Host: The Japan Radiation Research Society
Recent crystal structure and cryo-electron microscopy studies have revealed that proteins called translation factors mimic the shape of tRNA. One of them, a polypeptide release factor, encodes a tripeptide that serves as an ‘anticodon’ to decipher stop codons in mRNA. These findings established the novel concept of macromolecular mimicry between protein and RNA. We aimed to prove this concept by creating novel RNA molecules that mimic proteins of interest. The systematic evolution of ligands by exponential enrichment (SELEX) method is based on in vitro selection of oligo-nucleotide ligands from large random-sequence libraries by repeated reactions of DNA transcription, RNA selection and RT-PCR amplification. The selected oligonucleotide ligands, having both high affinity and specificity to target molecules, are called ‘aptamers’. We have initiated SELEX experiments using several mammalian proteins. Selected RNA aptamers against target proteins acquired several properties equivalent to, or more importantly, superior to antibodies. One of these aptamers had a Kd on the picomolar scale, an affinity which is a thousand-times stronger than normal antibody. Structural and biochemical analysis revealed that RNA aptamers could achieve specific high affinity to target protein by capturing its global conformation even if it does not bear RNA recognition motif or strong affinity to RNA. This is completely different from the pinpoint (i.e., epitope <10 amino acids) recognition of target protein by antibodies. For this reason, the RNA aptamer has promising potential to substitute for or complement the antibody as a new diagnostic or therapeutic tool that we refer to as “RNA super-antibody ”.
