Protein Surface Mimicry by Peptidic Foldamers Foldamers are unnatural oligomers that display discrete and predictable folding behavior. The proposed research explores the ability of foldamers to mimic recognition surfaces on natural proteins and thereby block the formation of specific protein-protein complexes. Interactions between specific pairs of proteins are critical for regulation and information transfer in living systems. Pathological interactions contribute to many human diseases. Such interactions are often difficult to inhibit with small molecules (the traditionally preferred source for drugs) because large surface areas are buried when one macromolecule binds to another. A principal hypothesis behind our work is that foldamers could provide a basis for rational development of inhibitors of protein-protein interactions. We are testing this hypothesis in three systems. First, we are trying to mimic alpha-helical Bcl-2 homology-3 (BH3) domains, segments of natural pro-apoptotic proteins that are recognized by complementary clefts on anti- apoptotic partner proteins. This system represents an excellent testbed for our efforts because robust protein-based assays are available, and there is a good prospect of acquiring thermodynamic data and high-resolution structural data. Strategies that are successful for BH3 domain mimicry will be examined in the context of a longer alpha-helical target, the C-terminal heptad repeat (CHR) segment of the HIV protein gp41. The CHR helix must dock into a complementary cleft formed by another portion of gp41 in order for the virus to infect target cells. Blocking this interaction can block infection. The final test of our hypothesis focuses on inhibiting interactions between vascular endothelial growth factor (VEGF), a soluble signaling protein, and its cell-surface receptors. VEGF induces development of new blood vessels ("angiogenesis"), and aberrant VEGF-induced angiogenesis is associated with a number of human diseases. Strategies identified in this component of our research could ultimately enable us to develop foldamer antagonists for a wide range of protein-receptor interactions that occur at the cell surface.
Interactions between specific proteins are critical for normal human physiology, and aberrant interactions underlie many diseases. The major goal of our research is to explore new strategies for blocking aberrant protein-protein interactions. Our experiments are very basic, but the results might provide a foundation for new therapeutic strategies. The agents with which we try to interfere with protein-protein interactions are oligomers that fold into well-defined shapes (foldamers).
|Cheloha, Ross W; Maeda, Akira; Dean, Thomas et al. (2014) Backbone modification of a polypeptide drug alters duration of action in vivo. Nat Biotechnol 32:653-5|
|Johnson, Lisa M; Barrick, Stacey; Hager, Marlies V et al. (2014) A potent ?/?-peptide analogue of GLP-1 with prolonged action in vivo. J Am Chem Soc 136:12848-51|
|Arnold, Ulrich; Huck, Bayard R; Gellman, Samuel H et al. (2013) Protein prosthesis: ?-peptides as reverse-turn surrogates. Protein Sci 22:274-9|
|Smith, Brian J; Lee, Erinna F; Checco, James W et al. (2013) Structure-guided rational design of ?/?-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. Chembiochem 14:1564-72|
|Johnson, Lisa M; Gellman, Samuel H (2013) ?-Helix mimicry with ?/?-peptides. Methods Enzymol 523:407-29|
|Haase, Holly S; Peterson-Kaufman, Kimberly J; Lan Levengood, Sheeny K et al. (2012) Extending foldamer design beyond ýý-helix mimicry: ýý/ýý-peptide inhibitors of vascular endothelial growth factor signaling. J Am Chem Soc 134:7652-5|
|Boersma, Melissa D; Haase, Holly S; Peterson-Kaufman, Kimberly J et al. (2012) Evaluation of diverse ýý/ýý-backbone patterns for functional ýý-helix mimicry: analogues of the Bim BH3 domain. J Am Chem Soc 134:315-23|
|Johnson, Lisa M; Mortenson, David E; Yun, Hyun Gi et al. (2012) Enhancement of ýý-helix mimicry by an ýý/ýý-peptide foldamer via incorporation of a dense ionic side-chain array. J Am Chem Soc 134:7317-20|
|Johnson, Lisa M; Horne, W Seth; Gellman, Samuel H (2011) Broad distribution of energetically important contacts across an extended protein interface. J Am Chem Soc 133:10038-41|
|Lee, Erinna F; Smith, Brian J; Horne, W Seth et al. (2011) Structural basis of Bcl-xL recognition by a BH3-mimetic ýý/ýý-peptide generated by sequence-based design. Chembiochem 12:2025-32|
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