Bacterially Secretable Single‐Chain Tandem Macrocyclic Peptides for High Affinity and Inhibitory Activity

• Published in: Chembiochem : a European journal of chemical biology Vol. 24; no. 2; pp. e202200599 - n/a
• Main Authors: Ito, Kenichiro, Matsuda, Yoshihiko, Mine, Ayako, Miyairi, Kyohei, Kikuchi, Yoshimi, Konishi, Atsushi
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17.01.2023
• Subjects: Avidity; Binding; Chains; dimerization; Growth factors; Intercellular Signaling Peptides and Proteins; macrocyclic peptides; microbial secretion; Peptides; Peptides - chemistry; Protein interaction; protein-protein interactions; Proteins; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; avidity; dimerization; macrocyclic peptides; microbial secretion; protein-protein interactions
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202200599

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. A heterodimeric macrocyclic peptide inhibitor against VEGF‐VEGFR2 interaction was designed and produced by a microbial secretion system. It showed stronger binding potency and >1000 higher inhibitory activity against VEGFR2 than parental monomeric macrocyclic peptides.