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Ziqing Qian Thesis PDF A.pdf (6.61 MB)

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Developments and Applications of Cyclic Cell Penetrating Peptides

Qian, Ziqing
http://rave.ohiolink.edu/etdc/view?acc_num=osu1405340891

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Chemistry.
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.
Dehua Pei (Advisor)
Dennis Bong (Committee Member)
Venkat Gopalan (Committee Member)
183 p.
Chemistry
Cell Penetrating Peptide; Drug delivery; cyclic peptide; cyclic cell penetrating peptide; protein delivery; endosomal escape; calcineurin; VIVIT

Recommended Citations

Citations

  • Qian, Z. (2014). Developments and Applications of Cyclic Cell Penetrating Peptides [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405340891

    APA Style (7th edition)

  • Qian, Ziqing. Developments and Applications of Cyclic Cell Penetrating Peptides. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1405340891.

    MLA Style (8th edition)

  • Qian, Ziqing. "Developments and Applications of Cyclic Cell Penetrating Peptides." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405340891

    Chicago Manual of Style (17th edition)

osu1405340891
1,240
© 2014, some rights reserved.Creative Commons License Developments and Applications of Cyclic Cell Penetrating Peptides by Ziqing Qian is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.