CN-121471381-B - TAT-PO1 and application thereof in treating neurodegenerative disease amyotrophic lateral sclerosis

Abstract

The invention relates to TAT-PO1 and application thereof in treating neurodegenerative diseases amyotrophic lateral sclerosis. The polypeptide is connected with a TAT sequence (SEQ ID NO. 1) and a PO1 sequence (SEQ ID NO. 2) through aminocaproic Acid (AHX), and the amino acid sequence is YGRKRRRQRRR { AHX } RHIFLIRHSQYHVDGSLEKDRTLTPLGREQAE. TAT-PO1 can competitively block the interaction of PGAM5 with OMA1, thereby interfering with the pathological mechanisms of ALS. The polypeptide TAT-PO1 can be prepared into medicines, and can be directly targeted to the central nervous system by intrathecal injection or intravenous administration, thereby providing a novel strategy for treating ALS. In addition, the design thought can be applied to other neurodegenerative diseases caused by abnormal protein interaction, and provides a technical paradigm for the development of related medicaments.

Inventors

• GUO XING
• ZHENG ZHILONG
• Yang Wangju
• WANG SHENGDA
• CHEN ZHEN

Assignees

• 南京医科大学

Dates

Publication Date

20260508

Application Date

20260112

Claims (5)

1. 1. The polypeptide TAT-PO1 is characterized in that the polypeptide is a TAT sequence shown in SEQ ID NO.1 and a PO1 sequence shown in SEQ ID NO.2 connected by aminocaproic acid, and the polypeptide TAT-PO1 is a TAT sequence shown in SEQ ID NO. 1-the PO1 sequence shown in SEQ ID NO.2 from the N end to the C end.
2. 2. A medicament for treating amyotrophic lateral sclerosis, comprising the polypeptide TAT-PO1 of claim 1, or a nucleotide sequence encoding the polypeptide TAT-PO1 of claim 1.
3. 3. The medicament of claim 2, further comprising a pharmaceutically acceptable adjuvant.
4. 4. The medicament according to claim 2, wherein the medicament is administered by intrathecal injection or intravenous injection.
5. 5. Use of the polypeptide TAT-PO1 of claim 1 or the medicament of claim 2 for the manufacture of a medicament for the treatment of amyotrophic lateral sclerosis.

Description

TAT-PO1 and application thereof in treating neurodegenerative disease amyotrophic lateral sclerosis Technical Field The invention belongs to the field of biological medicine, and particularly relates to TAT-PO1 and application thereof in treating neurodegenerative diseases amyotrophic lateral sclerosis. Background Amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis, ALS) is a fatal neurological disease with progressive degeneration of motor neurons as a core, with a median survival of only 3-5 years in patients due to muscle atrophy and respiratory failure. At present, only a few medicines are used for ALS treatment in batches, including riluzole, edaravone and AMX0035, but the medicines generally have the problems of limited efficacy, undefined target points and the like. Currently, clinical therapies for ALS mainly include small molecule neuroprotective agents, antioxidant stress drugs, gene therapies, and supportive therapies. Riluzole (Riluzole) can delay the survival of patients for about 3-6 months by inhibiting glutamate release and blocking sodium channels in FDA approved drugs, but does not significantly improve motor function degradation. Edaravone (Edaravone) as a free radical scavenger reduces oxidative damage, but is effective only in early ALS patients and requires repeated intravenous infusions. Sodium phenylbutyrate and taurine glycol combination drug (AMX 0035) obtained in 2022 plays a neuroprotective role by regulating endoplasmic reticulum-mitochondrial stress pathway, can delay the function decline for about 6.5 months, but still cannot reverse neuronal loss. In the field of gene therapy, antisense oligonucleotides can be targeted to silence SOD1 mutant genes, but are only applicable to ALS subtypes with specific gene mutations, and require intrathecal injection. While supportive treatment improves symptoms and quality of life, it does not alter disease progression. In general, the existing therapies have the problems of limited targets, narrow action range, short curative effect and the like, and the aim of accurately treating ALS is not realized. Especially, the existing medicine targets are ambiguous, so that the curative effect is insufficient, and accurate intervention tools aiming at pathological core signal paths are lacked. Although the clinical application of drugs (such as riluzole, edaravone and the like) can delay the course of the disease, the action mechanism of the drugs is not focused on the pathological process of the disease core, for example, the riluzole only plays a limited neuroprotection role by inhibiting the release of glutamic acid, and can not reverse the motor neuron degeneration driven by mitochondrial dysfunction, so that the clinical effect is weak. In addition, existing therapeutic strategies are mostly based on broad antioxidant or anti-inflammatory mechanisms, and lack of targeting design for ALS-specific molecular pathways leads to unstable drug efficacy and significant side effects. The problems described above arise from the complexity of the ALS pathology mechanism and limitations of existing research tools. The ALS pathogenic mechanism presents a multi-factor synergistic effect characteristic, the core pathological process of the ALS pathogenic mechanism involves dynamic cross-linking of multiple levels such as protein steady state unbalance, mitochondrial dysfunction, oxidative stress, axon transport abnormality and the like, and the existing drug development is mostly based on single target or linear signal path hypothesis, so that the complex cascade effect in the disease progression is difficult to cover. Therefore, there is a great need for new mechanisms for defining ALS disease progression, providing new targets for accurate intervention therapy of ALS patients, and developing reliable ALS treatment means. Integrated Stress Response (ISR) is an adaptive mechanism by which cells respond to a variety of pressure sources. However, recent studies have found that when they occur specifically in mitochondria (i.e., mitochondrial ISR, mtISR) and are chronically activated, they can lead to maladaptive responses, mediating neuronal dysfunction and degeneration. In ALS, mitochondrial dysfunction is in the central pathological position. Thus, targeting this pathological mtISR chronic activation may be a potential new strategy for intervention in ALS. mtISR is mediated primarily by the OMA1-DELE1-HRI signaling axis, which ultimately mediates transcriptional and translational reprogramming of cells by phosphorylating the downstream protein eIF2 alpha and inducing expression of the transcription factor ATF 4. Current studies have demonstrated abnormal activation of mtISR in a variety of ALS subtypes, but intervention strategies for this target remain to be broken through. Disclosure of Invention In view of the above technical problems in the prior art, the present invention finds that PGAM5 interacts with mtISR upstream core protease OMA1, and des