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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Smith, Ward
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Yale University
Schools of Arts and Sciences
New Haven
United States
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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
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
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
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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
Harker, Elizabeth A; Daniels, Douglas S; Guarracino, Danielle A et al. (2009) Beta-peptides with improved affinity for hDM2 and hDMX. Bioorg Med Chem 17:2038-46
Michel, Julien; Harker, Elizabeth A; Tirado-Rives, Julian et al. (2009) In Silico Improvement of beta3-peptide inhibitors of p53 x hDM2 and p53 x hDMX. J Am Chem Soc 131:6356-7
Bautista, Arjel D; Stephens, Olen M; Wang, Ligong et al. (2009) Identification of a beta3-peptide HIV fusion inhibitor with improved potency in live cells. Bioorg Med Chem Lett 19:3736-8
Harker, Elizabeth A; Schepartz, Alanna (2009) Cell-permeable beta-peptide inhibitors of p53/hDM2 complexation. Chembiochem 10:990-3
Goodman, Jessica L; Molski, Matthew A; Qiu, Jade et al. (2008) Tetrameric beta(3)-peptide bundles. Chembiochem 9:1576-8

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