title: Structural parameters modulating the cellular uptake of disulfide-rich cyclic cell-penetrating peptides: MCoTI-II and SFTI-1.
abstract: Peptides are emerging as a new class of therapeutics due to their high potency and specificity for a range of targets, including the inhibition of protein-protein interactions. Disulfide-rich cyclic peptides, in particular, have attracted much attention in drug design due to their ultra-stable structure. Moreover, some of them have been shown to internalize into cells, which makes them potential scaffolds to deliver pharmaceutically bioactive sequences to intracellular targets. Here we examined the effects of structural modifications on the cell-penetrating properties of two disulfide-rich cyclic cell-penetrating peptides, Momordica cochinchinensis trypsin inhibitor II (MCoTI-II) and sunflower trypsin inhibitor-1 (SFTI-1). We found that the cellular uptake of MCoTI-II can be improved by increasing the overall positive charge of the native sequence. On the other hand, mutations to SFTI-1 did not significantly influence its cellular uptake, suggesting a non-specific endocytosis-dependent mechanism of cellular uptake. This study provides an understanding of the structural features affecting the internalization of MCoTI-II and SFTI-1, and hence provides a guide for the development of these disulfide-rich cyclic scaffolds into potential drug leads.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Charlotte
authors.initials: C
authors.lastname: D'Souza
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Sónia Troeira
authors.initials: ST
authors.lastname: Henriques
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Conan K
authors.initials: CK
authors.lastname: Wang
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: d.craik@imb.uq.edu.au.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D047169:Cyclotides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D004220:Disulfides / Q000737:chemistry* / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011487:Protein Conformation
chemical_list: D057846:Cell-Penetrating Peptides; D047169:Cyclotides; D004220:Disulfides; D010456:Peptides, Cyclic; C448501:SFTI-1 peptide, sunflower; C409923:trypsin inhibitor MCoTI-II
keywords: Cell-penetrating peptides; Flow cytometry; Nuclear magnetic resonance spectroscopy; Peptides; Solid-phase peptide synthesis; Surface plasmon resonance