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.