Cerchia Laura, Ducongé Frédéric, Pestourie Carine, Boulay Jocelyne, Aissouni Youssef, Gombert Karine, Tavitian Bertrand, de Franciscis Vittorio, Libri Domenico
Istituto per I'Endocrinologia e Oncologia Molecolare G. Salvatore, CNR, Naples, Italy.
PLoS Biol. 2005 Apr;3(4):e123. doi: 10.1371/journal.pbio.0030123. Epub 2005 Mar 22.
Targeting large transmembrane molecules, including receptor tyrosine kinases, is a major pharmacological challenge. Specific oligonucleotide ligands (aptamers) can be generated for a variety of targets through the iterative evolution of a random pool of sequences (SELEX). Nuclease-resistant aptamers that recognize the human receptor tyrosine kinase RET were obtained using RET-expressing cells as targets in a modified SELEX procedure. Remarkably, one of these aptamers blocked RET-dependent intracellular signaling pathways by interfering with receptor dimerization when the latter was induced by the physiological ligand or by an activating mutation. This strategy is generally applicable to transmembrane receptors and opens the way to targeting other members of this class of proteins that are of major biomedical importance.
靶向包括受体酪氨酸激酶在内的大型跨膜分子是一项重大的药理学挑战。通过对随机序列库进行迭代进化（SELEX），可以针对多种靶点生成特异性寡核苷酸配体（适配体）。在改良的SELEX程序中，以表达RET的细胞为靶点，获得了识别人类受体酪氨酸激酶RET的耐核酸酶适配体。值得注意的是，当生理配体或激活突变诱导受体二聚化时，其中一种适配体通过干扰受体二聚化来阻断RET依赖的细胞内信号通路。这种策略普遍适用于跨膜受体，并为靶向这类具有重大生物医学意义的其他蛋白质成员开辟了道路。
