WO2025149089A1 - Composition et procédé de sédation - Google Patents

Composition et procédé de sédation

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Publication number
WO2025149089A1
WO2025149089A1 PCT/CN2025/072613 CN2025072613W WO2025149089A1 WO 2025149089 A1 WO2025149089 A1 WO 2025149089A1 CN 2025072613 W CN2025072613 W CN 2025072613W WO 2025149089 A1 WO2025149089 A1 WO 2025149089A1
Authority
WO
WIPO (PCT)
Prior art keywords
sedation
active peptide
amino acid
sequence
disorder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/072613
Other languages
English (en)
Chinese (zh)
Inventor
陈锦辉
王晓婷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huiankai Xiamen Pharmaceutical Technology Co Ltd
Quanzhou Haichuang Pharmaceutical Technology Co Ltd
Suzhou Glenkol Pharma Technology Co Ltd
Original Assignee
Huiankai Xiamen Pharmaceutical Technology Co Ltd
Quanzhou Haichuang Pharmaceutical Technology Co Ltd
Suzhou Glenkol Pharma Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Huiankai Xiamen Pharmaceutical Technology Co Ltd, Quanzhou Haichuang Pharmaceutical Technology Co Ltd, Suzhou Glenkol Pharma Technology Co Ltd filed Critical Huiankai Xiamen Pharmaceutical Technology Co Ltd
Publication of WO2025149089A1 publication Critical patent/WO2025149089A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention belongs to the technical field of pharmaceutical compounds, and in particular relates to the sedative use of active peptides.
  • Sedatives are drugs that have an inhibitory effect on brain nerve activity. They are needed in many cases, for example, to suppress the normal activity level of the central nervous system to achieve surgical sedation; to suppress excessive excitement of the central nervous system, help relieve people's anxiety, treat mental tension, and calm agitation symptoms caused by mental illness, neurological disease or other diseases.
  • sedative drugs include benzodiazepines Drugs, non-benzodiazepines Drugs such as midazolam, etomidate, propofol and dexmedetomidine have their own disadvantages.
  • midazolam will have an accumulation effect, resulting in respiratory depression and delayed awakening; etomidate is prone to muscle tremor and injection pain, and long-term use can easily inhibit the secretion of cortisol; propofol has significant cardiopulmonary depression; dexmedetomidine has adverse reactions such as hypotension and bradycardia. Therefore, new sedatives are needed to provide patients with more medication options.
  • Ideal sedatives should have the characteristics of rapid onset of action, rapid recovery after drug withdrawal, anterograde amnesia, low incidence of adverse reactions, predictable dose-effect, no accumulation, no toxicity, little inhibition of respiration and circulation, and metabolism that is not dependent on liver and kidney function. There is a strong demand for new sedatives in clinical practice.
  • the present disclosure aims to solve one of the technical problems in the related art at least to some extent.
  • the present disclosure provides an active peptide comprising an amino acid sequence KKNRNKLRRQHSY (SEQ ID NO: 1) or consisting of an amino acid sequence shown in SEQ ID NO: 1, or a functionally equivalent variant thereof for use in the preparation of a medicament for sedation or prevention and/or treatment of a disease or condition associated with a non-sedated state.
  • the present disclosure provides an active peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:1, or a functionally equivalent variant thereof, for use in sedation or prevention and/or treatment of diseases or conditions associated with a non-sedated state.
  • the functionally equivalent variant of the active peptide has 1, 2 or 3 conservative amino acid substitutions, additions or deletions relative to the active peptide, such as hydrophobic amino acid substitutions or additions.
  • hydrophobic amino acids that can be selected include tryptophan, phenylalanine, valine, leucine, isoleucine, alanine, proline and methionine (methionine) and the like.
  • the cell-penetrating peptide sequence is selected from: a TAT sequence, a MAP sequence, an MTS sequence or an R9 sequence.
  • the cell-penetrating peptide sequence is a TAT sequence added to the N-terminus.
  • the active peptide is an active peptide comprising the amino acid sequence YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2).
  • the active peptide is a functionally equivalent variant of S1 with an amino acid sequence of SEQ ID NO: 2, and the functionally equivalent variant has 1, 2 or 3 conservative amino acid substitutions, additions or deletions relative to S1 with an amino acid sequence of SEQ ID NO: 2.
  • the functionally equivalent variant has at least about 70%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or more sequence identity with the active peptide.
  • the sedation is sedation during or before a non-intubation procedure.
  • the subject to which the active peptides of the present disclosure are administered is a mammal, preferably a human.
  • the inventors of the present disclosure have found that the active peptides of the present disclosure can induce sedation, including by suppressing the normal activity level of the central nervous system and/or suppressing the overexcitation of the central nervous system to achieve sedation.
  • Figure 1 Statistical results of sedation levels of rats in each group after receiving S1 via tail vein infusion with normal saline, low-dose S1, medium-dose S1, and high-dose S1, respectively.
  • compositions, methods, and uses for sedation The disclosure of this application provides various compositions, methods, and uses for sedation.
  • mammal refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport or pet animals, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, etc.
  • peptides suitable for the present disclosure include the active peptide KKNRNKLRRQHSY (SEQ ID NO: 1) or a sequence (or variant) having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or 100% identity thereto. Also included are sequences (or variants) having YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2) or a sequence (or variant) having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or 100% identity thereto.
  • the variant has 1, 2 or 3 conservative amino acid substitutions, additions or deletions, and exhibits substantially similar in vivo or in vitro activity to the peptide examples of the present disclosure.
  • the active peptide KKNRNKLRRQHSY (SEQ ID NO: 1) in the present disclosure is named S3.
  • a peptide variant refers to an amino acid sequence in which one or more amino acids are altered.
  • a variant may have a "conservative" change, in which the substituted amino acid has similar structural or chemical properties, such as replacing leucine with isoleucine.
  • a variant may have a "non-conservative" change, such as replacing glycine with tryptophan. Similar lesser changes may also include amino acid deletions or insertions, or both.
  • the specific position of a named residue may vary slightly while still being present at a structurally and functionally similar position in the peptide (see Chang, Y., et al., Biochemistry 37:3258-3271 (1998)).
  • the peptides of the present disclosure may further comprise a membrane-penetrating peptide at its N-terminus or C-terminus that can guide the peptides of the present disclosure to cross the blood-brain barrier and the neural cell membrane.
  • a membrane-penetrating peptide at its N-terminus or C-terminus that can guide the peptides of the present disclosure to cross the blood-brain barrier and the neural cell membrane.
  • Suitable membrane-penetrating peptides known in the art can be used in the present disclosure as long as they can guide the peptides of the present disclosure to cross the blood-brain barrier and the neural cell membrane.
  • membrane-penetrating peptide can significantly enhance the inhibitory effect of S3 on brain neural activity.
  • exemplary membrane-penetrating peptides can be selected from human HIV-1 Tat protein fragment (TAT) sequence ("GRKKRRQRRR (SEQ ID NO: 3)", “YGRKKRRQRRR (SEQ ID NO: 4)", “YGRKKRRQRRRPPQ (SEQ ID NO: 5)” or “GRKKRRQRRRQ (SEQ ID NO: 6)”), model amphipathic peptide (MAP) sequence (“KLALKLALKALKAALKLA (SEQ ID NO: 7)”), membrane translocating peptide (MTS) sequence (“AAVALLPAVLLALLAP (SEQ ID NO: 8)”) or R9 (“RRRRRRRRR (SEQ ID NO: 9)”) sequence.
  • TAT human HIV-1 Tat protein fragment
  • MAP model amphipathic peptide
  • MTS membrane translocating peptide
  • R9 R9
  • the cell-penetrating peptide disclosed herein is a TAT sequence.
  • the peptide disclosed herein comprises or consists of the sequence YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2) (named as S1).
  • the cell-penetrating peptide is "YGRKKRRQRRR (SEQ ID NO: 4)".
  • the peptide of the present disclosure is a short-chain peptide with strong hydrophobicity, so that it can easily cross the blood-brain barrier and the nerve cell membrane with the help of a membrane-penetrating peptide.
  • the peptides disclosed in the present invention have a sedative effect.
  • the peptides disclosed in the present invention can be used to suppress the normal activity level of the central nervous system, and thus can be applied to sedation during intensive care, sedation during or before non-endotracheal intubation surgery, sedation during or before diagnosis or treatment of physical disease examinations/operations without endotracheal intubation, anesthesia induction, etc.
  • the peptides disclosed in the present invention can be used to suppress excessive excitement of the central nervous system, and thus can be used for non-sedated states such as anxiety, mental tension, convulsions or insomnia, as well as for sedation of agitation symptoms caused by mental illness, neurological disease or other diseases, and for sedation and tranquilization of patients with sleep disorders, promotion of relaxation, induction of sleep, prolonged sleep time, shortened sleep time, etc.
  • non-sedated states such as anxiety, mental tension, convulsions or insomnia
  • sedation of agitation symptoms caused by mental illness, neurological disease or other diseases and for sedation and tranquilization of patients with sleep disorders, promotion of relaxation, induction of sleep, prolonged sleep time, shortened sleep time, etc.
  • the mental illness, neurological disease or other disease can be Alzheimer's disease, schizophrenia, bipolar disorder, schizoaffective disorder, dementia, personality disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, autism spectrum disorder, psychoactive substance dependence or intoxication, alcohol or drug withdrawal, brain trauma, hyperthyroidism, severe pain, metabolic disorder, hypoxia, drug intoxication or electrolyte disorder.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • each rat was observed for 4 hours for its behavioral activity.
  • S1S1 used the observation of the general activity state of SD rats to evaluate the sedative effect of S1 inducing rat activity reduction, and evaluated the intensity of S1-induced sedation in rats at different doses, the onset time of induced sedation, and the maintenance time of induced sedation.
  • the statistical results of sedation are shown in Figure 1.
  • the statistical results in Figure 1 show that the rats in the saline group had normal activities and a sedation level of 0 ⁇ 0; the rats in the low-dose S1 group had normal activities and a sedation level of 0 ⁇ 0; the rats in the medium-dose S1 group generally had slightly weakened activities and an average sedation level of 0.7 ⁇ 0.1; the rats in the high-dose S1 group had slightly weakened activities and an average sedation level of 1 ⁇ 0.
  • the medium and high doses of S1 had a significant sedation-inducing effect, and the sedation level increased significantly with increasing doses.
  • the statistical results of the duration of induced sedation are shown in Figure 3.
  • the statistical results in Figure 3 show that the rats in the saline group had normal activities and no sedation; the rats in the low-dose S1 group had normal activities and no sedation; the rats in the medium-dose S1 group generally had slightly weakened activities, and the average duration of induced sedation was 12.15 ⁇ 0.88min; the rats in the high-dose S1 group had slightly weakened activities, and the average duration of induced sedation was 21.73 ⁇ 3.15min.
  • the medium and high doses of S1 had significant effects on inducing sedation, and the duration of induced sedation was significantly prolonged with the increase in dose.
  • S1 can induce sedation manifested by decreased activity, and the sedation effect increases with the increase in the dose of S1, that is, as the dose of S1 increases, the degree of sedation is significantly enhanced, the onset time of induced sedation is significantly shortened, the duration of induced sedation is significantly prolonged, and the success rate of induced sedation is significantly improved.
  • S1 can be used for sedation or prevention and/or treatment of diseases or symptoms associated with non-sedated states.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Normal SD rats were injected with physiological saline and different doses of S1 via tail vein injection, with the doses ranging from 10 mg/kg, 15 mg/kg, 30 mg/kg, 40 mg/kg, and 60 mg/kg.
  • the sedation depth of the rats was scored based on the six aspects of spontaneous activity level, anti-reflex, eyelid reflex, noise reflex, mouth opening resistance, and overall performance of the experimental rats. The scoring table is shown in Table 2.
  • the sedative effect of S1, S2, and S3 on the activity reduction of SD rats was evaluated by observing the general activity of SD rats.
  • 27 SPF male SD rats were randomly assigned to the S1 group, S2 group, and S3 group. After each group received a tail vein injection of 4 mL/kg of the corresponding drug, the general activity of the rats was observed for 4 hours.
  • the success rate of induced sedation is shown in Table 3.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • HEK-293 cells stably expressing hNMDAR were cultured in DMEM medium containing 10% fetal bovine serum, 100 ⁇ g/mL Zeocin, and 10 ⁇ g/mL Blastincidin at 37°C and 5% carbon dioxide. To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.
  • the cell membrane voltage was clamped at -70mV, and continuous drug administration was adopted for recording in the Gap-free mode.
  • 10 ⁇ M Glycine+10 ⁇ M L-Glutamate, 10 ⁇ M Glycine+10 ⁇ M L-Glutamate and a mixture of test substances at different concentrations were sprayed on the cell surface in sequence to observe the effect of drugs on the inward current of hNMDA.
  • test method is the same as that of Example 4.
  • the statistical results of the inhibition rates of S1 and S3 functional peptides at different doses on hNMDA receptors are shown in Table 4.
  • the disclosure has given the method and/or process of the present invention in a specific order of steps.
  • the method or process should not be limited to the specific order of steps described.
  • Other order of steps are possible. Therefore, the specific order of steps disclosed herein should not be interpreted as a limitation of the present invention.
  • the disclosure for the method and/or process should not be limited to performing their steps in the order described. Such an order can be changed and still within the scope of the present invention.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Anesthesiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé de sédation à l'aide d'un peptide actif, une composition comprenant le peptide, et l'utilisation du peptide.
PCT/CN2025/072613 2024-01-12 2025-01-15 Composition et procédé de sédation Pending WO2025149089A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410051028.1 2024-01-12
CN202410051028 2024-01-12

Publications (1)

Publication Number Publication Date
WO2025149089A1 true WO2025149089A1 (fr) 2025-07-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103230581A (zh) * 2011-11-10 2013-08-07 陈锦辉 用于治疗创伤性脑损伤的组合物和方法
CN107693774A (zh) * 2016-08-08 2018-02-16 北京大学 多肽类似物Tat‑NR2BCT在制备抗抑郁药物中的应用
CN111363014A (zh) * 2018-12-26 2020-07-03 苏州格兰科医药科技有限公司 用于治疗创伤性脑损伤的多肽及其用途和制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103230581A (zh) * 2011-11-10 2013-08-07 陈锦辉 用于治疗创伤性脑损伤的组合物和方法
CN107693774A (zh) * 2016-08-08 2018-02-16 北京大学 多肽类似物Tat‑NR2BCT在制备抗抑郁药物中的应用
CN111363014A (zh) * 2018-12-26 2020-07-03 苏州格兰科医药科技有限公司 用于治疗创伤性脑损伤的多肽及其用途和制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Doctoral thesis", 1 December 2014, ZHEJIANG UNIVERSITY, CN, article LU WEN: "A Study of Regulation of GluN2B Containing NMDA Receptor by Phosphorylation", pages: 1 - 99, XP093334798 *
"Doctoral thesis", 1 May 2015, HUAZHONG UNIVERSITY OF SCIENCE & TECHNOLOGY, CN, article YAN HONGLIN: "The Role of DAPK1 Associated Death Signals in the Treatments of Stroke", pages: 1 - 164, XP093334812 *
MELONI BRUNO P.; MILANI DIEGO; EDWARDS ADAM B.; ANDERTON RYAN S.; O'HARE DOIG RYAN L.; FITZGERALD MELINDA; PALMER T. NORMAN; KNUCK: "Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties", PHARMACOLOGY & THERAPEUTICS, vol. 153, 1 January 1900 (1900-01-01), GB , pages 36 - 54, XP029251637, ISSN: 0163-7258, DOI: 10.1016/j.pharmthera.2015.06.002 *
TU, W.H. ET AL.: "DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke", CELL, vol. 140, 21 January 2010 (2010-01-21), XP055243047, DOI: 10.1016/j.cell.2009.12.055 *

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