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Post Antibody Medicines: Generation of Molecular-targeting Peptides by Directed Evolution Ikuo Fujii Department of Biological Science, Graduate School of Science, Osaka Prefecture University The aim of our study is to investigate molecular design relying on evolutionary processes, called as “directed evolution”, to generate a novel class of biofunctional molecules. In our previous work, we have succeeded to develop a directed evolutionary process for improving catalytic efficiency and binding affinity of catalytic antibodies. Therefore, now, we apply our technology and know-how to directed evolution of antibody-like targeting peptides At present, antibodies are indisputably the most successful reagents in molecular targeting therapy. However, use of antibodies has been limited due to the biophysical properties and the cost to manufacture. To enable new applications where antibodies show some limitations, we have developed an alternative-binding molecule with non-immunoglobulin domain. The molecule is a helix-loop-helix peptide, which is stable against natural enzymes in vivo and is too small to be non-immunogenic. We constructed a phage-displayed library of the structured peptides and screened the library for G-CSF receptor. Finally, the screened peptides was cyclized by introduction of a disulfide-bond linkage into the N- and C-termini. The cyclic peptide showed strong binding affinity (Kd of 4 nM) to the receptor and a long half life (15 days) in mouse sera, proving an enzyme-resistant property. Futhermore, imminization of the peptide to mice elicited non-immunigenecity. The peptide is named “microAntibodes” due to haveing the same properties as those of antibodies.