Abstract

Protein-protein interactions are of great importance in cell function and, consequently, as targets for medicinal chemistry. Where traditional small-molecule based drug design has proven ineffective in the development of antagonists of certain interactions, macromolecular approaches are finding increasing utility. Human epidermal growth factor receptor (EGFR) is a membrane bound cell surface receptor the malfunction of which is linked to a number of cancers. We propose to identify beta-peptide foldamers capable of modulating EGFR function by mimicking protein surfaces involved in receptor dimerization. This project will allow us to explore the scope and limitations of beta-peptide scaffolds as mimics of natural protein surfaces and could lead to the development of new anticancer therapeutics. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA119875-02
Application #
7276089
Study Section
Special Emphasis Panel (ZRG1-F04B (20))
Program Officer
Lohrey, Nancy
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$45,976
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

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
Boersma, Melissa D; Haase, Holly S; Peterson-Kaufman, Kimberly J et al. (2012) Evaluation of diverse ?/?-backbone patterns for functional ?-helix mimicry: analogues of the Bim BH3 domain. J Am Chem Soc 134:315-23
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
Price, Joshua L; Horne, W Seth; Gellman, Samuel H (2010) Structural consequences of beta-amino acid preorganization in a self-assembling alpha/beta-peptide: fundamental studies of foldameric helix bundles. J Am Chem Soc 132:12378-87
Giuliano, Michael W; Horne, W Seth; Gellman, Samuel H (2009) An alpha/beta-peptide helix bundle with a pure beta3-amino acid core and a distinctive quaternary structure. J Am Chem Soc 131:9860-1
Horne, W Seth; Johnson, Lisa M; Ketas, Thomas J et al. (2009) Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers. Proc Natl Acad Sci U S A 106:14751-6
Horne, W Seth; Price, Joshua L; Gellman, Samuel H (2008) Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly. Proc Natl Acad Sci U S A 105:9151-6
Horne, W Seth; Boersma, Melissa D; Windsor, Matthew A et al. (2008) Sequence-based design of alpha/beta-peptide foldamers that mimic BH3 domains. Angew Chem Int Ed Engl 47:2853-6
Chi, Yonggui; English, Emily P; Pomerantz, William C et al. (2007) Practical synthesis of enantiomerically pure beta2-amino acids via proline-catalyzed diastereoselective aminomethylation of aldehydes. J Am Chem Soc 129:6050-5

Showing the most recent 10 out of 13 publications