Developments and Applications of Cyclic Cell Penetrating Peptides
Author | : Ziqing Qian |
Publisher | : |
Total Pages | : |
Release | : 2014 |
ISBN-13 | : OCLC:898035052 |
ISBN-10 | : |
Rating | : 4/5 ( Downloads) |
Download or read book Developments and Applications of Cyclic Cell Penetrating Peptides written by Ziqing Qian and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Cell penetrating peptides (CPP) have been featured as a powerful delivery vector for the intracellular delivery of membrane-impermeable cargoes. This dissertation primarily focuses on the development, characterization, and application of a new class of CPP: cyclic cell penetrating peptides. Prompted by long-standing interests of the Pei group in developing cyclic peptides as biological tools and potential therapeutics, I describe our exploration of the permeability properties of the cyclic peptides, leading to the discovery that cyclic peptides with a short sequence motif rich in arginine and hydrophobic residues display significantly higher cellular permeability than their linear counterparts. The resulting cyclic CPP also translocated into the mammalian cell interior at significantly higher efficiencies than canonical arginine-rich linear CPPs. Subsequent internalization mechanistic investigations involving model lipid vesicles and pharmacological inhibitors, as well as genetic mutations, which perturb individual internalization steps, have shown conclusively that cyclic CPPs enter cells through endocytosis and are capable of escaping from early endosomes. To explore the utilities of cyclic CPP as cytoplasmic delivery vehicles, we developed endocyclic, exocyclic, and bicyclic delivery methods to deliver monocyclic peptides, bicyclic peptides, and proteins into cells. Biologically active cargoes, such as fluorogenic phosphatase substrates, phosphatase inhibitors, green fluorescent protein, and protein tyrosine phosphatase 1B were efficiently delivered by cyclic CPP. Additionally, we explored a potentially general strategy to deliver linear peptidyl ligands into mammalian cells through reversible, disulfide bond mediated cyclization. Cell permeable fluorogenic caspase substrates and cell-permeable CAL-PDZ domain inhibitors were developed using this method.