Cellular function depends on highly specific interactions between biomolecules {proteins, RNA, DMA, 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 tools in molecular biology, and potential leads in drug development. A limitation of existing methods for helix stabilization is that they sacrifice side chain functionality to create crosslinks and nucleate helical conformations. Modifying side chains makes them unavailable for molecular recognition and blocks at least one face of the putative helix. We have succeeded in creating a general approach for the synthesis of short stable alpha helices that allows strict preservation of the helix surfaces. 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. In preliminary studies, 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 recognition of specific protein pockets and DNA major grooves. ? ? With regards to specific aims, (1) we will determine whether replacement of a main chain hydrogen bond in a putative helix with a carbon-carbon bond continually results in highly stable and helical peptides. (2) We will prepare artificial helices that target model (RNase S and GCN4) and therapeutically important protein-protein interactions (HIV-1 gp41) to assess the biological efficacy of these compounds. (3) We will initiate research efforts to develop a new class of sequence-specific DNA binding molecules. Combined these three aims will validate a new approach for the preparation of artificial alpha-helices and their potential use in biomolecular recognition. ? ?
| 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 |
| 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 |
| Rooklin, David; Modell, Ashley E; Li, Haotian et al. (2017) Targeting Unoccupied Surfaces on Protein-Protein Interfaces. J Am Chem Soc 139:15560-15563 |
| 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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