Abstract
Mimetics of growth factors and cytokines are promising tools for culturing large numbers of cells and manufacturing regenerative medicine products. In this study, we report single-chain tandem macrocyclic peptides (STaMPtides) as mimetics in a new multivalent peptide format. STaMPtides, which contain two or more macrocyclic peptides with a disulfide-closed backbone and peptide linkers, are successfully secreted into the supernatant by Corynebacterium glutamicum-based secretion technology. Without post-secretion modification steps, such as macrocyclization or enzymatic treatment, bacterially secreted STaMPtides form disulfide bonds, as designed; are biologically active; and show agonistic activities against respective target receptors. We also demonstrate, by cell-based assays, the potential of STaMPtides, which mimic growth factors and cytokines, in cell culture. The STaMPtide technology can be applied to the design, screening, and production of growth factor and cytokine mimetics.
Highlights
Mimetics of growth factors and cytokines are promising tools for culturing large numbers of cells and manufacturing regenerative medicine products
STaMPtides consisted of multiple macrocyclic peptides closed by disulfide bonds between cysteines, the C- and N-termini of which were linked by a peptide linker
Expression vectors encoding STaMPtides were transformed into C. glutamicum for secretion, as previously reported[21], Fig. 1 Overview of the research. a Activation mechanism of cytokine and growth factor receptors by their ligands
Summary
Mimetics of growth factors and cytokines are promising tools for culturing large numbers of cells and manufacturing regenerative medicine products. Macrocyclic peptide binders have been successfully turned into growth factor and cytokine mimetics by dimerization[4,5,6] (Fig. 1a) These mimetics activate endogenous receptors via receptor dimerization, evoke downstream cellular signalings[15], and promote changes in cellular morphologies in a similar manner to natural ligands, both in vitro and in vivo. The present work reports the use of single-chain tandem macrocyclic peptides (STaMPtides), a multivalent peptide format compatible with the secretory production method of Corynebacterium glutamicum[21]. Active growth factor and cytokine mimetic STaMPtides were designed based on previously reported macrocyclic peptide binders and successfully secreted by C. glutamicum. The results demonstrated the applicability of STaMPtide technology to the design, screening, and production of growth factor and cytokine mimetics for cell culture and regenerative therapy
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