The ability to cross the cell membrane and gain access to the cell interior is a requirement for any therapeutic agent intended for an intracellula target. Proteins, peptides, and small interfering RNA (siRNA) represent some of the emerging/expanding classes of therapeutic agents. However, these biological molecules are generally membrane impermeable on their own and must be delivered to the proper intracellular locations. Cell-penetrating peptides (CPPs) are short peptides (usually <30 amino acids) that have the ability to penetrate the plasma membrane of eukaryotic cells without causing significant membrane damage. Many CPPs have been discovered and some have been used to deliver a wide variety of cargos into cells. A major limitation of previous CPPs is that they have poor overall delivery efficiency due to inefficient endosomal escape. A new family of cyclic CPPs, e.g., cyclo(F?RRRRQ) (where ? is 2-naphthylalanine), was recently discovered in this laboratory and found to escape from the endosome efficiently. The overall objective of this project is to elucidate the mechanisms of CPP uptake and endosomal escape and develop more potent CPPs as general transporters for intracellular delivery of biological active molecules.
Specific Aim 1 is to synthesize and screen a focused cyclic peptide library to identify additional and potentially more active cyclic CPPs.
Specific Aim 2 is to test the limits of what ca be delivered by the cyclic CPPs and determine the mechanism of CPP endosomal release as well as the factors that control the endosomal escape efficiency. Finally, Specific Aim 3 is to utilize the cyclic CPPs to design cell permeable inhibitors against intracellular proteins such as the oncoprotein Ras.
Cyclic peptide transporters will be extremely useful for delivering small-molecule drugs, peptides, proteins, and potentially nucleic acids into mammalian cells. Inhibitors against the Ras oncoprotein will provide potential treatment for a wide variety of human cancers.
|Rhodes, Curran A; Dougherty, Patrick G; Cooper, Jahan K et al. (2018) Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-I?B Kinase Interaction Directly from a Combinatorial Library. J Am Chem Soc 140:12102-12110|
|Liao, Hui; Pei, Dehua (2017) Cell-permeable bicyclic peptidyl inhibitors against T-cell protein tyrosine phosphatase from a combinatorial library. Org Biomol Chem 15:9595-9598|
|Rhodes, Curran A; Pei, Dehua (2017) Bicyclic Peptides as Next-Generation Therapeutics. Chemistry 23:12690-12703|
|Bedewy, Walaa; Liao, Hui; Abou-Taleb, Nageh A et al. (2017) Generation of a cell-permeable cycloheptapeptidyl inhibitor against the peptidyl-prolyl isomerase Pin1. Org Biomol Chem 15:4540-4543|
|Qian, Ziqing; Dougherty, Patrick G; Pei, Dehua (2017) Targeting intracellular protein-protein interactions with cell-permeable cyclic peptides. Curr Opin Chem Biol 38:80-86|
|Dougherty, Patrick G; Qian, Ziqing; Pei, Dehua (2017) Macrocycles as protein-protein interaction inhibitors. Biochem J 474:1109-1125|
|Qian, Ziqing; Rhodes, Curran A; McCroskey, Lucas C et al. (2017) Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization. Angew Chem Int Ed Engl 56:1525-1529|
|Upadhyaya, Punit; Bedewy, Walaa; Pei, Dehua (2016) Direct Inhibitors of Ras-Effector Protein Interactions. Mini Rev Med Chem 16:376-82|
|Trinh, Thi B; Upadhyaya, Punit; Qian, Ziqing et al. (2016) Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides. ACS Comb Sci 18:75-85|
|Upadhyaya, Punit; Qian, Ziqing; Selner, Nicholas G et al. (2015) Inhibition of Ras signaling by blocking Ras-effector interactions with cyclic peptides. Angew Chem Int Ed Engl 54:7602-6|
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