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Bacterially Secretable Single-Chain Tandem Macrocyclic Peptides for High Affinity and Inhibitory Activity |
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| Authors: | Dr Kenichiro Ito Dr Yoshihiko Matsuda Ayako Mine Kyohei Miyairi Dr Yoshimi Kikuchi Dr Atsushi Konishi |
| Affiliation: | 1. Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki, 210-8681 Kanagawa, Japan;2. Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki, 210-8681 Kanagawa, Japan
Contribution: Data curation (supporting), Investigation (equal), Resources (equal), Visualization (supporting), Writing - original draft (supporting), Writing - review & editing (supporting);3. Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki, 210-8681 Kanagawa, Japan Contribution: Data curation (supporting), Investigation (supporting), Writing - original draft (supporting), Writing - review & editing (supporting);4. Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki, 210-8681 Kanagawa, Japan Contribution: Investigation (supporting), Writing - review & editing (supporting);5. Research Institute for Bioscience Products & Fine Chemicals, Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki, 210-8681 Kanagawa, Japan Contribution: Conceptualization (supporting), Supervision (supporting), Writing - review & editing (supporting) |
| Abstract: | The inhibition of protein-protein interactions (PPIs) is an effective approach for therapy. Owing to their large binding surface areas to target proteins, macrocyclic peptides are suitable molecules for PPI inhibition. In this study, we developed single-chain tandem macrocyclic peptides (STaMPtides) that inhibits the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2). They were artificially designed to comprise two different VEGFR2-binding macrocyclic peptides linked in tandem by peptide linkers and secreted by Corynebacterium glutamicum. Most potent VEGFR2-inhibitory STaMPtides with length-optimized linkers exhibited >1000 times stronger inhibitory activity than their parental monomeric peptides, possibly due to the avidity effect of heterodimerization. Our approach of using STaMPtides for PPI inhibition may be used to inhibit other extracellular factors, such as growth factors and cytokines. |
| Keywords: | avidity dimerization macrocyclic peptides microbial secretion protein-protein interactions |