Cellular function depends on highly specific interactions between biomolecules (proteins, RNA, DNA, and carbohydrates). Alpha-helices, ubiquitous elements of protein structures, play fundamental roles in many of these interactions. Alpha-helix mimetics that can predictably disrupt these interactions would be invaluable as tools in molecular biology, and as leads in drug development. We have succeeded in creating a general approach for the synthesis of short stable alpha helices that can target chosen biomolecular interactions. Our strategy involves replacement of one of the main chain hydrogen bonds in the target alpha-helix with a covalent bond. The internal placement of the crosslink makes it possible to take advantage of the full helix functionality for molecular recognition. We have demonstrated that this new method results in unusually stable artificial alpha-helices. In this application, we explore the utility of these artificial helices for targeting complex signaling networks. With regards to specific aims, (1) We will create a conformationally and metabolically robust family of HBS helices. (2) We will construct a database of experimentally determined structures of helix-mediated protein-protein interactions and determine hot-spot residues in the helical protein interfaces. (3) We will develop structure-based ligands to help decode the GTPase signaling networks, and evaluate a new paradigm for discovery of specific inhibitors of protein kinase activity. Combined these three aims will offer rationally designed inhibitors of protein- protein interactions, and validate our design principles that are rooted in the fundamental theories of biophysics and physical organic chemistry.
Selective modulation of protein-protein interactions is a grand challenge for chemists and biologists. The ability to systematically modulate protein-protein interactions would greatly facilitate the discovery of candidate therapeutic agents for a broad range of diseases. The proposed research offers a synthetic method for developing artificial alpha-helical ligands for targeting chosen protein interfaces.
| Wuo, Michael G; Arora, Paramjit S (2018) Engineered protein scaffolds as leads for synthetic inhibitors of protein-protein interactions. Curr Opin Chem Biol 44:16-22 |
| Rooklin, David; Modell, Ashley E; Li, Haotian et al. (2017) Targeting Unoccupied Surfaces on Protein-Protein Interfaces. J Am Chem Soc 139:15560-15563 |
| Watkins, Andrew M; Craven, Timothy W; Renfrew, P Douglas et al. (2017) Rotamer Libraries for the High-Resolution Design of ?-Amino Acid Foldamers. Structure 25:1771-1780.e3 |
| Sawyer, Nicholas; Watkins, Andrew M; Arora, Paramjit S (2017) Protein Domain Mimics as Modulators of Protein-Protein Interactions. Acc Chem Res 50:1313-1322 |
| Ghosal, Koyel; Colby, Jennifer M; Das, Debasis et al. (2017) Dynamic Phenylalanine Clamp Interactions Define Single-Channel Polypeptide Translocation through the Anthrax Toxin Protective Antigen Channel. J Mol Biol 429:900-910 |
| Joy, Stephen T; Arora, Paramjit S (2016) An optimal hydrogen-bond surrogate for ?-helices. Chem Commun (Camb) 52:5738-41 |
| Watkins, Andrew M; Bonneau, Richard; Arora, Paramjit S (2016) Side-Chain Conformational Preferences Govern Protein-Protein Interactions. J Am Chem Soc 138:10386-9 |
| Modell, Ashley E; Blosser, Sarah L; Arora, Paramjit S (2016) Systematic Targeting of Protein-Protein Interactions. Trends Pharmacol Sci 37:702-713 |
| Wuo, Michael G; Mahon, Andrew B; Arora, Paramjit S (2015) An Effective Strategy for Stabilizing Minimal Coiled Coil Mimetics. J Am Chem Soc 137:11618-21 |
| Watkins, Andrew M; Wuo, Michael G; Arora, Paramjit S (2015) Protein-Protein Interactions Mediated by Helical Tertiary Structure Motifs. J Am Chem Soc 137:11622-30 |
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