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Title:
INHIBITORS OF MEMAPSIN 2 AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO2001000665
Kind Code:
A3
Abstract:
Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (Figure 1). The inhibition constant of OM99-2 is 1.6 x 10<-9> M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound to this inhibitor was used to determine the three dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

Inventors:
TANG JORDAN J N
HONG LIN
GHOSH ARUN K
Application Number:
PCT/US2000/017742
Publication Date:
September 27, 2001
Filing Date:
June 27, 2000
Export Citation:
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Assignee:
OKLAHOMA MED RES FOUND (US)
UNIV ILLINOIS (US)
International Classes:
C12N15/09; A61K31/164; A61K38/00; A61K39/00; A61P25/28; A61P43/00; C07C235/06; C07C237/12; C07K1/113; C07K5/097; C07K5/113; C12N9/50; C12N9/64; C12N9/99; C12Q1/37; (IPC1-7): C07K14/81; A61K38/57; A61P25/28
Domestic Patent References:
WO1996040885A21996-12-19
Foreign References:
EP0855444A21998-07-29
Other References:
GHOSH, ARUN K. ET AL: "Design of potent inhibitors for human brain memapsin 2 (.beta.-secretase)", J. AM. CHEM. SOC. (2000), 122(14), 3522-3523, 12 April 2000 (2000-04-12), XP002161208
HONG, LIN ET AL: "Structure of the protease domain of memapsin 2 (.beta.-secretase) complexed with inhibitor", SCIENCE (WASHINGTON, D. C.) (2000), 290(5489), 150-153, 6 October 2000 (2000-10-06), XP002161207
LIN XINLI ET AL: "Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES, vol. 97, no. 4, 15 February 2000 (2000-02-15), Feb. 15, 2000, pages 1456 - 1460, XP002161209, ISSN: 0027-8424
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