CN-121987759-A - New application of polypeptide, polypeptide derivative and polypeptide conjugate

Abstract

The invention relates to a polypeptide, a derivative of the polypeptide, a conjugate of the polypeptide and novel application thereof. The amino acid sequence of the polypeptide is shown as SEQ ID No. 1. The polypeptide can reverse the attenuation of the proliferation activity of the mouse hippocampal neuron cells HT-22 induced by the Abeta 1‑40 oligomer, reduce the over expression of p-Tau protein in the HT-22 cells and the damage of cell axon structures caused by the Abeta 1‑40 oligomer, promote the proliferation and differentiation of a neural stem cell line C17.2 after the Abeta 1‑40 oligomer treatment, remarkably improve the related pathological changes of the mouse brain cortex and the hippocampus, and promote the neurogenesis of the hippocampus, thereby realizing the recovery of the related cognitive functions such as learning, memory and the like of the mice with the Alzheimer disease model, playing the role of treating the Alzheimer disease, and can be used for preparing low-toxicity safe and effective Alzheimer disease therapeutic agents, thereby providing a novel approach for treating the Alzheimer disease.

Inventors

• QI HONGYI
• LI LIN
• LI LI

Assignees

• 西南大学

Dates

Publication Date

20260508

Application Date

20251106

Priority Date

20241106

Claims (9)

1. 1. Application of polypeptide, polypeptide derivative and polypeptide conjugate in preparing medicine for treating Alzheimer disease is characterized in that the amino acid sequence of the polypeptide is shown in SEQ ID No. 1: Ala-Leu-Pro-Ala-Pro-Gly-Thr-Leu。
2. 2. The use according to claim 1, wherein the conjugate of the polypeptide is a conjugate of a polypeptide having the amino acid sequence shown in SEQ ID No.1 and a conjugate moiety, wherein the conjugate moiety is at least one member selected from the group consisting of a radionuclide, a drug, a toxin, a cytokine, an enzyme, a fluorescein, a carrier protein, and a biotin.
3. 3. The use according to claim 1, wherein the alzheimer's disease comprises pathological symptoms associated with alzheimer's disease.
4. 4. The use according to claim 3, wherein the pathological symptoms associated with alzheimer's disease include senile plaques formed by beta amyloid deposition, neurofibrillary tangles formed by Tau protein hyperphosphorylation, neuronal damage, cognitive dysfunction, speech and motor deficits, mental and psychological disorders.
5. 5. The use according to claim 4, wherein the cognitive dysfunction comprises impaired learning and memory, the speech and motor deficits comprise aphasia, disorganization, slow movement, and the mental and psychological disorders comprise depression, loss of emotion.
6. 6. The use according to claim 1, wherein the pharmaceutical dosage form comprises one of an oral liquid, a tablet, a granule, a capsule, a dripping pill, an injection, a transdermal absorption preparation, a nose drop, an external lotion and an in vivo implantation preparation.
7. 7. The application of polypeptide, polypeptide derivative and polypeptide conjugate in preparing health product for improving memory is characterized in that the amino acid sequence of the polypeptide is shown as SEQ ID No.1, ala-Leu-Pro-Ala-Pro-Gly-Thr-Leu.
8. 8. The use according to claim 7, wherein the conjugate of the polypeptide is a conjugate of a polypeptide having the amino acid sequence shown in SEQ ID No.1 and a conjugate moiety, wherein the conjugate moiety is at least one member selected from the group consisting of a radionuclide, a drug, a toxin, a cytokine, an enzyme, a fluorescein, a carrier protein, and a biotin.
9. 9. The use according to claim 7, wherein the formulation of the health product comprises one of an oral liquid, a tablet, a granule, a capsule, a dripping pill, an injection, a transdermal absorption preparation, a nasal drop, a lotion for external use, and an in vivo implantation preparation.

Description

New application of polypeptide, polypeptide derivative and polypeptide conjugate Technical Field The invention belongs to the technical field of medicines, and particularly relates to a polypeptide, a derivative of the polypeptide, a conjugate of the polypeptide, a new application of the conjugate. Background Alzheimer's Disease (AD), commonly known as "senile dementia", is the most common type of neurodegenerative disease in the current generation, and patients usually have symptoms such as memory decline, impaired learning ability, dysthymia, and loss of motor ability, and is clinically characterized by comprehensive dementia such as memory impairment, aphasia, disuse, impairment of vision space skills, dysfunction in executive function, and personality and behavior change. According to the latest data of world health organization, the number of people suffering from dementia worldwide is about 5500 ten thousand by 2019, and the number of people suffering from dementia is expected to increase to 1.39 hundred million in 2050. In China, about 1000 tens of thousands of elderly people over 60 years old have Alzheimer's disease, and it is expected that the number of patients in 2050 will exceed 4000 tens of thousands. Clearly, with the increasing aging of the population, alzheimer's disease has become a major public health problem affecting global population health and quality of life, threatening the health of the elderly at all times. Major pathological changes in AD patients include deposition of β -Amyloid (amyoid- β, aβ) in the brain to form senile plaques (Senile plaques, SP), hyperphosphorylation of Tau protein to form neurofibrillary tangles (Neurofibrillary tangles, NFT), hippocampal neuronal cytopenia, significant reductions in choline acetyltransferase (Choline acetyltransferase, chAT) and acetylcholine (Acetylcholine, ach) levels, etc., while different areas of the brain of the patient also undergo neuronal loss to varying degrees with pathological progression. The pathogenesis of the human body is indistinct due to various pathogenesis factors and complex pathological characteristics, and mainly comprises the following hypotheses of Abeta deposition and toxic effect hypothesis, tau protein hyperphosphorylation hypothesis, cholinergic dysfunction hypothesis, oxidative stress hypothesis, excitatory amino acid toxicity hypothesis, mitochondrial dysfunction hypothesis and the like. The complicated pathogenesis also causes the treatment progress of Alzheimer's disease to be lagged, and the treatment progress of Alzheimer's disease brings serious adverse effects to the daily life of patients, and is also a main cause of household and social burden. The current therapeutic drugs for Alzheimer's disease mainly include two major classes, namely acetylcholinesterase inhibitors (Acetylcholinesterase Inhibitors, ach EI) developed according to the cholinergic function impairment hypothesis, such as donepezil, rivastigmine, galantamine, etc., and NMDA receptor antagonists developed according to the excitatory amino acid toxicity hypothesis, such as hydrochloric acid Jin Meigang. However, the medicines only assist in improving the life quality of AD patients, and have no obvious improvement or delay effect on disease sources and disease processes of the patients. In addition, patients taking the medicines can have adverse reactions such as vomiting, insomnia, diarrhea and the like, the compliance of the patients is not high, and the treatment effect is not ideal. Next, aduhelm (aducanaumab, a Du Nashan antibody) and Leqembi developed according to the hypothesis of aβ deposition and toxic effects in recent years are also successively marketed by FDA approval, but are expensive and their indications and clinical actual efficacy remain to be confirmed. Although there is no clear statement about the pathogenesis of AD, AD patients eventually suffer from brain neuron damage loss, nerve circuit interruption, vascular abnormalities, and the like, thereby causing macroscopic brain atrophy. Therefore, promoting the regeneration of neurons, supplementing lost neurons and recovering the neural network has important significance for the prevention and treatment of AD. Neurogenesis refers to the differentiation of Neural Stem Cells (NSCs) under specific conditions to give rise to new neural cells (neurons, oligodendrocytes, astrocytes) which are involved in the repair process of neural function. Studies have demonstrated that the subventricular zone of the ventral side ventricle of the forebrain (subventricular zone, SVZ) and the granulosa cell lower layer of the hippocampal dentate gyrus (subgranular zone, SGZ) are two key areas of neurogenesis in the brain of adult mammals. It has been found that neural stem cells in the hippocampus of the adult brain have the ability to produce neonatal neurons throughout the life of mammals, a process known as adult hippocampal neurogenesis (adult hippocampal neurogenesis, AHN). Recent y