Compounds which prevent neuronal cell death and uses thereof

Details Compounds which prevent neuronal cell death and uses thereof Compounds which prevent neuronal cell death and uses thereof

1996-03-04

2003-10-21

Navarro, Mark (Department: 1645)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

C530S329000, C530S330000, C530S331000, C514S002600

Reexamination Certificate

active

06635738

ABSTRACT:

BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding the Sequence Listing. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Members of the family of cysteine proteases related to the interleukin 1&bgr; converting enzyme (ICE) have been shown to be necessary for programmed cell death in a number of biological systems (Yuan et al., 1993). For example, mutations of the ICE homologue, ced3, inhibit cell death which normally occurs during development in
C. elegans
(Hengartner et al., 1992) and overexpression of ICE or the ICE-like proteases NEDD-2/ICH-1 and Yama/apopain/CPP32 induces apoptosis in primary neurons, rat fibroblasts and insect cells (Gagliardini et al., 1994; Miura et al., 1994; Wang et al., 1994; Kumar et al., 1994; and Fernandes-Alnemri et al., 1994). Mice lacking ICE are resistant to apoptosis induced by Fas antibody. In the mammary gland, ICE mRNA is expressed during involution, when apoptosis occurs in this tissue. The pox virus product crmA, a serpin-like pseudosubstrate for ICE, protects sensory neurons and fibroblasts from trophic factor withdrawal-induced death (Gagliardini et al., 1994 and Miura et al., 1994), while Fas/APO-1 mediated apoptosis is blocked by the inhibitory peptide YVAD (Seq. I.D. No. 7), as well as crma (Tewari and Dixit, 1995; Enari et al., 1995; Los et al., 1995; and Tewari et al., 1995). Normal motor neuron loss in development is also blocked by YVAD (Seq. I.D. No. 7), a pseudosubstrate which mimics the pro-IL-1&bgr; cleavage site and thus inhibitis ICE-like proteases (Milligan et al., 1995). While ICE cleaves pro-IL-1&bgr; to produce IL-1&bgr;, the role of IL-L1&bgr; itself in apoptosis is unresolved and it has been suggested that other substrates may be critical in cell death (Lazebnik et al., 1994; Tewari et al., 1995; and Nicholson et al., 1995).
Although many researchers have focused their efforts on the identification and isolation of an inhibitor of the family of cysteine proteases related to the ICE enzyme, there has been little success in this area. Many of these research strategies involve searching through a multitude of compounds and agents which are extrinsic to the ICE protein normally. However, the present invention deviates from the established search strategies and provides for the surprising discovery that use of a piece of the ICE enzyme itself successfully inhibits ICE and thus prevents neuronal cell death.
SUMMARY OF THE INVENTION
This invention provides for a compound having the structure: (AA
1
)
n
-Cys-(AA
2
)
m
, wherein n=0,1,2,3,4 or 5 and m=0,1,2,3,4 or 5, provided the sum of (n+m) is greater than or equal to two and less than or equal to five, if n=1, (AA
1
)
n
=Ala-, if n=2, (AA
1
)
n
=Gln-Ala-, if n≧, (AA
1
)
n
=(Xaa)
p
-Gln-Ala-, and Xaa=any amino acid and wherein if n=3, p=1, if n=4, p=2, if n=5, p=3, if m=1, (AA
2
)
m
=-Arg, if m=2, (AA
2
)
m
=-Arg-Gly, if m≧3, (AA
2
)
m
m=-Arg-Gly-(Xaa)
q
, wherein if m=3, q=1, if m=4, q=2, if m=5, q=3. The present invention provides for a method of inhibiting cell death and a method for alleviating symptoms of a neurodegenerative disorder in a subject.


REFERENCES:
patent: 5672500 (1997-09-01), Litwack et al.
patent: 0425212 (1991-05-01), None
patent: 533 350 (1993-03-01), None
Jackowski et al (British Journal of Neurosurgery vol. 9 pp 303-317), 1995.*
Fersht “Enzyme Structure and Mechanism” WH Freeman & Company, USA (1985) pp 110, 12-23.*
Kibat et al (1990) FASEB J. 4: 2533-2539.*
Alnemri et al (1995) J. Biol. Chem. 270(9): 4312-4317.*
Milligan et al (1995) Neuron 15: 385-393.*
Barinaga, M. (1994) Cell Suicide: By ICE, Not Fire. Science 263:754-756.
Casciola-Rosen, L.A. et al. (1994) Specific Cleavage of the 70-kDa Protein Component of the U1 Small Nuclear Ribonucleoprotein Is a Characteristic Biochemical Feature of Apoptotic Cell Death. J. Biol. Chem. 269: 30757-30760.
Duggan, M.E. et al. (1995) Non-Peptide Fibrinogen Receptor Antagonists. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor Antagonist. J. of Med. Chem. 38(17):3332-3341.
Enari, M. et al. (1995) Involvement of an Ice-like protease in Fasmediated apoptosis. Nature 375:78-81.
Fernandes-Alnemri, T. et al. (1995) Mch2, a New Member of the Apoptotic Ced-3/Ice Cysteine Protease Gene Family. Cancer Res. 55:2737-2742.
Koivunen, E. et al. (1993) Selection of Peptides Binding to the &agr;5&bgr;1Integrin from Phage Display Library. J. of Biol. Chem. 27: 20205-20210.
Los, M. et al. (1995) Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis. Nature 375:81-83.
Luo, A.-M. et al. (Nov. 1993) Antigen Mimicry in Autoimmune Disease, Sharing of Amino Acid Residues Critical for Pathogenic T Cell Activation. Am. Soc. for Clin. Invest. 92:2117-2123.
Mashima, T. et al. (1995) Aspartate-Based Inhibitor of Interleukin-1&bgr;-Converting Enzyme Prevents Antitumor Agent-Induced Apoptosis in Human Myeloid Leukemia U937 Cells. Biochem. and Biophys. Res. Comm. 209(3):907-915.
Milligan, C.E. et al. (1995) Peptide Inhibitors of the ICE Protease Family Arrest Programmed Cell Death of Motoneurons In Vivo and In Vitro. Neuron 15:385-393.
Munday, N.A. et al. (1995) Molecular Cloning and Pro-apoptotic Activity of ICErelII and ICErelIII, Members of the ICE/CED-3 Family of Cysteine Proteases. J. of Biol. Chem. 270(26):15870-6.
Wang, L. et al. (1994) Ich-1, an ICE/ced-3-Related Gene, Encodes Both Positive and Negative Regulators of Programmed Cell Death. Cell 78:739-750.
Wang, X. et al. (1995) Purification of an Interleukin-1&bgr; Converting Enzyme-related Cysteine Protease That Cleaves Sterol Regulatory Element-binding Proteins between the Leucine Zipper and Transmembrane Domains. J. of Biol Chem. 270(3):18044-18055.
Xuan, J.-W. et al. (1995) Site-Directed Mutagenesis of the Arginine-Glycine-Aspartic Acid Sequence in Osteopontin Destroys Cell Adhesion and Migration Functions. J. of Cell. Biochem. 57:680-690.

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