This application requests support to continue our exploration of beta-peptide structure and biologic function. We build herein on two of the most exciting and impacting discoveries of the first funding cycle: (1) that carefully designed beta-peptides effectively mimic ?- helices and function as protein interaction inhibitors, with properties that are easily improved by combinatorial methods;and (2) that beta-peptides can be engineered to traverse the plasma membrane and retain biologic function in the cytosol, without the addition of a large """"""""octa-arginine"""""""" tag, facilitating their application to intracellular targets. Thus, the Specific Aims of this application are to first (Aim 1) move away from """"""""proof-of- principle"""""""" targets, and design beta-peptide ligands for two well-validated drug targets that could benefit from the unique combination of properties embodied by a beta-peptide: the GLP-1 receptor (GLP-1R), a target of the antidiabetes drug Byetta"""""""", and the ErbB2 receptor, a target of the mAb Herceptin"""""""". We also describe beta-peptides that either inhibit or activate CXCR4 and CCR5 chemokine receptors from within the plasma membrane.
In Aim 2, we described experiments to systematically optimize and exploit cell- permeable beta-peptides as a first step toward broadening their applicability to cytosolic targets. The fact that beta-peptides are immune to proteolytic degradation makes them uniquely capable of reporting on the myriad pathways by which peptides achieve uptake and traffic within the cell once they do.
Protein-protein interactions on the cell surface or in the cytosol are grossly underexploited in human medicine. beta-peptides possess unique advantages as inhibitors of these interactions. This proposal explores these advantages in the context of diseases as diverse as type 2 diabetes, cancer, osteoporosis, and hypoparathyrodism.
| LaRochelle, Jonathan R; Cobb, Garrett B; Steinauer, Angela et al. (2015) Fluorescence correlation spectroscopy reveals highly efficient cytosolic delivery of certain penta-arg proteins and stapled peptides. J Am Chem Soc 137:2536-2541 |
| Qian, Ziqing; LaRochelle, Jonathan R; Jiang, Bisheng et al. (2014) Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery. Biochemistry 53:4034-46 |
| Miller, Jonathan P; Melicher, Michael S; Schepartz, Alanna (2014) Positive allostery in metal ion binding by a cooperatively folded ?-peptide bundle. J Am Chem Soc 136:14726-9 |
| Hobert, Elissa M; Doerner, Amy E; Walker, Allison S et al. (2013) Effective molarity redux: Proximity as a guiding force in chemistry and biology. Isr J Chem 53:567-576 |
| Holub, Justin M; Larochelle, Jonathan R; Appelbaum, Jacob S et al. (2013) Improved assays for determining the cytosolic access of peptides, proteins, and their mimetics. Biochemistry 52:9036-46 |
| Denton, Elizabeth V; Craig, Cody J; Pongratz, Rebecca L et al. (2013) A ?-peptide agonist of the GLP-1 receptor, a class B GPCR. Org Lett 15:5318-21 |
| Appelbaum, Jacob S; LaRochelle, Jonathan R; Smith, Betsy A et al. (2012) Arginine topology controls escape of minimally cationic proteins from early endosomes to the cytoplasm. Chem Biol 19:819-30 |
| Wang, Pam Shou-Ping; Craig, Cody J; Schepartz, Alanna (2012) Relationship between side-chain branching and stoichiometry in ýý(3)-peptide bundles. Tetrahedron 68:4342-4345 |
| Bautista, Arjel D; Appelbaum, Jacob S; Craig, Cody J et al. (2010) Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability. J Am Chem Soc 132:2904-6 |
| Molski, Matthew A; Goodman, Jessica L; Craig, Cody J et al. (2010) Beta-peptide bundles with fluorous cores. J Am Chem Soc 132:3658-9 |
Showing the most recent 10 out of 24 publications
