The investigators are trying to identify unnatural polymeric backbones that adopt compact, specific and predictable conformations (""""""""foldamers""""""""). The inspiration for this work comes from biology: living systems overwhelmingly employ polymers (protein and RNA) to carry out complex chemical operations like catalysis and tight, specific binding. Proteins and RNA are unique relative to other known polymers, natural or synthetic, in that these biofoldamers fold to compact conformations; the folding process generates """"""""active sites"""""""" via precise spatial arrangement of reactive moieties scattered along the backbone. Therefore, if the investigators can identify new foldamer backbones with properties and capabilities analogous to but distinct from those of the biofoldamers. These hypothetical entities could be useful in a variety of applications:, including as medicinal agents, where they would presumably benefit from resistance to enzymatic degradation. Foldamer research is also likely to provide new scaffolds for combinatorial drug development; such systems should be particularly well suited to antagonism of specific protein-protein recognition. Preliminary results demonstrate that relatively small beta-amino acids oligomers (""""""""beta- peptides"""""""") can adopt very stable helical conformations in solution. They plan to use this secondary structural element to construct """"""""beta- proteins"""""""" with helical bundle tertiary structures, and will also explore the stabilization of alternative secondary structures with other beta-amino acids.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM056414-01
Application #
2387269
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1997-09-01
Project End
2000-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
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
Eddinger, Geoffrey A; Gellman, Samuel H (2018) Differential Effects of ?3 - versus ?2 -Amino Acid Residues on the Helicity and Recognition Properties of Bim BH3-Derived ?/?-Peptides. Angew Chem Int Ed Engl 57:13829-13832
Hager, Marlies V; Clydesdale, Lachlan; Gellman, Samuel H et al. (2017) Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1. Biochem Pharmacol 136:99-108
Checco, James W; Gellman, Samuel H (2017) Iterative Nonproteinogenic Residue Incorporation Yields ?/?-Peptides with a Helix-Loop-Helix Tertiary Structure and High Affinity for VEGF. Chembiochem 18:291-299
Cheloha, Ross W; Chen, Bingming; Kumar, Niyanta N et al. (2017) Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad ? Residue Distribution. J Med Chem 60:8816-8833
Checco, James W; Gellman, Samuel H (2016) Targeting recognition surfaces on natural proteins with peptidic foldamers. Curr Opin Struct Biol 39:96-105
Hager, Marlies V; Johnson, Lisa M; Wootten, Denise et al. (2016) ?-Arrestin-Biased Agonists of the GLP-1 Receptor from ?-Amino Acid Residue Incorporation into GLP-1 Analogues. J Am Chem Soc 138:14970-14979
Cheloha, Ross W; Watanabe, Tomoyuki; Dean, Thomas et al. (2016) Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist. ACS Chem Biol 11:2752-2762
Checco, James W; Kreitler, Dale F; Thomas, Nicole C et al. (2015) Targeting diverse protein-protein interaction interfaces with ?/?-peptides derived from the Z-domain scaffold. Proc Natl Acad Sci U S A 112:4552-7
Cheloha, Ross W; Gellman, Samuel H; Vilardaga, Jean-Pierre et al. (2015) PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 11:712-24
Checco, James W; Lee, Erinna F; Evangelista, Marco et al. (2015) ?/?-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells. J Am Chem Soc 137:11365-75

Showing the most recent 10 out of 75 publications