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  Stereoselective antifibrillogenic peptides and peptidomimetics thereofUSPTO Application #: 20060199771Title: Stereoselective antifibrillogenic peptides and peptidomimetics thereof Abstract: The present invention relates to antifibrillogenic agents for inhibiting amyloidosis and/or for cytoprotection for the treatment of amyloidosis disorders. These agents include peptides, isomers thereof and peptidomimetic compounds thereof. These agents comprise a peptide having a sequence identified from the glycosaminoglycan (GAG) binding region and the prot-prot interaction region of the amyloid protein. The peptide has at least one [D] amino acid isomer substitution. The invention also relates to the peptide bound to a label for in vivo imaging of amyloid deposits. (end of abstract) Agent: Clark & Elbing LLP - Boston, MA, US Inventors: Robert Chalifour, Francine Gervais, Ajay Gupta USPTO Applicaton #: 20060199771 - Class: 514017000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 5 Or 6 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20060199771. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. Ser. No. 10/009,122, filed Jun. 18, 2002 (pending), which claims priority under 35 U.S.C. .sctn. 371 from PCT/CA00/00515, filed May 4, 2000, which claims priority from U.S. Ser. No. 60/132,592, filed May 5, 1999, the contents of each of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] (a) Field of the Invention [0003] The invention relates to agents having potent antifibrillogenic activity for the treatment of amyloidosis disorders and for imaging of amyloid deposits. These agents include peptides and peptidomimetic compounds thereof. [0004] (b) Description of Prior Art [0005] Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibers. Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits that are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits share common morphologic properties, stain with specific dyes (e.g. Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural, x-ray diffraction and infrared spectra features. [0006] Some amyloidotic diseases can be idiopathic but most of these diseases appear as a complication of a previously existing disorder. For example, primary amyloidosis can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma. Secondary amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis). A familial form of secondary amyloidosis is also seen in Familial Mediterranean Fever (FMF). This familial type of amyloidosis, as one of the other types of familial amyloidosis, is genetically inherited and is found in specific population groups. Isolated forms of amyloidosis are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by congophilic cerebral angiopathy, neuritic plaques and neurofibrillary tangles. In this case, the plaque and blood vessel amyloid is formed by the deposition of fibrillar A.beta. amyloid protein. In adult-onset diabetes, amyloids containing the IAPP amyloid protein accumulate in the pancreas. Other systemic diseases, complications of long-term hemodialysis and sequelae of long-standing inflammation or plasma cell dyscrasias are characterized by the accumulation of amyloids systemically. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition. [0007] Once these amyloids have formed, there is no known, widely accepted therapy or treatment that significantly dissolves the deposits in situ. [0008] Each amyloidogenic protein has the ability to organize into .beta.-sheet and to form insoluble fibrils that get deposited extracellularly. Each amyloidogenic protein, although different in amino acid sequence has the same property of forming fibrils and binding to other elements such as proteoglycan (glycosaminoglycan), amyloid P and complement component. Moreover, each amyloidogenic protein has amino acid sequences, which, although different, will show similarities such as regions with the ability to bind to GAG's (referred to as the GAG binding site) as well as other regions that will promote .beta.-sheet formation referred to as .beta.-sheet region. [0009] In specific cases, amyloidotic fibrils once deposited can become toxic to the surrounding cells. As per example, the A.beta. fibrils organized as senile plaques have been shown to be associated with dead neuronal cells and microgliosis in patients with Alzheimer's disease. When tested in vitro, A.beta. peptide was shown to be capable of triggering an activation process of the microglia (brain macrophages), which would explain the presence of microgliosis and brain inflammation found in the brain of patients with Alzheimer's disease. [0010] In another type of amyloidosis seen in patients with Type II diabetes, the amyloidogenic protein IAPP, has been shown to induce .beta.-islet cell toxicity in vitro. Hence, appearance of IAPP fibrils in the pancreas of Type II diabetic patients could contribute to the loss of the .beta. islet cells (Langerhans) and organ dysfunction. [0011] Particularly, in patients with Alzheimer's Disease, an agent capable 1) of preventing amyloid fibril formation and deposition and 2) of directly or indirectly inhibiting A.beta.-induced neurotoxicity and inflammation (microgliosis), could be a treatment of choice to prevent and arrest the development of Alzheimer's disease. [0012] It would be highly desirable to be provided with agents having potent antifibrillogenic activity for the treatment of amyloidosis disorders. SUMMARY OF THE INVENTION [0013] One aim of the present invention is to provide agents having potent antifibrillogenic activity for the treatment of amyloidosis disorders. [0014] Another aim of the present invention is to provide a method for the treatment of amyloidosis disorders, such as Alzheimer's' disease. [0015] A number of strategies for possible therapeutic intervention in amyloid development have been proposed. These strategies include reduction of the pool of precursor proteins, prevention of the interaction of precursor proteins and disruption of preformed amyloid. The present invention deals mainly with the second approach, prevention of precursor protein interactions. The ideal molecule to fulfill this function, would interact specifically with the amyloid protein and would in so doing prevent the protein from interacting with itself. When dealing with molecules that are chiral, it is standard practice to identify which of the stereoisomers possesses the activity, since in general, activity can be attributed to one or the other of the isomers. By using a stereochemically pure isomer, side reactions can be avoided or reduced. [0016] In accordance with one embodiment of the present invention there is provided an antifibrillogenic agent for inhibiting amyloidosis and/or for cytoprotection, which comprises a peptide of Formula I, an isomer thereof, a retro or a retro-inverso isomer thereof or a peptidomimetic thereof: Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4 I wherein, Xaa.sub.1 is absent or selected from the group consisting of Lys, Lys-Lys, Xaa.sub.5-Lys-, and Ala; Xaa.sub.5 is absent or selected from the group consisting of His-Gln-, His-His-Gln-, Val-His-His-Gln-, Glu-Val-His-His-Gln-, Asp-Asp-Asp-, Lys-Val-Asp-Asp-Gln-Asp-, Gln-; Xaa.sub.2 is absent or any amino acid; Xaa.sub.3 is absent, Val or Phe; Xaa.sub.4 is absent or selected from the group consisting of Phe, Phe-NH.sub.2, Phe-Phe, Phe-Phe-Ala, Phe-Phe-Ala-NH.sub.2, Phe-Phe-Ala-Gln, Phe-Phe-Ala-Gln-NH.sub.2, Val-Leu-Lys, Val-Leu-Lys-NH.sub.2; wherein the peptide of formula I contains at least one Lys or Asp; and wherein the peptide has at least one [D] amino acid residue, with the proviso that Lys-Lys-Leu-Val-Phe-Phe-Ala is an all-[D] peptide; and with the proviso that when Xaa.sub.5 is Lys-Val-Asp-Asp-Gln-Asp- all of Xaa.sub.2, Xaa.sub.3, and Xaa.sub.4 are absent. [0017] Preferably, Xaa.sub.2 is a hydrophobic amino acid residue such as a leucine residue. [0018] In one embodiment of the invention, the peptide of formula I has at least two [D] amino acid residues, and more preferably at least three [D] amino acid residues. Optionally, the peptide of formula I has one [L] amino acid residue, or more preferably the peptide is an all-[D] isomer peptide. [0019] In another embodiment of the invention, the peptide of Formula I is selected from the group consisting of: TABLE-US-00001 Lys-Ile-Val-Phe-Phe-Ala; (SEQ ID NO:1) Lys-Lys-Leu-Val-Phe-Phe-Ala; (SEQ ID NO:2) Lys-Leu-Val-Phe-Phe-Ala; (SEQ ID NO:3) Lys-Phe-Val-Phe-Phe-Ala; (SEQ ID NO:4) Ala-Phe-Phe-Val-Leu-Lys; (SEQ ID NO:5) Lys-Leu-Val-Phe; (SEQ ID NO:6) Lys-Ala-Val-Phe-Phe-Ala; (SEQ ID NO:7) Lys-Leu-Val-Phe-Phe; (SEQ ID NO:8) Lys-Val-Val-Phe-Phe-Ala; (SEQ ID NO:9) Lys-Ile-Val-Phe-Phe-Ala-NH.sub.2; (SEQ ID NO:10) Lys-Leu-Val-Phe-Phe-Ala-NH.sub.2; (SEQ ID NO:11) Lys-Phe-Val-Phe-Phe-Ala-NH.sub.2; (SEQ ID NO:12) Ala-Phe-Phe-Val-Leu-Lys-NH.sub.2; (SEQ ID NO:13) Lys-Leu-Val-Phe-NH.sub.2; (SEQ ID NO:14) Lys-Ala-Val-Phe-Phe-Ala-NH.sub.2; (SEQ ID NO:15) Lys-Leu-Val-Phe-Phe-NH.sub.2; (SEQ ID NO:16) Lys-Val-Val-Phe-Phe-Ala-NH.sub.2; (SEQ ID NO:17) Lys-Leu-Val-Phe-Phe-Ala-Gln; (SEQ ID NO:18) Lys-Leu-Val-Phe-Phe-Ala-Gln-NH.sub.2; (SEQ ID NO:19) His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala- (SEQ ID NO:20) NH.sub.2; Asp-Asp-Asp; (SEQ ID NO:21) Lys-Val-Asp-Asp-Gln-Asp; (SEQ ID NO:22) His-His-Gln-Lys; (SEQ ID NO:23) and Gln-Lys-Leu-Val-Phe-Phe-NH.sub.2. (SEQ ID NO:24) [0020] More preferably, the peptide of formula I is a peptide as set forth in SEQ ID NO:2 or SEQ ID NO:3. [0021] In accordance with one embodiment of the present invention there is provided a labeled conjugate for in vivo imaging of amyloid plaque, which comprises a conjugate of formula II: A-B-C II wherein A is an amyloid plaque-targeting moiety selected from the group consisting of a peptide of Formula I as defined above, an isomer thereof, a retro or a retro-inverso isomer thereof and a peptidomimetic thereof, wherein B is a linker portion allowing attachment of the amyloid plaque-targeting moiety to C; and wherein C is a label that allows for in vivo imaging. Preferably, the linker portion B is selected from the group consisting of Glucose and Phe. Preferably, the label C is .sup.99mTc. Continue reading... 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