Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 15 to 23 amino acid residues in defined sequence
Reexamination Certificate
1996-12-12
2002-10-08
Duffy, Patricia A. (Department: 1645)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
15 to 23 amino acid residues in defined sequence
C530S327000, C530S230000, C530S329000, C530S330000, C514S014800, C514S015800, C514S016700, C514S017400, C514S018700
Reexamination Certificate
active
06462171
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of therapeutic peptides for the prevention and treatment of disorders or diseases resulting from abnormal formation of amyloid or amyloid-like deposits, such as, but not limited to, prion-related encephalophathies, Alzheimer's dementia or disease (AD), and other amyloidosis disorders. This invention also relates to the use of the peptides in preventing the formation of or in promoting the redissolution of these insoluble amyloid or amyloid-like deposits.
2. Description of the Background Art
Alzheimer's disease (AD) is the most common form of dementia in adults (C. Soto et al.
J. Neurochem
. 63:1191-1198, 1994), constituting the fourth leading cause of death in the United States. Approximately 10% of the population over 65 years old is affected by this progressive degenerative disorder that is characterized by memory loss, confusion and a variety of cognitive disabilities. One of the key events in AD is the deposition of amyloid as insoluble fibrous masses (amyloidogenesis) resulting in extracellular neuritic plaques and deposits around the walls of cerebral blood vessels. The main component of amyloid is a 4.1-4.3 kDa hydrophobic peptide, named amyloid &bgr;-peptide (A&bgr;), that is codified in chromosome 21 as part of a much longer amyloid precursor protein APP (Muller-Hill and Beyreuther,
Ann. Rev. Biochem
. 38:287-307, 1989). The APP starts with a leader sequence (signal peptide), followed by a cysteine-rich region, an acidic-rich domain, a protease inhibitor motif, a putative N-glycosylated region, a transmembrane domain, and finally a small cytoplasmic region. The A&bgr; sequence begins close to the membrane on the extracellular side and ends within the membrane. Two-thirds of A&bgr; faces the extracellular space, and the other third is embedded in the membrane (Kang et al.
Nature
325:503-507, 1987; Dyrks et al.
EMBO J
. 7:949-957, 1988). Several lines of evidence suggest that amyloid may play a central role in the early pathogenesis of AD.
Evidence that amyloid may play an important role in the early pathogenesis of AD comes primarily from studies of individuals affected by the familial form of AD (FAD) or by Down's syndrome. Down's syndrome patients have three copies of APP gene and develop AD neuropathology at an early age (Wisniewski et al.,
Ann. Neurol
. 17:278-282, 1985). Genetic analysis of families with hereditary AD revealed mutations in chromosome 21, near or within the A&bgr; sequence (Forsell et al.,
Neurosci. Lett
. 184:90-93, 1995). Moreover, recently it was reported that transgenic mice expressing high levels of human mutant APP progressively develop amyloidosis in brain (Games et al.,
Nature
373:523-527, 1995). These findings appear to implicate amyloidogenesis in the pathophysiology of AD.
Recently, the same peptide that forms amyloid deposits in AD brain was also found in a soluble form (sA&bgr;) normally circulating in the human body fluids (Seubert et al., Nature 359:355-327, 1992; Shoji et al.,
Science
258:126-129, 1992). Zlokovic et al.,
Biochem. Biophys. Res. Commun
. 205:1431-1437 (1994), reported that the blood-brain barrier (BBB) has the capability to control cerebrovascular sequestration and transport of circulating sA&bgr;, and that the transport of the sA&bgr; across the BBB was significantly increased when sA&bgr; was perfused in guinea pigs as a complex with apolipoprotein J (apoJ). The sA&bgr;-apoJ was found in normal cerebrospinal fluid (CSF; Ghiso et al. Biochem. J. 293:27-30, 1994) and in vivo studies indicated that sA&bgr; is transported with apoJ as a component of the high density lipoproteins (HDL) in normal human plasma (Koudinov et al.,
Biochem. Biophys. Res. Commun
. 205:1164-1171, 1994). It was also recently reported by Zlokovic et al.,
Proc. Natl. Acad. Sci. USA
93:4229-04233 (1996), that the transport of sA&bgr; across the BBB was almost abolished when the apoJ receptor gp330 was blocked. It is believed that the conversion of sA&bgr; to insoluble fibrils is initiated by a conformational or proteolytic modification of the 2-3 amino acid longer soluble form. It has been suggested that the amyloid formation is a nucleation-dependent phenomena in which the initial insoluble “seed” allows the selective deposition of amyloid (Jarrett et al.,
Biochem
. 32 :4693-4697, 1993).
Peptides containing the sequence 1-40 or 1-42 of A&bgr; and shorter derivatives can form amyloid-like fibrils in the absence of other protein (Soto et al.,
J. Neurochem.
63:1191-1198, 1994), suggesting that the potential to form amyloid resides mainly in the structure of A&bgr;. The relation between the primary structure of A&bgr; and its ability to form amyloid-like fibrils was analyzed by altering the sequence of the peptide. Substitution of hydrophilic residues for hydrophobic ones in the internal A&bgr; hydrophobic regions (amino acids 17-21) impaired fibril formation (Hilbich et al.,
J. Mol. Biol
. 228:460-473, 1992), suggesting that A&bgr; assembly is partially driven by hydrophobic interactions. Indeed, larger A&bgr; peptides (A&bgr;1-42/43) comprising two or three additional hydrophobic C-terminal residues are more amyloidogenic (Jarrett et al.,
Biochem
32:4693-4697, 1993). Secondly, the conformation adopted by A&bgr; peptides is crucial in amyloid formation. A&bgr; incubated at different pH, concentrations and solvents has mainly an a-helical (random coil) or a &bgr;-sheet secondary structure (Barrow et al.,
J. Mol. Biol.
225:1075-1093, 1992: Burdick'et al.,
J. Biol. Chem
. 267:546-554, 1992; Zagorski et al.,
Biochem
. 31:5621-5631, 1992). The A&bgr; peptide with &agr;-helical or random coil structure aggregates slowly; A&bgr; with &bgr;-sheet conformation aggregates rapidly (Zagorski et al.,
Biochem
. 31:5621-5631, 1992; Soto et al.,
J. Biol. Chem
. 270:3063-3067, 1995; Soto and Castano,
Biochem. J.
314:701-707, 1996). The importance of hydrophobicity and &bgr;-sheet secondary structure on amyloid formation also is suggested by comparison of the sequence of other amyloidogenic proteins.
Analysis of A&bgr; aggregation by turbidity measurements indicates that the length of the C-terminal domain of A&bgr; influences the rate of A&bgr; assembly by accelerating nucleus formation (Jarrett et al.,
Cell
73:1055-1058, 1993 ). Thus, the C-terminal domain of A&bgr; may regulate fibrillogenesis. However, in vitro modulators of A&bgr; amyloid formation, such as metal cations (Zn, Al) (Bush et al.,
Science
265:1464-1467, 1994; Exley et al.,
FEBS Lett
. 324:293-295, 1993) heparin sulfate proteoglycans, and apoliprotein E (Strittmatter et al.,
Proc. Natl. Acad. Sci. USA
90:1977-1981, 1993) interact with the 12-28 region of A&bgr;. Moreover, mutations in the &bgr; PP gene within the N-terminal A&bgr; domain yield analogs more fibrillogenic (Soto et al., 1995, supra; Wisniewski et al.,
Biochem. Biophys. Res. Commun
. 179:1247-1254, 1991). Finally, while the C-terminal domain of A&bgr; invariably adopts a &bgr;-strand structure in aqueous solutions, environmental parameters determine the existence of alternative conformation in the A&bgr; N-terminal domain (Barrow et al., 1992, supra; Soto et al., 1995, supra; Burdick et al., 1992, supra). Therefore, the N-terminus may be a potential target site for inhibition of the initial random coil to &bgr;-sheet conformational change.
The emerging picture from studies with synthetic peptides is that A&bgr; amyloid formation is dependent on hydrophobic interactions of A&bgr; peptides adopting an antiparallel &bgr;-sheet conformation and that both the N- and C-terminal domains are important for amyloid formation. The basic unit of fibril formation appears to be the conformer adopting an antiparallel &bgr;-sheet composed of strands involving the regions 10-24 and 29-40/42 of the peptide (Soto et al., 1994, supra). Amyloid formation proceeds by intermolecular interactions between the &bgr;-strands of several monomers to form an oligomeric &bgr;-sheet structure precursor of the fibrillar &
Baumann Marc H.
Frangione Blas
Soto-Jara Claudio
Browdy and Neimark
Duffy Patricia A.
New York University
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