| Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide -> Monitor Keywords |
|
|
  Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptideUSPTO Application #: 20060069058Title: Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide Abstract: The present invention provides peptide analogs and peptide mimetics that inhibit pleated sheet formation in amyloid β-peptide, pharmaceutical compositions thereof and their therapeutic use. The inhibitory peptides possess activity as inhibitors in the formation of amyloid-like deposits and are useful in the treatment of Alzheimer's Disease. (end of abstract) Agent: Trask Britt - Salt Lake City, UT, US Inventor: Claudio Soto-Jara USPTO Applicaton #: 20060069058 - Class: 514044000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20060069058. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 10/726,366, filed Dec. 3, 2003, which is a continuation of U.S. patent application Ser. No. 09/706,540, filed Nov. 4, 2000, now U.S. Pat. No. 6,689,753, issued Feb. 10, 2004, which claims the benefit of U.S. Provisional Application No. 60/163,911, filed Nov. 5, 1999, the entirety of each of which is incorporated by reference. FIELD OF THE INVENTION [0002] The present invention relates to peptide analogs and peptide mimetics of .beta.-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. BACKGROUND [0003] 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). [0004] 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.beta.) 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). [0005] Amyloid is a generic term that describes fibrillar aggregates that have a common structural motif, i.e., the .beta.-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). [0006] The formation of amyloid is basically a problem of protein folding, whereby a mainly random coil soluble peptide becomes aggregated, adopting a .beta.-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 0-sheet conformation upon peptide interaction. The hydrophobicity appears to be important to induce interaction of the monomers leading to aggregation, while the .beta.-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 .beta.-sheet conformation (called .beta.-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-US-00001 TABLE 1 Disorders related with amyloidosis and the protein component of the amyloid fibrils DISEASE FIBRIL COMPONENT Alzheimer's disease Amyloid-.beta. protein Primary systemic amyloidosis Immunoglobulin light chain or fragments thereof Secondary systemic amyloidosis, Fragments of serum Familial Mediterranean fever amyloid-A Spongiform encephalopathy Fragments of prion protein Senile systemic amyloidosis, Transthyretin and fragments thereof Familial amyloid polyneuropathy Hemodialysis-related amyloidosis .beta.2-microglobulin Hereditary cerebral amyloid Cystain C angiopathy, 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 amyloidosis thereof Hereditary renal amyloidosis Fibrinogen fragments Islet amyloid Insulin Amyloidosis in senescence Apolipoprotein A-II [0007] .beta.-sheet breaker peptides have so far been designed to block the conformational changes that occur in both A.beta.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 five-residue .beta.-sheet breaker peptides (namely, iA.beta.1 and iA.beta.5, respectively) homologous to the central hydrophobic region of A.beta. 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 five-residue peptide is capable of preventing the neuronal death induced by the formation of .beta.-sheet rich oligomeric A.beta. structures in cell culture experiments (Soto et al., 1998, supra). Furthermore, by using a rat model of amyloidosis induced by intracerebral injection of A.beta.1-42, the prior art has shown that co-injections of the five-residue .beta.-sheet breaker peptide decreased cerebral A.beta. accumulation and completely blocked the deposition of fibrillar amyloid-like lesions in the rat brain (Soto et al., 1998, supra). Finally, the .beta.-sheet breaker peptide injected eight days after the injection of A.beta. was able to disassemble preformed A.beta. fibrils in the rat brain in vivo, that leads to a reduction in the size of amyloid deposits (E. M. Sigurdsson, B. Permanne, C. Soto, T. Wisniewski, B. Frangione, J. Neuropathol. Exp. Neurol. January 2000; 59(1):11-7). Interestingly, removal of amyloid by the .beta.-sheet breaker peptide reverts the associated cerebral histologic damage, including neuronal shrinkage and microglial activation. [0008] .beta.-sheet breaker peptides have also been designed to prevent and to revert conformational changes caused by prions (PrP). Based on the same principles and using as a template the PrP sequence 114-122, the prior art has shown that when a set of .beta.-sheet breaker peptides was synthesized, a 13-residue peptide (iPrP13) showed the greatest activity (Soto, 1999, supra). Several in vitro cell culture and in vivo assays were used to test for inhibitory activity and the results clearly indicated that it is possible not only to prevent the PrP.sup.c.fwdarw.PrP.sup.sc conversion, but more interestingly to revert the infectious PrP.sup.sc conformer to a biochemical and structural state similar to PrP.sup.c (Soto et al., manuscript submitted). [0009] Short peptides have been utilized extensively as drugs in medicine (Rao et al., C. Basava and G. M. Anantharamaiah, eds. Boston: Birkhauser, pp. 181-198, 1994). However, the development of peptide drugs is strongly limited by their lack of oral bioavailability and their short duration of action resulting from enzymatic degradation in vivo (Fauchere and Thurieau, Adv. Drug Res. 23:127-159, 1992). Progress in recent years toward the production of peptide analogs (such as pseudopeptides and peptide mimetics) with lower susceptibility to proteolysis has increased the probability to obtain useful drugs structurally related to their parent peptides (Fauchere and Thurieau, 1992, supra). Improving peptide stability to proteases not only increases the half-life of the compound in the circulation but also enhances its ability to be transported or absorbed at different levels, including intestinal absorption and blood-brain barrier permeability, because transport and absorption appear to be highly dependent upon the time of exposure of membranes or barriers to the bioactive species (Fauchere and Thurieau, 1992, supra). SUMMARY OF THE INVENTION [0010] The present invention is an inhibitory peptide capable of inhibiting .beta.-pleated sheet formation in amyloid .beta.-peptide, the inhibitory peptide being a .beta.-sheet breaker peptide analog designed by chemical modification of a 0-sheet breaker peptide capable of inhibiting .beta.-pleated sheet formation in amyloid .beta.-peptide. [0011] The peptide is altered chemically by: (1) modifications to the N- and C-terminal ends of the peptide; (2) changes of the side-chain, which can involve amino acid substitutions; (3) modification in the a-carbon including methylations, alkylations and dehydrogenations; (4) chirality changes by replacing D- for L-residue; (5) head-to-tail cyclizations; and (6) introduction of amide bond replacements, i.e., changing the atoms participating in the peptide (or amide) bond. [0012] The present invention also includes an inhibitory peptide capable of inhibiting conformational changes in prion PrP protein associated with amyloidosis, the inhibitory peptide being a .beta.-sheet breaker peptide analog designed by chemical modification of a .beta.-sheet breaker peptide capable inhibiting the conformational changes in prior PrP protein associated with amyloidosis. [0013] In addition, the present invention includes a peptide mimetic with the following structure: [0014] In another embodiment, the peptide mimetic has the following structure: [0015] In yet another embodiment, the peptide mimetic has the following structure: [0016] The present invention also includes a method 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 is claimed. BRIEF DESCRIPTION OF THE DRAWINGS [0017] FIG. 1 is a schematic representation of the peptide bond and the potential target sites for peptide modifications. [0018] FIG. 2 is a graph depicting the pharmacokinetics of an 11-residue .beta.-sheet breaker peptide inhibitor of Alzheimer's amyloidosis (Seq. RDLPFYPVPID, SEQ ID NO:9) in its natural L-configuration and in the non-natural D-form. [0019] FIGS. 3A and 3B are representations of the tridimensional structure of Alzheimer's and prion .beta.-sheet breaker peptides iA.beta.5 and iPrP13, respectively. Continue reading... Full patent description for Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide or other areas of interest. ### Previous Patent Application: Ache antisense oligonucleotide as an anti-inflammatory agent Next Patent Application: Compositions and methods for the therapy and diagnosis of breast cancer Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide patent info. IP-related news and info Results in 0.20318 seconds Other interesting Feshpatents.com categories: Medical: Surgery , Surgery(2) , Surgery(3) , Drug , Drug(2) , Prosthesis , Dentistry |
||
