Description:FIELD OF INVENTION
The present disclosure relates to developing a therapeutic peptide against Alzheimer’s disease. Particularly, the present disclosure is related to designing and developing the synthetic peptide from F-spondin to treat Alzheimer’s disease condition.
BACKGROUND OF INVENTION
Alzheimer’s disease (AD) is the most common fatal age-related neurodegenerative disease and it is reported to be the fifth leading cause of death worldwide. Accumulation of extracellular amyloid plaques and formation of intracellular neurofibrillary tangles are the key pathological characteristics of AD. Aß generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: ß-secretase and ?-secretase. Inhibiting amyloid aggregation using peptide-based inhibitors have emerged as a significant therapeutic approach to alleviate AD.
The complicated and multiple characteristics of AD make it an incurable disease. AD has limited treatment options and further, the high failure rates of lead compounds in clinical trials restrict the number of approved drugs for AD. Currently, there are no FDA-approved peptide-based drugs to treat AD. ADUHELM (Aducanumab) is an FDA-approved antibody used in the management and treatment of Alzheimer’s disease. It’s an amyloid beta-directed monoclonal antibody (mAb) and targets the severe form of amyloid plaques. It is used in the treatment of patients with mild cognitive impairment stage of AD. LEQEMBI (Lecanemab) is yet another FDA-approved antibody used in the treatment of AD. It is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against the soluble and insoluble forms of amyloid beta (Aß) aggregates. Leqembi binds strongly to the smaller and soluble form of amyloid plaque. However, administration of both these mAb poses risks of developing amyloid-related imaging abnormalities (ARIA).
Currently, there is no effective treatment for Alzheimer’s disease which is a mounting and extremely costly public health problem. For the past one decade, peptide therapeutics has played a significant role in drug discovery. Consequently, there is an increased interest on peptides in pharmaceutical research and development. High specificity, high biological activity, low cost and high membrane penetration ability makes them advantageous over small molecules. Many of the clinically approved peptide based drugs show promising biological activity and have entered into human clinical trials but very few of them have been approved by the US FDA. Owing to the continuously escalating global impact of AD, there is an immense need to develop disease modifying drugs. The present invention thus aims to identify and develop synthetic peptides to treat and manage AD.
SUMMARY OF INVENTION
AD is a progressive neurodegenerative disease that affects cognitive functions, including learning and memory. Very few approved treatments such as acetylcholinesterase inhibitors such as doneprezil, are limited to the symptomatic control of AD and possess associated side effects resulting in discontinuation of treatment. One possible therapeutic approach is to target the enzymes that process amyloidogenesis. Aß is derived from the amyloid precursor protein (APP) through sequential cleavages by beta site amyloid precursor protein cleaving the enzyme 1 (BACE1) and ?-secretase. Reduction of Aß through inhibition of BACE1 has been studied as a treatment strategy for AD. However BACE1 not only initiates amyloidogenesis, but also conducts other functions in brain physiological activity, such as processing sodium current, synaptic transmission and myelination. Thus inhibition of BACE1 could cause dysfunctions in the brain physiological activities.
Current drawbacks can be overcome by using SPONDIN also known as F-spondin as a novel therapeutic approach. F- Spondin is an extracellular matrix protein, consisting of three domains: spondin, reelin and thrombospondin and plays an essential role in neuronal survival and the migration of commissural axons. Spondin binds to the BACE1 cleavage site of APP and prevents further cleavage and release of Aß. Spondin interacts with the apolipoprotein E receptor and clusters with APP resulting in decreased production of Aß potentially inhibiting the amyloidogenic pathway.
Non-fucosylated glycoconjugates that cause the defects in mental development are unknown. It is interesting to point out that the thrombospondin type I repeat (TSR) proteins TSP-1, F-spondin, Unc-5, and the semaphorins 5A and B, all play a major role in neuronal development. Further investigations are also needed to identify what triggers the down-regulation of F-spondin in AD and under what circumstances this protein gets activated to interfere eventually with MAPT protein phosphorylation and the chaperone/proteasomal degradation system in order to develop better therapeutics for the treatment of AD.
The present invention involves the development of peptides from F-spondin which is an extracellular matrix protein involved in the growth of axons during differentiation of neural cells and reduction of Aß plaque load. The present invention relates to the design and development of peptides for treating Alzheimer’s disease by preventing amyloid-beta protein aggregations and exerting neuroprotective effects.
In an embodiment, the invention comprises, consists essentially, or consists of amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO:108, SEQ ID NO: 109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO: 159, SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO:182, SEQ ID NO: 183, SEQ ID NO:184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, and SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226.
In one instance, the peptide is a design of F-Spondin that are useful in the treatment of Alzheimer’s.
In one instance, the peptide contributes to positive regulation of amyloid precursor protein (APP) catabolic process.
In one instance, the peptide binds to the central extracellular domain of APP and inhibits beta-secretase cleavage of APP.
DETAILED DESCRIPTION
Those skilled in the art can select, without requiring excessive trial and error, a peptide that exerts the action and effect to treat cognitive impairment induced by amyloid ß protein among the peptides having the amino acid sequences as defined in the embodiments, and use the selected peptide in the present invention.
The “amyloid ß protein” herein is a polypeptide generally known to accumulate in the brain as Alzheimer's disease progresses, and may be in any of the form of a monomer composed of a single polypeptide chain, the form of an oligomer composed of several (usually 2 to 6) polypeptide chains, and the form of an aggregate composed of a plurality of such oligomers. The “cognitive impairment induced by amyloid ß protein” includes memory disorder, disorientation, learning disability, disturbance of attention, and disorders of spatial cognitive function and problem-solving abilities, which are generally known as symptoms of Alzheimer's disease.
As used herein the terms “amino acid” and “amino acid identity” refers to one of the 20 naturally occurring amino acids or any non-natural analogues that may be in any of the antibodies, variants, or fragments disclosed. Thus “amino acid” as used herein means both naturally occurring and synthetic amino acids. “Amino acid” also includes amino acid residues such as proline and hydroxyproline. The side chain may be in either the (R) or the (S) configuration. In an aspect, the amino acids are in the D- or L-configuration. If non-naturally occurring side chains are used, non-amino acid substituents may be used, for example to prevent or retard in vivo degradation.
As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, relieving, delaying onset of, inhibiting or slowing progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition. For example, the disease, disorder, and/or condition can be Alzheimer’s disease.
In an embodiment, the invention comprises, consists essentially, or consists of amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO:108, SEQ ID NO: 109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO: 159, SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO:182, SEQ ID NO: 183, SEQ ID NO:184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, and SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226.
In one instance, the peptide comprises or consists of 11 amino acids as in amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64.
In one instance, the peptide comprises or consists of 15 amino acids as in amino acid sequences of SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86.
In one instance, the peptide comprises or consists of 14 amino acids as in amino acid sequences of SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO:108, SEQ ID NO: 109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO:124.
In one instance, the peptide comprises or consists of 19 amino acids as in amino acid sequences of SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151.
In one instance, the peptide comprises or consists of 20 amino acids as in amino acid sequences of SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO: 159, SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173.
In one instance, the peptide comprises or consists of 21 amino acids as in amino acid sequences of SEQ ID NO: 174, SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180.
In one instance, the peptide comprises or consists of 28 amino acids as in amino acid sequences of SEQ ID NO: 181, SEQ ID NO:182, SEQ ID NO: 183, SEQ ID NO:184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187
In one instance, the peptide comprises or consists of 29 amino acids as in amino acid sequences of SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, and SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226.
In one instance, the peptide is a design of F-Spondin that are useful in the treatment of Alzheimer’s.
In one instance, the peptide promotes the attachment of spinal cord and sensory neuron cells.
In one instance, the peptide contribute to the growth and guidance of axons in both the spinal cord and the periphery nervous system.
In one instance, the peptide contributes to negative regulation of amyloid-beta formation.
In one instance, the peptide contributes to positive regulation of amyloid precursor protein (APP) catabolic process.
In one instance, the peptide binds to the central extracellular domain of APP and inhibits beta-secretase cleavage of APP.
The peptides used in the embodiments can be prepared by a known method, and the method of preparation is not limited. For example, a peptide consisting of a desired amino acid sequence can be prepared by sequentially linking amino acids using the Fmoc-peptide solid-phase synthesis, which is a conventionally used method for peptide synthesis.
The therapeutic agent according to the present invention comprises the peptide selected from SEQ ID NO:1 to SEQ ID NO: 226, or the predetermined peptide contained therein, can be suitably used as an effective component of therapeutic drugs for Alzheimer's disease. However, the embodiment of the therapeutic agent according to the present invention or the predetermined peptide contained therein is not limited to the uses for such drugs (pharmaceuticals).
The therapeutic agent according to the present invention comprises the peptide selected from SEQ ID NO:1 to SEQ ID NO: 226 which may be prepared as an agent containing only a predetermined peptide as an effective component, and the peptide alone or a solution of the peptide in an appropriate solvent (for example, artificial cerebrospinal fluid) may be used for the administration or the addition. Alternatively, the therapeutic agent according to the present invention may be prepared as a formulation according to the therapeutic peptide described herein, to be used for the administration or the addition.
The therapeutic drug for Alzheimer's disease according to the present invention contains the therapeutic agent according to the present invention, and may optionally contain, for example, an effective component other than the therapeutic agent (predetermined peptide) of the present invention, a pharmaceutically acceptable carrier suitable for the dosage form, and/or other pharmaceutical additives used for common pharmaceuticals. That is, the therapeutic drug for Alzheimer's disease according to the present invention may be prepared as a pharmaceutical composition containing such a component(s).
Examples of the dosage form of the therapeutic drug which may be selected include dosage forms for oral administration, such as tablets, capsules, soft capsules, granules, powders, fine granules, (dry) syrups, solutions, and suspensions; and dosage forms for parenteral administration, such as injections for subcutaneous, intramuscular, or intravenous administration, drops, suppositories, and transnasal agents. , Claims:We claim;
A method for treatment of cognitive impairment induced by amyloid Beta protein or Alzheimer’s disease, comprising:
A step of administering an effective amount of a peptide selected from the group consisting of the following claims 1 to 7 to a mammal which developed cognitive impairment induced by amyloid beta protein or Alzheimer’s disease, or to an animal model thereof.
1. A peptide comprising the amino acid sequence as in SEQ ID No: 1 to SEQ ID NO: 226 or a fragment or a variant or has at least 85% sequence identity, at least 90% sequence identity, at least 95% sequence identity or at least 98% sequence identity to any of SEQ ID No: 1 to SEQ ID NO: 226
2. A peptide comprising of amino acid sequence of SEQ ID No: 1 to SEQ ID NO: 226, except that one, two or three amino acids are altered by any one or more of deletion, addition, substitution and side chain modification.
3. A peptide which is a partial sequence of the amino acid sequence of SEQ ID No: 1 to SEQ ID NO: 226.
4. A peptide as claimed in claims 1 to 3, which promotes the attachment of spinal cord and sensory neuron cells.
5. A peptide as claimed in claims 1 to 3, which contribute to the growth and guidance of axons in both the spinal cord and the periphery nervous system.
6. A peptide as claimed in claims 1 to 3, which contribute to negative regulation of amyloid-beta formation.
7. A peptide as claimed in claims 1 to 3, which contributes to positive regulation of amyloid precursor protein (APP) catabolic process.
8. A peptide as claimed in claim 1 to 3 binds to the central extracellular domain of APP and inhibits beta-secretase cleavage of APP.