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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM074756-08
Application #
8536825
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Smith, Ward
Project Start
2005-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$325,968
Indirect Cost
$117,492
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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 137:2536-41
Miller, Jonathan P; Melicher, Michael S; Schepartz, Alanna (2014) Positive allostery in metal ion binding by a cooperatively folded β-peptide bundle. J Am Chem Soc 136:14726-9
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
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 β-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