Search

CN-121991251-A - Autophagy-inducing peptides and uses thereof

CN121991251ACN 121991251 ACN121991251 ACN 121991251ACN-121991251-A

Abstract

The present disclosure relates to autophagy-inducing peptides comprising an autophagy-inducing peptide core sequence comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID No.1, and uses thereof. The disclosure also relates to nucleic acid molecules or vectors or recombinant cells for expressing the autophagy-inducing peptides, compositions comprising the autophagy-inducing peptides, and uses of the autophagy-inducing peptides in the prevention or treatment of diseases.

Inventors

  • DONG XIAONAN
  • XU XIU

Assignees

  • 广州国家实验室

Dates

Publication Date
20260508
Application Date
20260214

Claims (14)

  1. 1. An autophagy inducing peptide comprising an autophagy inducing peptide core sequence, wherein the autophagy inducing peptide core sequence has autophagy inducing activity and comprises an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID No. 1, preferably the autophagy inducing peptide core sequence comprises the amino acid sequence shown in SEQ ID No. 1, more preferably the autophagy inducing peptide core sequence is shown in SEQ ID No. 1.
  2. 2. The autophagy-inducing peptide according to claim 1, further comprising a cell penetrating peptide linked at the amino-or carboxy-terminus, preferably at the amino-terminus, of the autophagy-inducing peptide core sequence, optionally directly or via a linker.
  3. 3. The autophagy-inducing peptide of claim 1, wherein the cell penetrating peptide comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs 2-4.
  4. 4. The autophagy-inducing peptide of claim 1, wherein the autophagy-inducing peptide comprises or consists of the amino acid sequence shown in SEQ ID No.6 or 7.
  5. 5. A nucleic acid molecule encoding the autophagy inducing peptide of any one of claims 1-4.
  6. 6. A vector comprising the nucleic acid molecule of claim 5.
  7. 7. A recombinant cell comprising the nucleic acid molecule of claim 5 or the vector of claim 6.
  8. 8. A composition comprising the autophagy-inducing peptide of any one of claims 1-4.
  9. 9. A pharmaceutical composition comprising the autophagy-inducing peptide of any one of claims 1-4 and a pharmaceutically acceptable excipient.
  10. 10. An autophagy agonist comprising the autophagy-inducing peptide of any one of claims 1-4 or the composition of claim 8.
  11. 11. A method of inducing or promoting autophagy in a cell, the method comprising contacting the cell with an effective amount of the autophagy-inducing peptide of any one of claims 1-4, the composition of claim 8, the pharmaceutical composition of claim 9, or the autophagy agonist of claim 10.
  12. 12. Use of an autophagy-inducing peptide according to any one of claims 1 to 4, a composition according to claim 8, a pharmaceutical composition according to claim 9 or an autophagy agonist according to claim 10 for the preparation of a medicament for inducing or promoting autophagy.
  13. 13. Use of an autophagy-inducing peptide according to any one of claims 1-4, a composition according to claim 8, a pharmaceutical composition according to claim 9 or an autophagy agonist according to claim 10 in the manufacture of a medicament for preventing or treating a disease in a subject, wherein the subject is preferably a mammal, more preferably a human; the disease is a disease which can be prevented or treated by inducing or promoting autophagy, for example, a disorder associated with impaired autophagy, Preferably, the disease is selected from the group consisting of a tumor, cancer, pathogen infection, neurodegenerative disorder or aging, for example, The tumor is selected from an epithelial tissue-derived tumor (e.g., papilloma, adenoma, etc.), a mesenchymal tissue-derived tumor (e.g., fibroma, smooth myoma, etc.), a lymphohematopoietic tissue-derived tumor (e.g., multiple myeloma, lymphoma, etc.), a neural tissue-derived tumor (e.g., neurofibroma, neuroblastoma, etc.), or other tissue-derived tumor (e.g., melanoma, etc.); The cancer is selected from lung cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer or skin cancer; The pathogen infection comprises infection of pathogens such as viruses, bacteria, fungi, mycoplasma, chlamydia and the like, wherein (I) the virus infection comprises infection caused by coronaviridae such as new coronavirus, SARS virus, seasonal coronavirus and the like, orthomyxoviridae such as influenza A virus, influenza B virus and the like, pneumoviridae such as respiratory syncytial virus, metapneumovirus and the like, adenoviruses such as parainfluenza virus, measles virus, mumps virus and the like, picornaviridae such as enteroviruses, rhinoviruses, polioviruses, coxsackie virus B3 and the like, picornaviridae such as chikungunya virus, western equine encephalitis virus and the like, flaviviridae such as hepatitis C virus, szebra virus, west nile encephalitis virus, dengue virus and the like, orthomyxoviridae such as varicella-zoster virus, human cytomegalovirus, nasopharyngeal sarcoma virus and the like, adenoviridae such as adenovirus type 5 and the like, pneum virus and the like, pneumovieae such as varicella virus, kaposi virus and the like, and the virus of the family of the order of the virus such as the virus, the virus of the Willionaceae such as the Willipes, the Wikid, the virus, the Rheudragae virus and the Rheuviridae virus, the Rheumaae virus and the Rheumatoid virus and the virus; (ii) Bacterial infections include infections caused by pathogenic bacteria of the family Mycobacteriaceae such as Mycobacterium tuberculosis, of the family Streptococcaceae such as Streptococcus pneumoniae, of the family Sinorhizodiac such as Haemophilus influenzae, of the family Staphylococcus such as Staphylococcus aureus, of the family Enterobacteriaceae such as Klebsiella pneumoniae, or of the family Pseudomonas aeruginosa; (iii) The fungal infection includes diseases caused by infection with Aspergillus such as pulmonary aspergillosis, nasal sinus aspergillosis, invasive aspergillosis, superficial aspergillosis, allergic bronchopulmonary aspergillosis, acute pulmonary histoplasmosis, progressive histoplasmosis, chronic cavity histoplasmosis, etc., diseases caused by infection with histoplasmosis such as invasive candidiasis, esophageal candidiasis, etc., diseases caused by infection with Candida such as acute primary coccidioidomycosis, progressive coccidioidomycosis, etc., diseases caused by infection with coccidiomycosis such as nasal and cerebral mucosis, mucormycosis dermalis, etc., diseases caused by infection with blastomycosis such as dermatitis, diseases caused by infection with cryptococcosis such as paracoccidiosis, diseases caused by infection with paracoccidiomycosis such as sporotrichincosis, diseases caused by infection with mycosis such as mycosis, skin infection with mycosis such as mycosis or with candida such as epidermomyces, or diseases caused by infection with skin such as dermatophytes, sporotrichiomycosis and dermatophytes such as dermatophytes (Iv) Mycoplasma or chlamydia infections include infections caused by mycoplasma pathogens such as mycoplasma pneumoniae or chlamydiaceae pathogens such as chlamydia trachomatis, respectively.
  14. 14. A conjugate comprising the autophagy-inducing peptide of any one of claims 1-4 and one or more active agents, wherein the active agents are conjugated to the autophagy-inducing peptide, optionally the active agents are selected from a therapeutic agent, a diagnostic agent, a detection agent, or an imaging agent.

Description

Autophagy-inducing peptides and uses thereof Technical Field The present application is in the field of biology, in particular, the present application relates to autophagy inducing peptides and uses thereof. The application also relates to a nucleic acid molecule or vector or recombinant cell for expressing said autophagy-inducing peptide, a composition comprising said autophagy-inducing peptide and the use of said autophagy-inducing peptide in the prevention or treatment of a disease. Background Autophagy (Autophagy) is an evolutionarily conserved mechanism of cell degradation. Cells maintain stable intracellular conditions by encapsulating cytoplasmic components, damaged organelles, abnormal protein aggregates, or exogenous infectious substances such as viruses, bacteria, etc., into vesicles (i.e., autophagosomes) and fusing with lysosomes to form autophagic lysosomes to degrade the encapsulated contents. Autophagy plays a vital role in controlling pathogenic infection, inhibiting tumorigenesis, inhibiting neurodegenerative disease, resisting aging and other various biological functions in mammals. Many human diseases occur and develop in close association with reduced or defective autophagy functions, including cancer, aging, immune system disorders, muscle diseases, metabolic disorders, inflammation, age-related macular degeneration, and neurodegenerative diseases (e.g., alzheimer's disease, parkinson's disease, huntington's disease, tauopathies, amyotrophic lateral sclerosis, etc.). Selective delivery of harmful contents (e.g., neurotoxic protein aggregates, viral proteins) in cells to lysosomal degradation clearance by targeting autophagy processes is considered a valuable new means of treating a range of debilitating diseases (e.g., neurodegenerative diseases) and infectious diseases. The discovery of autophagy mechanisms was awarded in 2016 for a Nobel medical and physiological prize. Autophagy activation is widely regarded by the international academia and industry as a therapeutic intervention tool with great application value. Currently, the application basic research in the aspect of autophagy regulation drug development is significantly behind compared with the progress of rapid progress in the basic research field of autophagy molecule mechanisms. To date, most agents used to induce autophagy, such as rapamycin (rapamycin) and Torin 1, while agonizing the autophagy pathway, also inhibit mTOR-mediated multiple downstream signaling pathway functions, potentially causing side effects such as immunosuppression. Thus, there is a great global need for specific autophagy agonists/inducers that can enter the clinical trial phase. BCL2 (NCBI Gene ID:596;Reference Sequence ID:NP-000624) is an important autophagy and apoptosis signaling pathway inhibiting protein. BCL2 inhibits autophagy by interacting with autophagy key molecule machine protein BECN1 (NCBI Gene ID:8678;Reference Sequence ID: np_ 001300927) to inhibit activation of the key kinase complex type III phosphatidylinositol 3-kinase (PI 3KC 3) complex that mediates autophagosome initiation. Meanwhile, BCL2 inhibits apoptosis by preventing mitochondrial outer membrane permeabilization and cytochrome C release from mitochondria to the cytoplasm caused by apoptosis activation signals through binding to pro-apoptotic proteins (e.g., BAX and BAK). BCL2 is therefore considered an important target for pro-autophagy and pro-apoptotic drugs. For example, a class of small molecules targeting BCL2, represented by ABT-737 (CAS ID: 852808-04-9), can induce both autophagy and apoptosis. There is currently no pro-autophagy or pro-apoptotic drug that is capable of specifically modulating autophagy or apoptosis by targeting BCL 2. Yu-Zu Pan et al （"Structural insights for selective disruption of Beclin 1 binding to Bcl-2",Communications Biology,, volume 6, phase 1, pages 1-13) disclose nuclear magnetic resonance patterns of BH3 polypeptide, ABT-737, compound 35 from BECN, respectively, with two lengths of artificial chimeric proteins (BCL 2-xL) consisting of BCL2 and BCL2L1 (NCBI Gene ID:598;Reference Sequence ID: NP-001304848), which suggest that all three autophagic-activating molecules bind to two lengths of BCL2-xL artificial chimeric proteins, and speculate about the sites at which these three molecules bind to these two artificial chimeric proteins, and that these findings agree with the knowledge in the prior academy that they exert biological activity for direct binding to the native BCL2 protein. However, this study did not reveal the function of the perimembrane region of BCL2 to regulate autophagy or apoptosis. Thus, there remains a need in the art to develop novel autophagy-inducing peptides. Disclosure of Invention The inventor designs and prepares an autophagy-inducing peptide, and experiments prove that the autophagy-inducing peptide can induce autophagy activation in cells from different tissues, inhibit various human virus infections, effectiv