WO2022022226A1 - 一种具有抗衰老活性的多肽及其应用 - Google Patents
一种具有抗衰老活性的多肽及其应用 Download PDFInfo
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- WO2022022226A1 WO2022022226A1 PCT/CN2021/104283 CN2021104283W WO2022022226A1 WO 2022022226 A1 WO2022022226 A1 WO 2022022226A1 CN 2021104283 W CN2021104283 W CN 2021104283W WO 2022022226 A1 WO2022022226 A1 WO 2022022226A1
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
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- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions
- Aging is a process in which the body goes through a period of sexual maturity, the self-renewal and repair capabilities of cells are weakened, the structure and function of tissues and organs degenerate, and eventually die. Risk increases. With the aging of the global population, various degenerative diseases of the elderly and the huge medical expenses incurred have become more and more serious social problems. Maintaining the healthy state of the elderly population is a key link in reducing the social and economic burden brought about by population aging. Therefore, it is of great significance to explore measures and methods for intervening in aging and aging-related diseases that are simple, economical, effective, safe and suitable for promotion.
- C. elegans As a classic model animal for studying aging, C. elegans has the following advantages: firstly, its relatively short lifespan, only 2-3 weeks under standard laboratory conditions, makes lifespan survival analysis possible; secondly, in controlled It is easy to obtain a large number of genetically identical animals under environmental conditions; third, the transparency of the worm body facilitates the direct observation of how cells and tissues change with age; Research to aid in anti-aging.
- a major advantage of the C. elegans model is the ease with which genetic methods can be used to provide biological information, allowing the identification of a large number of genetic mutations that can alter lifespan.
- C. elegans lifespan exhibits remarkable plasticity and may be affected by environmental, nutritional, and genetic mutations, and even under controlled conditions, individual lifespan may vary, revealing stochastic factors in aging. Therefore, C. elegans can be used as a model animal to study the anti-aging activity of drugs.
- anti-aging drugs By far the most common form of anti-aging is the use of anti-aging drugs.
- Most of the anti-aging drugs used clinically are synthetic drugs, such as vitamin E, which can promote cell division and inhibit the generation of oxygen free radicals, procaine preparations can prolong cell lifespan, and amidopyrone can delay brain aging, etc.
- Oxidative stress delaying the decline of body function caused by aging, thereby prolonging the lifespan of nematodes
- Metformin as an activator of adenylate-activated protein kinase (AMPK)
- AMPK adenylate-activated protein kinase
- PAL-12 A six-membered peptide
- resveratrol analogs and other drugs are also favored for their anti-aging effects.
- the polypeptide is characterized in that X is T or A.
- the polypeptide can enhance the motor behavior ability of C. elegans, improve the pressure stress ability, improve the decline of the exercise ability in the aging process, and prolong the average lifespan.
- one or more pharmaceutically acceptable adjuvants can also be added to the above-mentioned medicines, and the adjuvants include conventional diluents, fillers, adhesives, wetting agents, absorption enhancers, surface active agents in the pharmaceutical field. agents, lubricants and stabilizers.
- the medicine of the present invention can be made into various forms such as injection, freeze-dried powder injection, tablet or granule.
- the medicines in the above-mentioned various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.
- the polypeptide of the present invention has a novel structure, the basic unit of which is composed of natural amino acids, and is easy to synthesize, separate and purify;
- the polypeptide of the present invention has good safety, weak adverse reactions and toxic side effects, does not affect the growth and development of Caenorhabditis elegans, and does not affect the reproductive ability of the nematodes;
- the anti-aging effect of the polypeptide involved in the invention has good performance in the Caenorhabditis elegans model, and is specifically embodied in significantly improving the motor behavior of the nematode, delaying the decline of the motor ability in the aging process of the nematode, prolonging half of the survival days of the nematode, and increasing the pressure of the nematode Stress capacity, extending the lifespan of nematodes.
- Figure 2 Results of the effect of polypeptides on the body length and width of Caenorhabditis elegans. Among them, picture A is the result of body length, and picture B is the result of body width. The results are expressed as Mean ⁇ SEM. Compared with the blank group, n.s. means no significant difference, *P ⁇ 0.05 means significant difference, **P ⁇ 0.01 means very significant difference. There was no significant difference between the polypeptide group and the blank group, indicating that the polypeptides Ace and RV1 did not affect the normal growth and development of C. elegans, and the polypeptides had good safety.
- Figure 3 Results of the effect of polypeptides on the number of broods in Caenorhabditis elegans. The results are expressed as Mean ⁇ SEM. Compared with the blank group, n.s. means no significant difference, *P ⁇ 0.05 means significant difference, **P ⁇ 0.01 means very significant difference. There was no significant difference between the polypeptide group and the blank group, indicating that the polypeptides Ace and RV1 did not affect the normal reproductive ability of C. elegans, and the polypeptide had good safety.
- Figure 4 Results of the effect of polypeptides on the motor behavior of Caenorhabditis elegans.
- picture A is the result of head swing
- picture B is the result of body bending
- picture C is the result of pharyngeal pump frequency.
- the results are expressed as Mean ⁇ SEM.
- n.s. means no significant difference
- *P ⁇ 0.05 means significant difference
- **P ⁇ 0.01 means very significant difference.
- the polypeptide group had significant differences, indicating that both polypeptides Ace and RV1 could enhance the muscle movement of C. elegans and improve the locomotor behavior of C. elegans.
- FIG. 5 Survival curves of acute heat stress experiments in C. elegans. Picture A is the survival curve of Day4 acute heat stress experimental nematodes, and picture B is the survival curve of Day8 acute heat stress experimental nematodes. It can be seen from the figure that both Ace and RV1 peptide groups can significantly improve the ability of nematodes to acute heat stress, indicating that the peptide drug can prolong the life cycle of nematodes in a thermal environment.
- Fig. 7 The detection results of the acute oxidative stress experiment of Caenorhabditis elegans. Picture A is the detection result of the acute oxidative stress test on Day4, and picture B is the detection result of the acute oxidative stress test on Day8. The results are expressed as Mean ⁇ SEM. Compared with the blank group, *P ⁇ 0.05 is a significant difference, and **P ⁇ 0.01 is a very significant difference. It can be seen from the figure that the survival rate of nematodes in the Ace and RV1 polypeptide groups is significantly higher than that in the blank group, which indicates that the polypeptide drug can prolong the life cycle of nematodes in an oxidative environment.
- Figure 8 Motility rating results of acute oxidative stress experiments in C. elegans.
- picture A shows the exercise rating results of the nematodes in the acute oxidative stress experiment on Day 4
- picture B shows the exercise ability grading results in the nematodes in the acute oxidative stress experiment on Day 8.
- the proportion of nematodes in the Ace and RV1 polypeptide groups in the A-level group is higher than that of the blank group, which further indicates that the polypeptide drug can enhance the ability of C. elegans acute oxidative stress;
- the Day4 acute oxidative stress experiment there was no difference in exercise between the peptide group and the blank group.
- Figure 9 Results of motility rating of C. elegans at different ages.
- picture A is the grading result of the nematode motility at the time point of Day4
- picture B is the grading result of the movement ability of the nematodes at the time point of Day8
- picture C is the grading result of the movement ability of the nematodes at the time point of Day12.
- Ace and RV1 peptide groups at Day8 and Day12 had a significantly higher proportion of nematodes in grade A than the blank group, which means that the peptides can delay the muscle aging of C. elegans. Increases the mobility of the nematode, thereby extending the lifespan of the nematode.
- Figure 10 The results of motility testing of C. elegans at different ages. Among them, picture A is the test result of nematode motility at the time point of Day4, picture B is the test result of the movement ability of nematodes at the time point of Day8, and picture C is the test result of the movement ability of nematodes at the time point of Day12. The results are expressed as Mean ⁇ SEM. Compared with the blank group, *P ⁇ 0.05 is a significant difference, and **P ⁇ 0.01 is a very significant difference.
- the Ace and RV1 peptide groups had significantly higher head swings than the blank group, and the frequency of pharyngeal pump at Day 12 was also significantly higher than that of the blank group, which means that the peptide can delay
- the muscle aging of C. elegans increases the motor behavior of the nematode, delays the decline of the nematode's mobility, and thus prolongs the lifespan of the nematode.
- Escherichia coli OP50 culture conditions: shaking incubator, 220rpm, 37°C
- RV1 AKFAA, 10 nM
- Synchronization of Caenorhabditis elegans Select an NGM petri dish with a moderate nematode density, pick L4 larvae with a picking needle, transfer them to a blank NGM petri dish, pick about 20 larvae in total, and wait until they develop into adults and give birth After the first batch of eggs, all the adults were picked away. After about 12 hours, the eggs hatched into larvae, and the synchronized L1-stage larvae were obtained.
- Preliminary preparation for the C. elegans lifespan experiment Rinse the NGM medium with 1 ml of M9 buffer, collect the buffer containing the L1 stage larvae in an EP tube, place in a chromatographic cabinet at 4°C for 5 minutes, centrifuge at 1500xg/4°C for 3 minutes, and discard After the supernatant was resuspended in 100 ⁇ l buffer, the nematodes were counted under the microscope, and then the nematode concentration was diluted to 30 worms/10 ⁇ l; the NGM culture dish inoculated with E. , to ensure that the number of nematodes is about 30, and then place the NGM petri dish in a constant temperature incubator for cultivation.
- Caenorhabditis elegans lifespan experiment After the L1 stage nematodes developed to the L4 stage, 100 ⁇ l of 15.6 ⁇ g/ml 5-FUDR was added to inhibit the oviposition of C. elegans; when the nematodes developed into adults, the drug was started and divided into control groups , 10nM administration group, this time was recorded as the first day of the lifespan experiment; after that, daily administration, observed and recorded the number of nematodes that survived, died and unexpectedly died, and observed and recorded the state of nematodes until the last nematode died. The criteria for judging death are: C.
- Reproductive ability detection of Caenorhabditis elegans Collect the larvae at L1 stage after synchronization, spread them on NGM solid medium inoculated with Escherichia coli OP50, and divide them into Control group and 10nM administration group, which are placed in a constant temperature and humidity incubator Cultured to L4 stage larvae.
- Detection of motor behavior of C. elegans larvae at L1 stage after synchronization were plated on NGM solid medium inoculated with Escherichia coli OP50, divided into Control group and 10nM administration group, placed in a constant temperature and humidity incubator Culture for 48h. Then, the following three indicators of motor behavior were detected: head swing frequency, 20 nematodes were picked from each group to a new clean medium, and after 1 hour of adaptation and recovery, an appropriate amount of M9 buffer was added and observed under an inverted microscope.
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Abstract
Description
Claims (7)
- 一种多肽,其特征在于:具有氨基酸序列XKFAA或其药学上可以接受的盐;其中X=任意一个以上的氨基酸,或酰基,。
- 根据权利要求1所述的一种多肽,其特征在于:X为H-Pro-Pro-Thr-Thr-、H-Pro-Thr-Thr-、H-Thr-Thr-、T或者A。
- 根据权利要求1或2中所述的一种多肽,其特征在于所述多肽序列分别为,PPTTKFAA、PTTKFAA、TTKFAA、TKFAA或AKFAA。
- 根据权利1-3任意一项所述的多肽,其特征在于所述的多肽的每一个氨基酸为D或L型。
- 权利要求1-4任意一项所述的多肽在制备抗衰老的药物或保健品中的应用。
- 根据权利要求5所述的应用,其特征在于在多肽中还加入一种或多种药学上可接受的辅料,所述辅料包括药学领域常规的稀释剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂和稳定剂。
- 根据权利要求6所述的应用,其特征在于所述的多肽制成注射液、冻干粉针剂、片剂或颗粒剂。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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US17/767,403 US20240067676A1 (en) | 2020-07-27 | 2021-07-02 | Polypeptide having anti-aging activity, and application thereof |
EP21849796.4A EP4190796A1 (en) | 2020-07-27 | 2021-07-02 | Polypeptide having anti-aging activity, and application thereof |
AU2021314719A AU2021314719A1 (en) | 2020-07-27 | 2021-07-02 | Polypeptide having anti-aging activity, and application thereof |
JP2022521564A JP2022551893A (ja) | 2020-07-27 | 2021-07-02 | 抗老化活性を有するポリペプチド及びその使用 |
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CN111793117A (zh) * | 2020-07-27 | 2020-10-20 | 南京安吉生物科技有限公司 | 一种具有抗衰老活性的多肽及其应用 |
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