The goal of this research is to develop new methods for the design and synthesis of Type-III Peptidomimetic inhibitors of aspartic proteases. A Type-III mimetic, is an organic structure, distinctly different in shape and atom type from a peptide substrate, that binds so as to complement the local topography in the enzyme active site. These are considered likely to lead efficiently to orally bioavailable enzyme inhibitors. Model studies with pepsin and R. Chinensis pepsin will be continued by creating potential candidates for synthesis by applying the structure-generating program, GrowMol, to two different classes of enzyme-inhibitor complexes: (1) those formed from tight-binding transition-state analogs bound to the target enzyme; and (2) those formed from weaker binding inhibitors bound to a destabilized enzyme. Of the many potential synthetic targets generated, Beilstein's CrossFire is used to identify synthetically accessible templates or core structures from which to build the peptidomimetic. These are further refined by the chemist, synthesized, assayed against the target enzyme and when active, their binding mode to the enzyme will be determined by X-ray crystrallography. New strategies for the Design of Protease Inhibitors will result and the goal is to find ways to design Type-III peptidomimetic inhibitors directly from the structures of peptide inhibitors bound to the target enzyme. These strategies will be applied to two clinically important aspartic proteases, HIV protease and plasmepsin II.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050113-07
Application #
6180439
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Schwab, John M
Project Start
1994-09-01
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
7
Fiscal Year
2000
Total Cost
$293,828
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Bursavich, Matthew G; Rich, Daniel H (2002) Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. J Med Chem 45:541-58
Rich, Daniel H; Bursavich, Matthew G; Estiarte, M Angels (2002) Discovery of nonpeptide, peptidomimetic peptidase inhibitors that target alternate enzyme active site conformations. Biopolymers 66:115-25
Bursavich, M G; Rich, D H (2001) Solid-phase synthesis of aspartic peptidase inhibitors: 3-alkoxy-4-aryl piperidines. Org Lett 3:2625-8
West, C W; Estiarte, M A; Rich, D H (2001) New methods for side-chain protection of cysteine. Org Lett 3:1205-8
Ripka, A S; Satyshur, K A; Bohacek, R S et al. (2001) Aspartic protease inhibitors designed from computer-generated templates bind as predicted. Org Lett 3:2309-12
Dales, N A; Bohacek, R S; Satyshur, K A et al. (2001) Design and synthesis of unsymmetrical peptidyl urea inhibitors of aspartic peptidases. Org Lett 3:2313-6
Bursavich, M G; West, C W; Rich, D H (2001) From peptides to non-peptide peptidomimetics: design and synthesis of new piperidine inhibitors of aspartic peptidases. Org Lett 3:2317-20
Travins, J M; Bursavich, M G; Veber, D F et al. (2001) Aspartic protease inhibitors: expedient synthesis of 2-substituted statines. Org Lett 3:2725-8
Flentke, G R; Glinski, J; Satyshur, K et al. (1999) Purification and crystallization of rhizopuspepsin: the use of nickel chelation chromatography to select for catalytically active species. Protein Expr Purif 16:213-20
West, C W; Rich, D H (1999) Novel cyclic tripeptides and substituted aromatic amino acids via ruthenium-activated S(N)Ar reactions. Org Lett 1:1819-22

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