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 #
5R01GM056414-03
Application #
6019348
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1997-09-01
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
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
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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
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