The thrust of this continuing program is to develop and apply principles of structure-based design in devising molecules that mimic peptides and proteins. These goals encompass both the control of peptide conformation, with small oligomers imitating important domains of larger proteins, as well as the design of non-peptidic structures that can compete with peptides in binding to macromolecular receptors. Five projects are outlined: 1) Host molecules that are capable of complexing peptide guests through a beta-sheet motif will be developed as chemical antibodies ; self-complementary hosts will be able to dimerize and provide stabilized segments of four-stranded beta-sheets. 2) The 5- aza-3-amino-2-cyclohexenone unit will be explored as a beta-sheet- stabilizing moiety in the context of peptide-co-oligomers. These units will be used a) to induce self-assembly of these co-oligomers, b) to enhance the complexing ability of the peptide hosts in part 1), and c) as the key feature in molecules that may be able to block the formation of amyloid beta-sheets. 3) Molecules that induce the alpha-helical conformation when appended to the termini of an oligopeptide will be explored further. Synthesis of a C-terminal template will be completed, and this and the N-terminal template developed during the previous grant period will be used to make mimics of the CMV protease dimerization helix and the p53 tumor suppressor transactivation domain. 4) A general process developed in the preceding grant period for identification of macrocyclic peptidase inhibitors will be elaborated. The approach will be used to make analogs of the trypsin inhibitor A90720A, and will also be generalized to novel ring systems, transition state analogs, and other peptidase classes. 5) The chemistry of peptide-ketals will be explored as a route to novel structures which may serve as beta-turn mimetics and which are readily assembled in a combinatorial fashion. The results from these studies will afford molecules with novel activity whose behavior will provide insight into biological structure and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030759-26
Application #
6385446
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Schwab, John M
Project Start
1977-09-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2004-03-31
Support Year
26
Fiscal Year
2001
Total Cost
$450,070
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Hammond, Ming C; Bartlett, Paul A (2007) Synthesis of amino acid-derived cyclic acyl amidines for use in beta-strand peptidomimetics. J Org Chem 72:3104-7
Phillips, Scott T; Blasdel, Landy K; Bartlett, Paul A (2005) @-tides as reporters for molecular associations. J Am Chem Soc 127:4193-8
Hansen, Kristina K; Grosch, Benjamin; Greiveldinger-Poenaru, Sorana et al. (2003) Synthesis and evaluation of macrocyclic transition state analogue inhibitors for alpha-chymotrypsin. J Org Chem 68:8465-70
Hansen, Kristina K; Hansen, Henrik C; Clark, Ryan C et al. (2003) Identification of novel macrocyclic peptidase substrates via on-bead enzymatic cyclization. J Org Chem 68:8459-64
Lewis, Jason G; Bartlett, Paul A (2003) Amino acid-derived heterocycles as combinatorial library targets: bicyclic aminal lactones. J Comb Chem 5:278-84
Trump, Ryan P; Bartlett, Paul A (2003) Amino acid-derived heterocycles as combinatorial library targets: spirocyclic ketal lactones. J Comb Chem 5:285-91
Todd, Matthew H; Ndubaku, Chudi; Bartlett, Paul A (2002) Amino acid derived heterocycles: lewis acid catalyzed and radical cyclizations from peptide acetals. J Org Chem 67:3985-8
Spaller, Mark R; Thielemann, Wolfgang T; Brennan, Paul E et al. (2002) Combinatorial synthetic design. Solution and polymer-supported synthesis of heterocycles via intramolecular aza Diels-Alder and imino alcohol cyclizations. J Comb Chem 4:516-22
Bartlett, Paul A; Yusuff, Naeem; Rico, Alice C et al. (2002) Antihydrophobic solvent effects: an experimental probe for the hydrophobic contribution to enzyme-inhibitor binding. J Am Chem Soc 124:3853-7
An, M; Toochinda, T; Bartlett, P A (2001) Five-membered ring analogues of shikimic acid. J Org Chem 66:1326-33

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