Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-11-04
2004-02-10
Spector, Lorraine (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S300000, C530S330000, C530S345000, C424S085100, C424S184100
Reexamination Certificate
active
06689753
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to peptide analogs and peptide mimetics of &bgr;-sheet breaker peptides suitable for in vivo use in treating mammals with protein conformational diseases such as Alzheimer's and prion disease. More particularly, the present invention is directed to novel peptide analogs and mimetics, pharmaceutical compositions containing one or a mixture of such peptide analogs and mimetics, and methods for preventing, treating, or detecting disorders or diseases associated with abnormal protein folding into amyloid or amyloid-like deposits or precursors thereof having a pathological beta-sheet structure.
2. Description of Related Art
Extensive evidence has been accumulated indicating that several diverse disorders have the same molecular basis, i.e. a change in a protein conformation (Thomas et al.,
Trends Biochem. Sci
. 20: 456-459, 1995; Soto,
J. Mol. Med
. 77: 412-418, 1999). These protein conformational diseases include Alzheimer's disease, prion-related disorders, systemic amyloidosis, serpin-deficiency disorders, Huntington's disease and Amyotrophic Lateral Sclerosis (Soto 1999, supra). The hallmark event in protein conformational disorders is a change in the secondary and tertiary structure of a normal protein without alteration of the primary structure. The conformationally modified protein may be implicated in the disease by direct toxic activity, by the lack of biological function of normally-folded protein, or by improper trafficking (Thomas et al., 1995, supra). In the cases where the protein is toxic, it usually self-associates and becomes deposited as amyloid fibrils in diverse organs, inducing tissue damage (Thomas et al., 1995, supra; Kelly,
Curr. Opin. Struct. Biol
. 6: 11-17, 1996; Soto, 1999, supra).
Alzheimer's disease (AD) is a devastating neurodegenerative problem characterized by loss of short-term memory, disorientation, and impairment of judgment and reasoning. AD is the most common dementia in elderly population. It is estimated that more than twenty-five million people worldwide are affected in some degree by AD (Teplow,
Amyloid
5: 121-142, 1998). A hallmark event in AD is the deposition of insoluble protein aggregates, known as amyloid, in brain parenchyma and cerebral vessel walls. The main component of amyloid is a 4.3 KDa hydrophobic peptide, named amyloid beta-peptide (A&bgr;) that is encoded on the chromosome 21 as part of a much longer precursor protein (APP) (Selkoe,
Science
275: 630-631, 1997). Genetic, biochemical, and neuropathological evidence accumulated in the last 10 years strongly suggest that amyloid plays an important role in early pathogenesis of AD and perhaps triggers the disease (Soto et al.,
J. Neurochem
. 63: 1191-1198, 1994; Selkoe, 1997, supra; Teplow, 1998, supra; Sisodia and Price,
FASEB J
. 9: 366-370, 1995; Soto,
Mol. Med. Today
5: 343-350, 1999).
Amyloid is a generic term that describes fibrillar aggregates that have a common structural motif, i.e., the &bgr;-pleated sheet conformation (Serpell et al.,
Cell Mol. Life Sci
. 53: 887, 1997; Sipe,
Ann. Rev. Biochem
. 61: 947-975, 1992). These aggregates exhibit specific tinctorial properties, including the ability to emit a green birefringent glow after staining with Congo red, and the capacity to bind the fluorochrome, thioflavin S (Sipe, 1992, supra; Ghiso et al.,
Mol. Neurobiol
. 8: 49-64, 1994). There are more than a dozen human diseases of different etiology characterized by the extracellular deposition of amyloid in diverse tissues, which lead to cell damage, organ dysfunction, and death. Among the diseases involving amyloidosis, it is possible to highlight Alzheimer's disease, prion-related disorders (also known as transmissible spongiform encephalopathy), and systemic amyloidosis (Table 1). The amyloid fibrils are usually composed of proteolytic fragments of normal or mutant gene products. There are over 16 different proteins (Table 1) involved in amyloid deposition in distinct tissues (Ghiso et al., 1994, supra).
The formation of amyloid is basically a problem of protein folding, whereby a mainly random coil soluble peptide becomes aggregated, adopting a &bgr;-pleated sheet conformation (Kelly, 1996, supra; Soto, 1999, supra). Amyloid formation proceeds by hydrophobic interactions among conformationally altered amyloidogenic intermediates, which become structurally organized into a &bgr;-sheet conformation upon peptide interaction. The hydrophobicity appears to be important to induce interaction of the monomers leading to aggregation, while the &bgr;-sheet conformation might determine the ordering of the aggregates in amyloid fibrils. In an attempt to inhibit amyloid fibril formation, these two properties were separated by designing short synthetic peptides bearing sequence homology and a similar degree of hydrophobicity as the peptide domain implicated in the conformational change, but having a very low propensity to adopt a &bgr;-sheet conformation (called &bgr;-sheet breaker peptides) (Soto et al., 1996, supra; Soto et al., 1998, supra). The aim was to design a peptide with the ability to bind specifically to the amyloidogenic peptide forming a complex that stabilizes the physiological conformation and destabilizes the abnormal conformation of the peptide (Soto, 1999, supra).
TABLE 1
Disorders related with amyloidosis and the protein component of the
amyloid fibrils
DISEASE
FIBRIL COMPONENT
Alzheimer's disease
Amyloid-&bgr; protein
Primary systemic amyloidosis
Immunoglobulin light chain or
fragments thereof
Secondary systemic amyloidosis,
Fragments of serum amyloid-A
Familial Mediterranean fever
Spongiform encephalopathy
Fragments of prion protein
Senile systemic amyloidosis,
Transthyretin and fragments
Familial amyloid polyneuropathy
thereof
Hemodialysis-related amyloidosis
&bgr;2-microglobulin
Hereditary cerebral amyloid angiopathy,
Cystain C
Icelandic type
Familial amyloidosis, Finnish type
Gelsolin fragments
Type II diabetes
Fragments of islet amyloid
polypeptide
Familial amyloid polyneuropathy
Fragments of apolipoprotein A-1
Medullar carcinoma of the thyroid
Fragments of calcitonin
Atrial amyloidosis
Atrial natriuretic factor
Hereditary non-neuropathic systemic
Lysozyme or fragments thereof
amyloidosis
Hereditary renal amyloidosis
Fibrinogen fragments
Islet amyloid
Insulin
Amyloidosis in senescence
Apolipoprotein A-II
&bgr;-sheet breaker peptides have so far been designed to block the conformational changes that occur in both A&bgr; and prion protein (PrP), which are implicated in the pathogenesis of Alzheimer's and prion disease, respectively. The prior art has previously shown that 11- and 5-residue &bgr;-sheet breaker peptides (namely, iA&bgr;1 and iA&bgr;5, respectively) homologous to the central hydrophobic region of A&bgr; inhibit peptide conformational changes that result in amyloid formation and also dissolved preformed fibrils in vitro (Soto et al.,
Biochem. Biophys. Res. Commun
. 226: 672-680, 1996; Soto et al.,
Nature Med
. 4: 822-826, 1998). In addition, the 5-residue peptide is capable of preventing the neuronal death induced by the formation of &bgr;-sheet rich oligomeric A&bgr; structures in cell culture experiments (Soto et al., 1998, supra). Furthermore, by using a rat model of amyloidosis induced by intracerebral injection of A&bgr;1-42, the prior art has shown that co-injections of the 5-residue &bgr;-sheet breaker peptide decreased cerebral A&bgr; accumulation and completely blocked the deposition of fibrillar amyloid-like lesions in the rat brain (Soto et al., 1998, supra). Finally, the &bgr;-sheet breaker peptide injected eight days after the injection of A&bgr; was able to disassemble preformed A&bgr; fibrils in the rat brain in vivo, that leads to a reduction in the size of amyloid deposits (Sigurdsson, E. M.; Permanne, B.; Soto, C.; Wisniewski, T.; Frangione, B.;
J. Neuropathol. Exp. Neurol
. January 2000; 59(1): 11-7). Interestingly, removal of amyloid by the &bgr;-sheet breaker peptide reverts the associated ce
Axonyx, Inc.
Bunner Bridget E.
Gibbons Del Deo Dolan Griffinger & Vecchione
Spector Lorraine
LandOfFree
&bgr; sheet breaker peptide analogs that inhibit &bgr;... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with &bgr; sheet breaker peptide analogs that inhibit &bgr;..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and &bgr; sheet breaker peptide analogs that inhibit &bgr;... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3335083