大降低患者的预期寿命。早老症主要是由一种称为 progerin 的缺陷蛋白在细胞内积累引起的，该蛋白是由 LMNA 基因突变产生的。目前，仅有一种批准用于治疗早老症的药物，但疗效有限。人们认为 progerin 水平是与疾病严重程度最相关的重要生物标志物。然而，由于缺乏有效的工具来直接在天然细胞模型中可视化 progerin，因为市售的抗体不适用于直接可视化来自疾病的小鼠模型的细胞中的 progerin。在这种情况下，用于可视化蛋白质的替代方法依赖于使用荧光化学探针，即对蛋白质具有亲和力和特异性的分子。在这项工作中，我们报告了一种新的荧光探针（UCM-23079）的合成和表征，该探针允许在最广泛使用的早老症小鼠模型的细胞中直接可视化 progerin。因此，UCM-23079 是一种新的工具化合物，可帮助优先考虑针对早老症的潜在临床前疗法，最终目标是找到明确的治疗方法。
