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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073943-08
Application #
8326211
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Fabian, Miles
Project Start
2005-03-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$396,061
Indirect Cost
$134,235
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
Watkins, Andrew M; Arora, Paramjit S (2015) Structure-based inhibition of protein-protein interactions. Eur J Med Chem 94:480-8
Miller, Stephen E; Thomson, Paul F; Arora, Paramjit S (2014) Synthesis of hydrogen-bond surrogate ?-helices as inhibitors of protein-protein interactions. Curr Protoc Chem Biol 6:101-16
Watkins, Andrew M; Arora, Paramjit S (2014) Anatomy of ?-strands at protein-protein interfaces. ACS Chem Biol 9:1747-54
Miller, Stephen E; Watkins, Andrew M; Kallenbach, Neville R et al. (2014) Effects of side chains in helix nucleation differ from helix propagation. Proc Natl Acad Sci U S A 111:6636-41
Xie, X; Piao, L; Bullock, B N et al. (2014) Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma. Oncogene 33:1037-46
Raj, Monika; Bullock, Brooke N; Arora, Paramjit S (2013) Plucking the high hanging fruit: a systematic approach for targeting protein-protein interactions. Bioorg Med Chem 21:4051-7
Kushal, Swati; Lao, Brooke Bullock; Henchey, Laura K et al. (2013) Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling. Proc Natl Acad Sci U S A 110:15602-7
Bergey, Christina M; Watkins, Andrew M; Arora, Paramjit S (2013) HippDB: a database of readily targeted helical protein-protein interactions. Bioinformatics 29:2806-7
Drew, Kevin; Renfrew, P Douglas; Craven, Timothy W et al. (2013) Adding diverse noncanonical backbones to rosetta: enabling peptidomimetic design. PLoS One 8:e67051
Henchey, Laura K; Kushal, Swati; Dubey, Ramin et al. (2012) Correction to Inhibition of Hypoxia Inducible Factor 1-Transcription Coactivator Interaction by a Hydrogen Bond Surrogate ýý-Helix. J Am Chem Soc 134:8000

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