Protein-protein interactions regulate fundamental cellular events and misregulation of these interactions leads to disease states. Several approaches centered on high-throughput screening and rational design approaches are being evaluated for development of synthetic compounds as protein-protein interaction (PPI) inhibitors. Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these folded domains we can specifically inhibit chosen PPIs with rationally designed synthetic molecules. Based on this hypothesis, we have developed cell permeable stabilized helices termed hydrogen bond surrogate or HBS helices to target intracellular PPIs. This work has created a foundation for the development of a new class of structure-based therapeutics. As part of these recent studies, we have also developed computational algorithms to predict targets for these helix mimics. The present proposal builds on this success to target therapeutically important interfaces that have not yielded to our past designs. We will build new experimental approaches to overcome hurdles. The three specific aims are to (1) develop a protein surface analysis approach to target recalcitrant helical and non-helical complexes, (2) establish an approach for target-guided assembly of stabilized helices, and (3) assess properties that aid cellular uptake of HBS helices and explore mechanism of entry for stabilized peptide helices. Studies in each Aim will make significant contributions to general approaches to inhibit PPIs and allow advancement of synthetic helices as distinct constructs spanning the molecular size space between small molecules and proteins.

Public Health Relevance

Protein-protein interactions are vital for numerous biological processes, from cellular signaling to gene regulation, and their misregulation has been associated with a variety of diseases. Selective modulation of protein-protein interactions would, therefore, facilitate the discovery of candidate therapeutic agents for a broad range of diseases. The proposed research describes synthetic approaches for developing artificial alpha- helical ligands for targeting chosen protein interfaces.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073943-12
Application #
9185319
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fabian, Miles
Project Start
2005-03-01
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
12
Fiscal Year
2017
Total Cost
Indirect Cost
Name
New York University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Sawyer, Nicholas; Watkins, Andrew M; Arora, Paramjit S (2017) Protein Domain Mimics as Modulators of Protein-Protein Interactions. Acc Chem Res 50:1313-1322
Rooklin, David; Modell, Ashley E; Li, Haotian et al. (2017) Targeting Unoccupied Surfaces on Protein-Protein Interfaces. J Am Chem Soc 139:15560-15563
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
Modell, Ashley E; Blosser, Sarah L; Arora, Paramjit S (2016) Systematic Targeting of Protein-Protein Interactions. Trends Pharmacol Sci 37:702-713
Watkins, Andrew M; Bonneau, Richard; Arora, Paramjit S (2016) Side-Chain Conformational Preferences Govern Protein-Protein Interactions. J Am Chem Soc 138:10386-9
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
Watkins, Andrew M; Arora, Paramjit S (2015) Structure-based inhibition of protein-protein interactions. Eur J Med Chem 94:480-8
Rooklin, David; Wang, Cheng; Katigbak, Joseph et al. (2015) AlphaSpace: Fragment-Centric Topographical Mapping To Target Protein-Protein Interaction Interfaces. J Chem Inf Model 55:1585-99

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