Abstract
Cell penetrating peptides have been regarded as promising vectors to deliver hydrophilic molecules inside cells. Although they are great tools for research and have high potential as drug delivery systems, their application as drugs is impaired by their low stability in serum. Cyclotides, cyclic disulfide-rich peptides from plants, are ultra-stable molecules that have inspired applications in drug design as they can be used as scaffolds to stabilize linear bioactive sequences. Recently, they have also been shown to possess cell-penetrating properties. The combination of their remarkable stability and cell-penetrating properties opens new avenues for the application of peptides to bind to and inhibit intracellular proteins. Nevertheless, for a broader application of these molecules as vectors is of utmost importance to improve their cellular internalization efficiency. In this study we successfully modified MCoTI-II, one of the most widely studied cyclotide scaffolds in drug design, and improved its internalization properties. The internalization of the newly designed MCoTI-II is as efficient as the gold standard cell-penetrating peptide (CPP) TAT and maintains all the required features as a template to graft desired bioactivities.
Highlights
Despite their high selectivity, potency and low toxicity, peptides have in the past been discounted as good therapeutics due to their poor stability and low delivery efficiency
REENGINEERING THE CYCLOTIDE FRAMEWORK Previous studies on MCoTI-II and its analogs have shown that the overall positive charge and the distribution of the basic residues on the surface of the molecule (Figure 1B) are important for its cellular internalization (Cascales et al, 2011; D’Souza et al, 2014)
Arising from the success of MCoTI-II as a novel scaffold for drug design (Poth et al, 2013), in the present study we were interested in improving the uptake of this peptide for its more efficient use as a drug template and delivery system to inhibit intracellular targets
Summary
Potency and low toxicity, peptides have in the past been discounted as good therapeutics due to their poor stability and low delivery efficiency. Recent advances that improve their stability have stimulated interest in pursuing peptides as alternative therapeutics. The discovery of stable disulfide-rich peptides with high potency, specificity and tolerance to sequence modification have provided strong support for the use of peptides as therapeutic templates (Craik et al, 2013). Examples include disulfide-rich toxins isolated from the venoms of cone snails, which have exquisite selectivity for membrane receptors (Schroeder and Craik, 2012). The peptide field received renewed interest upon the discovery of positively-charged sequences, named cell-penetrating peptides (CPPs), able to carry and translocate large proteins or other hydrophilic molecules, into cells (Henriques et al, 2006). A proven research tool, CPPs still have limitations for therapeutic protein delivery due to the low enzymatic stability of the CPP protein conjugates, a drawback in both oral and injection delivery
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