A polypeptide derivative, a pharmaceutical composition containing the polypeptide derivative, and use and application method thereof

Abstract

The polypeptide derivative of the present application is characterized by comprising a polypeptide chain and a palmitic acid group modified on the polypeptide chain, and having the structure shown in the following general formula I or general formula II; the general formula I is C-X2, wherein X2 in the general formula I is nothing, any amino acid or any peptide segment, and C is modified with one palmitic acid group; the general formula II is X1-C-X3; wherein X1 and X3 in the general formula II are any amino acid or any peptide segment, and C is modified with two palmitic acid groups. The polypeptide derivative in the present application can specifically bind to Piezo2 and reduce the tactile threshold, thereby playing a role in enhancing the Piezo2 target agonist. The pharmaceutical composition adopts the above polypeptide derivative, and when applied to mice, can effectively reduce the mechanical pain threshold, thereby improving the tactile sensitivity; when applied to humans, can improve the pleasure of human sexual life.

Description

Technical Field

[0001] This invention relates to the technical field of peptides having an indeterminate number of amino acids, and more particularly to a polypeptide derivative that can act as an agonist of the tactile receptor Piezo2 and its applications. Background Technology

[0002] Touch plays an important role in daily life. The clinical manifestation of tactile hyposensitivity is a dulled sense of touch, making it difficult to avoid dangers that normal people can avoid, thus increasing vulnerability to injury. Current traditional treatments include behavioral and psychotherapy, with limited drug therapy options. Furthermore, tactile sensitivity is also related to sexual experience; lower sensitivity can negatively impact sexual harmony.

[0003] Regarding improving sexual experience, existing technology includes Chinese invention application CN201880098478.9 (publication number CN112839645A), entitled "Compositions and Methods for Treating Sexual Dysfunction and Enhancing Sexual Response and Pleasure," which discloses a drug that enhances human sexual response and sensitivity. Its active ingredients are cannabinoid derivatives and sexual response-enhancing components. Cannabinoid derivatives regulate dopamine secretion by activating the cannabinoid receptor CB1, thereby increasing sexual pleasure. While such drugs can enhance sexual pleasure in both men and women, cannabinoid derivatives are listed as Class I psychotropic drugs in my country, limiting their use and production processes, and posing a significant risk of addiction with long-term use. Therefore, the search for new drugs with novel mechanisms of action to enhance sexual pleasure is urgently needed.

[0004] Studies have shown that activating the Piezo2 channel can enhance both the perception of mechanical force and sexual pleasure. Piezo2 is a mechanogated ion channel protein that can sense and respond to mechanical stimuli in cells, providing the molecular basis for the generation of tactile sensation. The Klaus corpuscle nerve endings in the sexual organs are enriched with the mechanosensitive channel Piezo2, demonstrating that the presence of Piezo2 is essential for the sensitivity of the perineum caused by touch. Therefore, if Piezo2 could be activated by a certain chemical substance, the activator could be a potential drug for treating tactile hyposensitivity and enhancing sexual pleasure. However, no compound or pharmaceutical composition capable of activating Piezo2 and its application have yet been developed. Summary of the Invention

[0005] The first technical problem to be solved by the present invention is to provide a polypeptide derivative that can specifically bind to the Piezo2 channel, in light of the above-mentioned existing technology.

[0006] The second technical problem to be solved by the present invention is to provide a pharmaceutical composition containing the above-mentioned polypeptide derivative in view of the current state of the prior art.

[0007] The third technical problem to be solved by the present invention is to provide the use of the above-mentioned pharmaceutical composition in view of the current state of the prior art.

[0008] The fourth technical problem to be solved by the present invention is to provide a method for improving sexual pleasure by using the above-mentioned polypeptide derivatives or pharmaceutical compositions, in view of the current state of the prior art.

[0009] The fifth technical problem to be solved by the present invention is to provide a method for improving tactile sensitivity by applying the above-mentioned polypeptide derivatives or pharmaceutical compositions, in view of the current state of the prior art.

[0010] The technical solution adopted by the present invention to solve the first technical problem is as follows: the polypeptide is characterized by comprising a polypeptide chain and palmitic acid groups modified on the polypeptide chain, and has the structure shown in general formula I or general formula II below;

[0011] General Formula I: C-X2;

[0012] In general formula I, X2 can be any amino acid or any peptide, and C is modified with a palmitic acid group.

[0013] General Formula II: X1-C-X3;

[0014] In formula II, X1 and X3 are any amino acids or peptides, and C is modified with two palmitic acid groups.

[0015] Furthermore, the amino acid sequence of the polypeptide chain is selected from any one of SEQ ID No. 1-14, and polypeptides of their functional equivalent fragments, derivatives and variants;

[0016] In particular, the first cysteine ​​residue of the amino acid sequences SEQ ID No. 1-6, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 14 is modified with a palmitic acid group;

[0017] The cysteine ​​residue at the third position of the amino acid sequences of SEQ ID No. 9 and SEQ ID No. 12 is modified with two palmitic acid groups;

[0018] The fourth cysteine ​​residue in the amino acid sequence of SEQ ID No. 8 is modified with two palmitic acid groups;

[0019] The cysteine ​​residue at position 6 of the amino acid sequence of SEQ ID No. 13 is modified with two palmitic acid groups.

[0020] Furthermore, the amino acid sequence of the polypeptide chain is selected from SEQ ID No. 1, and the first cysteine ​​residue of the polypeptide chain is modified with a palmitic acid group.

[0021] In addition, the present invention also synthesizes a probe characterized by being obtained by fluorescent labeling of any of the polypeptide derivatives selected above.

[0022] Furthermore, the fluorescent labeling operation involves labeling with FITC dye.

[0023] The purpose of the probes described above is to indicate the location of Piezo2 in cells.

[0024] The technical solution adopted by the present invention to solve the second technical problem is: the pharmaceutical composition is characterized by comprising any of the above-mentioned polypeptide derivatives or combinations.

[0025] Furthermore, it contains a polypeptide derivative with the amino acid sequence SEQ ID No. 1 and a palmitic acid group modified by the cysteine ​​residue at the first position of the polypeptide chain.

[0026] Furthermore, the dosage form of the pharmaceutical composition is a topical preparation.

[0027] The technical solution adopted by the present invention to solve the third technical problem is: the above-mentioned pharmaceutical composition is used in any of the following groups:

[0028] (i) Improve tactile sensitivity;

[0029] (ii) Enhance the pleasure of human sexual life.

[0030] The technical solution adopted by the present invention to solve the fourth technical problem is as follows: the method for improving sexual pleasure, characterized in that the method includes the steps of: administering an effective amount of the above-mentioned polypeptide derivative or the above-mentioned pharmaceutical composition to the subject.

[0031] The technical solution adopted by the present invention to solve the fifth technical problem is as follows: the method for improving tactile sensitivity is characterized in that the method includes the steps of: applying an effective amount of the above-mentioned polypeptide derivative or the above-mentioned pharmaceutical composition to the test subject.

[0032] Compared with the prior art, the advantages of the present invention are as follows:

[0033] (1) The polypeptide derivatives in this invention can specifically bind to Piezo2 and reduce the tactile threshold, thereby enhancing the effect of Piezo2 target agonist.

[0034] (2) The polypeptide derivatives in this invention act on the Piezo2 channel, are non-addictive, and have high safety when used as drugs or as formulations.

[0035] (3) The probe in this invention can specifically bind to Piezo2 and can be used to indicate the location of Piezo2 in the cell;

[0036] (4) The pharmaceutical composition of the present invention uses the above-mentioned polypeptide derivatives. When applied to mice, it can effectively reduce the mechanical pain threshold and thereby improve tactile sensitivity; when applied to humans, it can improve the pleasure of human sexual life. Attached Figure Description

[0037] Figures 1a to 1d This is a fluorescence colocalization map of the FITC-M peptide and Piezo2 fluorescent antibody in HeLa cells according to Example 2 of the present invention; wherein, Figure 1a The image shows the results of red fluorescent labeling with Piezo antibody; Figure 1b The image shows the results of green fluorescent labeling of FITC-M peptide; Figure 1c for Figure 1a , Figure 1b Fluorescence signal overlap diagram; Figure 1d for Figure 1c A magnified view of a portion of the image;

[0038] Figures 2a-2b The images shown are flow cytometry results of 293T cells and HeLa cells treated with peptide probes in Example 2 of this invention; wherein, Figure 2a Flow cytometry analysis of 293T cells after treatment with a peptide probe; Figure 2b Flow cytometry analysis of HeLa cells after treatment with peptide probes;

[0039] Figure 3 This is a schematic diagram of the operation of the mechanical pain measurement experiment of mouse foot in Example 4 of the present invention;

[0040] Figure 4 This is a bar chart showing the 50% withdrawal response threshold of the experimental group and the control group in the mechanical pain test of mouse foot in Example 4 of the present invention; where Control is the control group and M-peptide is the experimental group; the relevant samples were subjected to a two-tailed t-test (n=8), p=0.017;

[0041] Figure 5 This is a bar chart showing the 50% withdrawal response threshold of peptides M0 to M13 in the experimental group of the mouse plantar mechanical pain test in Example 4 of the present invention.

[0042] Figure 6 This is a graph showing the proportion of mouse paw withdrawal responses in Example 4 of the present invention.

[0043] Figure 7a and Figure 7bThis is a flowchart of the mouse mating behavior test in Example 4 of the present invention, and a bar chart showing the thrombus detection rates of the experimental and control groups; wherein, Figure 7a This is a flowchart of the experimental procedure for testing mouse mating behavior. Figure 7b A bar chart showing the thrombus detection rate in the experimental and control groups during a mouse mating behavior test;

[0044] Figure 8 This is a bar chart showing the improvement in the sexual life of subjects by the M0 peptide and its pharmaceutical composition in Example 5 of the present invention. Detailed Implementation

[0045] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0046] Existing drugs enhance sexual pleasure by activating the CB1 receptor and promoting dopamine secretion, but there is a risk of addiction with long-term use. This invention designs and develops peptide derivatives and pharmaceutical compositions that target and activate Piezo2, primarily to improve tactile sensitivity and enhance sexual pleasure.

[0047] In this invention, the inventors first designed a polypeptide derivative with the amino acid sequence shown in SEQ ID No. 1-14 and modified with palmitic acid groups, based on the modification of one palmitic acid group with a cysteine ​​residue at position C (hereinafter abbreviated as C) and two palmitic acid groups with cysteine ​​residues at non-first and last positions. The inventors demonstrated through confocal microscopy and flow cytometry that the above polypeptide derivative can specifically bind to Piezo2. In animal experiments, the inventors found that administration to mice increased mating rates and improved tactile sensitivity; in human experiments, the inventors found that application to the genital area enhanced sexual pleasure. Furthermore, in verifying the specific binding of the above polypeptide derivative to Piezo2, the inventors also designed a probe capable of marking the location of Piezo2 in cells.

[0048] Example 1: Polypeptide Derivatives

[0049] The polypeptide derivative of this embodiment includes a polypeptide chain and a palmitic acid group modified on the polypeptide chain, and has the structure shown in general formula I or general formula II below;

[0050] General Formula I: C-X2,

[0051] In general formula I, X2 can be any amino acid or any peptide, and C is modified with a palmitic acid group.

[0052] General Formula II: X1-C-X3;

[0053] In formula II, X1 and X3 are any amino acids or peptides, and C is modified with two palmitic acid groups.

[0054] The amino acid sequence of the polypeptide chain is selected from any one of SEQ ID No. 1-14, wherein the first cysteine ​​residue of the amino acid sequence of SEQ ID No. 1-6, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 14 is modified with a palmitic acid group;

[0055] The cysteine ​​residue at position 3 in the amino acid sequences of SEQ ID No. 9 and SEQ ID No. 12 is modified with two palmitic acid groups;

[0056] The fourth cysteine ​​residue in the amino acid sequence of SEQ ID No. 8 is modified with two palmitic acid groups;

[0057] The cysteine ​​at position 6 of the amino acid sequence of SEQ ID No. 13 is modified with two palmitic acid groups.

[0058] The amino acid sequences and their modifying groups of 14 polypeptide derivatives are shown below (Pal refers to the palmitic acid group):

[0059] SEQ ID NO.01(M0):Pal-CMECCGICFPS

[0060] SEQ ID NO.02(M1):Pal-CMECCGIC

[0061] SEQ ID NO.03(M2): Pal-CMECC

[0062] SEQ ID NO.04(M3): Pal-CCGIC

[0063] SEQ ID NO.05(M4):Pal-CLEICMECCGICFPS

[0064] SEQ ID NO.06(M5):Pal-CLEICMECCGIC

[0065] SEQ ID NO.07(M6):Pal-CLEICMECC

[0066] SEQ ID NO.08(M7):CMEC(-2Pal)CGICFPS

[0067] SEQ ID NO.09(M8):MDC(-2Pal)GIMDACCESSDCLEICMECCGICFPS

[0068] SEQ ID NO.10(M9):Pal-CESSDCLEICMECCGICFPS

[0069] SEQ ID NO.11(M10):Pal-CCESSDCLEICMECCGICFPS

[0070] SEQ ID NO.12(M11):DAC(-2Pal)CESSDCLEICMECCGICFPS

[0071] SEQ ID NO.13(M12): GIMDAC(-2Pal)CESSDCLEICMECCGICFPS

[0072] SEQ ID NO.14(M13): Pal-CGIMDACCESSDCLEICMECCGICFPS;

[0073] Specifically, the amino acid sequence of the polypeptide chain is preferably selected from SEQ ID No. 1, which has a palmitic acid group modified at the first cysteine ​​residue. The synthesis and purification of the polypeptide derivatives involved in this embodiment were entrusted to Nanjing Jietai Biotechnology Co., Ltd. The corresponding polypeptide derivatives were synthesized according to the amino acid sequences of SEQ ID No. 1-14 and their corresponding modified groups, and were respectively denoted as peptides M0 to M13, collectively referred to as M peptides.

[0074] In this invention, equivalent changes and modifications of polypeptide derivatives are all within the scope of protection. Specifically, this should also include polymers with structures shown in Formula I, such as dimers, trimers, etc. In this invention, polypeptide derivatives can also be modified or labeled by other common proteins, compounds, or polymers (e.g., phosphorylation, ubiquitination, PEG modification, etc.) to obtain fusion proteins or modified polypeptide derivatives.

[0075] Example 2: Synthesis of peptide probes and experimental verification of their specific binding to Piezo2.

[0076] I. Synthesis of Peptide Probes

[0077] The polypeptide chain sequence of the polypeptide derivative in this embodiment can be selected from any of SEQ ID No. 1-14. The polypeptide chain sequence of the polypeptide derivative selected in this embodiment is preferably SEQ ID No. 1. After synthesizing the M0 peptide modified with palmitic acid group according to the sequence, fluorescent labeling with fluorescein isothiocyanate (FITC) is used to obtain the polypeptide probe.

[0078] II. Confocal Experiment

[0079] To verify the specific binding of the synthesized peptide to Piezo2, HeLa cells highly expressing Piezo2 were used in this experiment. The cells were then conjugated with a 500 nM peptide probe and a fluorescently labeled Piezo2 antibody, respectively. The fluorescent colocalization of the peptide probe and the Piezo2 antibody in HeLa cells was observed using laser confocal microscopy. The experimental results are as follows: Figures 1a to 1d As shown in the figure, red represents the fluorescence signal of the Piezo2 antibody, used to indicate the location of Piezo2 in the cell. Green represents the fluorescence signal of the peptide probe, used to indicate the location of Piezo2 in the cell. The figure shows that the red fluorescence can be well superimposed on the green fluorescence, with a co-localization coefficient M = 0.912 (M represents the Manders overlap coefficient, or MOC for short. When MOC is close to 1, it means that one signal almost completely overlaps with another signal, that is, the two signals are highly consistent in spatial location in the cell. When MOC is close to 0, it means that the two signals hardly overlap, that is, their positions in the cell structure are relatively independent). The peptide probe and Piezo2 exhibit strong co-localization, and the peptide probe can be used to indicate the location of Piezo2 in the cell, indicating that the peptide derivative of this embodiment can specifically bind to Piezo2.

[0080] III. Cell Flow Cytometry Experiment

[0081] To further verify that the polypeptide derivative synthesized in this embodiment can specifically bind to Piezo2, experiments were conducted using 293T cells that do not express Piezo2 and HeLa cells that highly express Piezo2. The two cell groups were treated with a 500 nM polypeptide probe to obtain experimental groups of 293T cells and HeLa cells. Within each cell population, control groups of 293T cells and HeLa cells were separated without probe treatment. The results were then analyzed by flow cytometry.

[0082] The results are as follows Figure 2a and Figure 2b As shown, compared with the blank control group, 293T cells treated with FITC-M peptide did not exhibit fluorescence shift, indicating that due to the lack of Piezo2 receptor, FITC-M peptide could not specifically bind to 293T cells. In contrast, HeLa cells treated with FITC-M peptide showed significant fluorescence shift, demonstrating that M peptide specifically binds to Piezo2.

[0083] Example 3 Pharmaceutical Composition

[0084] The pharmaceutical composition of this embodiment includes a polypeptide derivative M peptide or combination thereof, in which the amino acid sequence of the polypeptide chain selected from the polypeptide chain of Example 1 is selected from any of SEQ ID No. 1-14, and the amino acid sequence of the polypeptide chain in the polypeptide derivative is preferably SEQ ID No. 1, i.e., M0 peptide.

[0085] In this embodiment, the carrier or excipient of the pharmaceutical composition may be: sterile water, lauryl azone, solubilizer, propylene glycol, xanthan gum, hyaluronic acid, p-hydroxyacetophenone, 1,2-hexanediol, etc.

[0086] The specific preparation method of the drug composition is as follows: taking M0 peptide as an example, sterile water, lauryl azone, solubilizer, propylene glycol, xanthan gum, hyaluronic acid, p-hydroxyacetophenone, 1,2-hexanediol and other reagents are used as auxiliary reagents to prepare a gel formulation (the content of each excipient component varies from 0.5% to 90%), wherein the concentration of M0 peptide in the drug composition is 1-20 μM.

[0087] In addition, the dosage form of the drug composition can be an oral preparation, an injectable preparation or a topical preparation. In this embodiment, the dosage form is preferably a skin-applied preparation. The absorption principle of the drug composition in the skin-applied preparation is as follows: taking M0 peptide as an example, M0 peptide is absorbed into the body through the skin. Lauryl azone and propylene glycol in the formula can act as transdermal agents to help M0 molecules pass through the skin.

[0088] The dosage of the drug composition is designed as follows: 2 mL per person per use, in which the M peptide content is 10 μM. The actual dosage may be increased or decreased according to individual circumstances.

[0089] Example 4: Mouse Behavioral Testing

[0090] I. Mechanical Pain Test in Mice

[0091] The Von Frey (up-down) test (also known as the mouse plantar mechanical pain test) is used to measure the behavioral outcome of changes in the response of rodents to mechanical or thermal stimuli. The experimental procedure is as follows:

[0092] M0 to M13 peptides at 10 μM were formulated into topical formulations and applied to the soles of mice as the experimental group. Mice with a formulation without active peptides applied to their soles served as the control group. The other components and contents of the formulation without active peptides were the same as those in the experimental group.

[0093] The experimental mice (SPF mice, BALB / cJGpt) in both the experimental and control groups were gently placed in the compartments of the test stand and allowed to acclimatize for 1 hour. The experimental procedures were as follows: Figure 3As shown, Von Frey filaments were applied from the underside of the net to the sole of the mouse's hind paw, with the applied force starting at 0.6g. The test followed an up-down method to obtain maximum sensitivity until the filaments bent or the mouse responded.

[0094] A positive response is indicated by the animal readily withdrawing its paw upon application of a stimulus. Paw withdrawal responses in mice are observed; no response is recorded as a negative response "O", and a response (paw withdrawal or licking) is recorded as a positive response "X". If there is no response to the first filament stimulation, a filament with a slightly higher intensity is applied; if there is a response, a filament with a slightly lower intensity is applied, and so on, for a total of 5 measurements starting from the one with a response. This yields a sequence of "O" or "X" combinations. This sequence, along with the intensity (f) of the last filament, is input into a formula to calculate the mechanical pain threshold. The formula is: 50% paw withdrawal response threshold (g) = (10[Xf + kδ]) / 10000. Where Xf = log(f); δ is the average difference of each filament intensity after taking the logarithm, approximately 0.224 in this case; k is the value obtained by looking up the "X" and "O" sequences from a table. Data analysis uses the Up-Down Reader open-source program to effectively determine the 50% Von Frey threshold.

[0095] Experimental results are as follows Figure 4 and Figure 5 As shown, the results indicate that the 14 polypeptide derivatives and their drugs from Example 1 can reduce the 50% withdrawal threshold (g) in mice to varying degrees, with M0 showing the most significant reduction. Therefore, the polypeptide derivatives synthesized in Example 1 (especially M0) can reduce the mechanical pain threshold, thereby improving tactile sensitivity. Thus, the polypeptide derivatives of Example 1 have the function of Piezo2 agonists.

[0096] II. Von Frey mouse paw withdrawal response ratio curve test

[0097] Experimental subjects: male or female SPF mice (BALB / cJGpt, 8-12 weeks old) from the same cohort;

[0098] Experimental reagents: Peptides M0 to M13 were prepared into topical formulations for skin application.

[0099] Experimental procedure: Mice in the experimental group were divided into 14 groups. Each group was treated with a skin-applied preparation of peptides M0 to M13 and applied to the soles of their feet. Mice in the control group were treated with a preparation without active peptides. Other components and contents were the same as those in the experimental group.

[0100] Before the experiment on the day of testing, mice were placed on a platform with an acrylic glass cover to acclimate for at least 30 minutes. Eight Von Frey microfilaments (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1.0, 1.4, 2 g) were applied, starting from the area with the lowest fiber strength (0.008 g) and progressing to the area with the highest fiber strength (2 g), for a total of three applications. Each experiment was repeated three times. Mice that retracted their paws in all applications were included in the statistical analysis. Sixteen mice were tested at each fiber strength level, and the percentage of mice retracting their paws was recorded. Each test was repeated at least three times within the same mouse cohort. A curve was plotted with the logarithm of fiber strength on the x-axis and the percentage of mice exhibiting paw-retraction in each group on the y-axis. Figure 6 .

[0101] like Figure 6 As shown, the experimental results indicated a statistically significant difference in mouse datasets between the control group and the M0 peptide-treated group; there were 16 female mice. This suggests that M0 peptide can activate Piezo2 in mice, significantly increasing their sensitivity and the rate of foot withdrawal response.

[0102] III. Mouse Mating Behavior Test

[0103] Experimental environment: The test was conducted in a cage with a transparent plexiglass cover, which allowed for video recording and accurate behavioral scoring, and was carried out during a dark period;

[0104] Experimental subjects: asexual male and female SPF mice, BALB / cJGpt mice aged 8 to 16 weeks, with testosterone and follicle-stimulating hormone (FSH) levels in the mice within the same range as normal adult mice.

[0105] Experimental Procedure: On the first day, pretreatment was performed. Mice were grouped into cohorts of eight, with equal numbers of males and females. The experimental group received a topical formulation of M0-M13 peptides applied to the gonads of both male and female mice. The control group received a formulation without active peptides. All other components and concentrations were the same as the experimental group. Before being placed in the same cages, male mice were housed separately and acclimatized to the laboratory for 1 hour. Female mice were housed in groups, and their estrus status was confirmed by vaginal irrigation and cytological examination before entering the test cages. After housing and confirmation, the mice were placed in the same cages, following the specific steps below:

[0106] The first step is to select one male mouse in estrus and one or two female mice between 4:30 and 5:00 a.m. on the second day and put them into the cage in the order of male first and female second.

[0107] The second step is overnight mating; mice usually mate at night, and a plug will form in the vagina after mating. This is the result of the coagulation gland secretion of the male mouse hardening when exposed to air.

[0108] The third step is to check the vaginal plugs between 8:30 and 9:00 AM on the second day after the couple is put together. Larger vaginal plugs tend to protrude outwards, while smaller ones are located inside the vagina or at the cervix, requiring the vaginal opening to be opened to see them. The vaginal plugs are used to determine whether mating was successful.

[0109] like Figure 7a and Figure 7b As shown, the results indicated that the detection rate of thrombi in the experimental group was 75%, while that in the control group was 50%. The difference between the experimental group and the control group was significant, indicating that M-peptide and its drug composition can improve the mating rate of mice.

[0110] Example 5: Experiment on the improvement of human sexual life by M0 peptide preparation

[0111] Based on the skin-topical formulation containing M0 in Example 4, this example further develops a lubricant gel formulation by using the M0 peptide to prepare a gel solution for enhancing pleasure during human sexual activity.

[0112] In the initial phase, 22 physiologically healthy volunteers were recruited for the trial. The experimental dosage was 2 mL per person per use, containing 10 μM of M0 peptide. Five indicators were statistically analyzed using questionnaires: changes in sexual satisfaction, libido, sensitivity, sexual pleasure, and frequency of orgasm.

[0113] like Figure 8 As shown, in the 22 samples collected, sexual satisfaction was improved in 63.3% of the subjects, with significant differences in total scores. This demonstrates that the M0 peptide and its drug in Example 1 have a significant effect on improving tactile sensitivity and sexual pleasure during sexual intercourse.

Claims

1. A polypeptide derivative, characterized in that: It includes a polypeptide chain and palmitic acid groups modified on the polypeptide chain, and has the structure shown in general formula I or general formula II below; General Formula I: C-X2; In general formula I, X2 can be any amino acid or any peptide, and C is modified with a palmitic acid group. General Formula II: X1-C-X3; In formula II, X1 and X3 are any amino acids or peptides, and C is modified with two palmitic acid groups.

2. The polypeptide derivative according to claim 1, characterized in that: The amino acid sequence of the polypeptide chain is selected from any one of SEQ ID No. 1-14. In particular, the first cysteine ​​residue of the amino acid sequences SEQ ID No. 1-6, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 14 is modified with a palmitic acid group; The cysteine ​​residue at the third position of the amino acid sequences of SEQ ID No. 9 and SEQ ID No. 12 is modified with two palmitic acid groups; The fourth cysteine ​​residue in the amino acid sequence of SEQ ID No. 8 is modified with two palmitic acid groups; The cysteine ​​residue at position 6 of the amino acid sequence of SEQ ID No. 13 is modified with two palmitic acid groups.

3. The polypeptide derivative according to claim 2, characterized in that: The amino acid sequence of the polypeptide chain is selected from SEQ ID No.1, and the first cysteine ​​residue of the polypeptide chain is modified with a palmitic acid group.

4. A probe, characterized in that: Obtained by fluorescent labeling of any of the polypeptide derivatives as described in claim 2.

5. The probe according to claim 4, characterized in that: The fluorescent labeling operation involves labeling with FITC dye.

6. The use of the probe as described in claim 4 or 5, for: marking the location of Piezo2 in cells.

7. A pharmaceutical composition, characterized in that: It includes any polypeptide derivative or combination thereof as described in claim 2.

8. The pharmaceutical composition according to claim 7, characterized in that: It contains a polypeptide derivative with the amino acid sequence SEQ ID No.1 and a palmitic acid group modified by the cysteine ​​residue at the first position of the polypeptide chain.

9. The pharmaceutical composition according to claim 7 or 8, characterized in that: The dosage form of the pharmaceutical composition is a topical preparation.

10. Use of the pharmaceutical composition according to any one of claims 8 to 9, for use in any one of the following groups: (i) Improve tactile sensitivity; (ii) Enhance the pleasure of human sexual life.

11. A method for enhancing sexual pleasure, characterized in that, The method includes the steps of administering to a subject an effective amount of the polypeptide derivative as described in claim 3, or the pharmaceutical composition as described in claim 8 or 9.

12. A method for improving tactile sensitivity, characterized in that: The method includes the steps of administering to a test subject an effective amount of the polypeptide derivative as described in claim 3, or the pharmaceutical composition as described in claim 8 or 9.

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