CN117143197A - Peptides for targeted expression of Nectin-4 cells for treating cancers and application thereof - Google Patents
Peptides for targeted expression of Nectin-4 cells for treating cancers and application thereof Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links 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
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The application discloses a peptide for treating cancers by targeting cells expressing Nectin-4, which contains a sequence SEQ ID No.1, and can act on cells with high expression of Nectin-4 to reduce Nectin-4 expression, so that cancer cells are not proliferated any more, and even apoptosis of the cancer cells is induced.
Description
Technical Field
The present application relates to a peptide for treating cancer, and more particularly, to a peptide for treating cancer by targeting Nectin-4-expressing cells.
Background
NECTIN-4 (poliovirus receptor-4, or PVRL 4) is a Ca-independent type 2+ Belonging to the Nectin family of Ig superfamily proteins. Nectin-4 is highly abundant in normal embryonic and fetal tissues, declines in adulthood, and has a limited distribution in healthy tissues. Nectin-4 is highly expressed in a variety of tumor cells such as cervical cancer, urothelial cancer, breast cancer, lung cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, ovarian cancer, pancreatic cancer, bladder cancer, and the like.
Recent studies have also shown the molecular mechanism of Nectin-4 mediated cancer progression, nectin-4 promoting cancer cell proliferation and metastasis by activating WNT- β -catenin and Rac small G proteins in the PI3K-AKT signaling pathway. Nectin-4 also interacts with the tyrosine kinase receptor ERBB2 to promote activation thereof, thereby stimulating the PI3K-AKT signal pathway, promoting proliferation, differentiation, migration, invasion and the like of tumor cells, and has close relationship with the occurrence and metastasis of tumors.
In addition, nectin-4 promotes the attachment of individual cells to juxtaposed cells and maintains the transformation characteristics of breast cancer cells in vitro. Studies have shown that by transfecting siRNA or intravenous injection of anti-Nectin-4 monoclonal antibodies to knock-out Nectin-4, tumor growth in breast cancer cell lines can be inhibited and intercellular contact reduced.
Patients with high expression of Nectin-4 have a poorer post-operative prognosis than patients with lower expression. Importantly, multivariate analysis showed that expression of Nectin-4 had significant independent prognostic value.
It can be said that the overexpression of Nectin-4 is associated with various aspects of tumor progression, such as proliferation, angiogenesis, epithelial to mesenchymal transition, metastasis, DNA repair, tumor recurrence, poor prognosis, and the like. Therefore, targeting Nectin-4 as a therapeutic target may be an effective strategy for treating cancers with high Nectin-4 expression. Nectin-4 is one of the hot targets in the field of tumor treatment at present. PADCEV drugs targeting Nectin-4 were approved by the FDA in 2019 (AstellasPharma US, inc.) on the market, but overall, there are still few cancer therapeutic drugs targeting Nectin-4.
Disclosure of Invention
The present application provides a peptide comprising the sequence of SEQ ID No.1 for use in the treatment of cancer.
Wherein the peptide is preferably one or more selected from the sequences of SEQ ID No.2-SEQ ID No. 6.
SEQ ID No.1
Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.2
Ala-Val-Ala-Phe-Tyr-Ile-Pro-Asp-Gln-Ala-Thr-Leu-Leu-Arg-Gly-Trp-Thr-Arg-Le u-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.3
Ala-Val-Pro-Phe-Tyr-Leu-Pro-Glu-Gly-Gly-Ala-Asp-Asp-Val-Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.4
Ala-Ile-Ala-Tyr-Phe-Ile-Pro-Asp-Gln-Ala-Gln-Leu-Leu-Ala-Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.5
Ala-Val-Pro-Ile-Ala-Asn-Lys-Ser-Glu-Pro-His-Ser-Leu-Ser-Ser-Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.6
Ala-Val-Pro-Ser-Pro-Pro-Pro-Ala-Ser-Pro-Arg-Ser-Asn-Tyr-Asn-Gly-Trp-Thr-Ar g-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
In a second aspect, the application provides a medicament for treating cancer, comprising the peptide, and pharmaceutically acceptable auxiliary materials and/or other active ingredients.
In a preferred embodiment, the pharmaceutically acceptable excipients and/or other active ingredients may be those comprising: amino acid, polysaccharide, vitamin, solvent, dispersing agent, solubilizer, cosolvent, sustained-release agent, emulsifier, colorant, disintegrating agent, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, antiseptic, suspending agent, aromatic, anti-adhesive agent, integrating agent, penetration enhancer, pH regulator, buffer, surfactant, foaming agent, defoaming agent, absorbent, diluent, deflocculant, and release retarder.
In a preferred embodiment, the pharmaceutical product may be one or more of a transdermal preparation and an injectable preparation.
In a preferred embodiment, the pharmaceutical product may be selected from: solutions, lyophilized powders, and the like.
In a preferred embodiment, the cancer may be selected from: cervical cancer, urothelial cancer, breast cancer, lung cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, pancreatic cancer, ovarian cancer, and bladder cancer.
The peptide provided by the application can act on cells with high expression of Nectin-4, and can reduce the expression of Nectin-4, so that cancer cells can not proliferate any more, and even apoptosis of the cancer cells is induced.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. In the drawings:
FIG. 1 is a graph showing the effect of the peptides of the application on Nectin-4 expression levels;
FIG. 2 is a graph comparing the effect of the peptides of the application on Nectin-4 expression;
FIG. 3 is a graph showing tumor volume change after the use of the peptides of the present application.
Detailed Description
The present application provides a peptide and its application, and for the purpose, technical scheme and effect of the present application are more clear and definite, the present application is further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application.
It is noted that the terms "first," "second," and the like in the description and claims of the present application and in the foregoing figures are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order, and it is to be understood that the data so used may be interchanged where appropriate. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
The polypeptides of the application may be synthesized by prior art techniques, for example:
acyl azide process: this is one of the oldest condensation methods, and as early as 1902, the therador Curtius introduced the acyl azide method into peptide chemistry, and amino acid esters were available in organic solvents in addition to free amino acids and peptides condensed with acyl azides in basic aqueous solutions.
Anhydride method/mixed anhydride method/symmetrical anhydride method: the initial consideration of the use of anhydrides for the synthesis of polypeptides was traced back to early studies in 1881 of the synthesis of benzoylglycine by Theodor Curtius; later on, the Theodor Wieland used mixed anhydrides for the synthesis of modern polypeptides; symmetrical anhydrides are highly reactive intermediates for peptide bond formation, and the use of symmetrical anhydride methods in the stepwise extension of peptide chains is becoming increasingly important.
Carbodiimide method: the carbodiimide compound can be used for condensation of amino and carboxyl, and through a great deal of research personnel, a peptide condensation reaction mechanism with carbodiimide as a condensing agent is established, and carboxylate ions are added to protonated carbodiimide to form high-activity O-acyl urea.
Example 1:
in a first-stage clinical experiment, a tumor-bearing mouse model of the triple-negative breast cancer is constructed, then the peptide of the application is injected, the injection is carried out for 5 days (the injection amount is 3mg/kg body weight), and the expression level of Nectin-4 in cancer cells is observed by a imprinting method after 5 days and is compared with a tumor-bearing mouse (a control group) without the injection of the peptide composition of the application. After 12 days of continuous injection, tumor growth was observed.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is widely present in numerous organisms and is expressed at high levels in almost all tissues. It has long been thought that the protein expression level of the enzyme in the same cell or tissue is generally constant and has been used as a standard reference for experimental operations such as RT-PCR and Western blot. Referring to FIG. 1, GAPDH expression is substantially constant in triple negative breast cancer cells and Nectin-4 expression levels are higher in the cancer cells. After injection of the peptide compositions of the application, the expression level of Nectin-4 decreased significantly, and the ratio Nectin-4/GAPDH decreased significantly (from 120% to about 20%).
Referring to fig. 3, in the case where the treatment is not performed, the tumor gradually increases with time, and in the case where the treatment of the present application is performed, the tumor volume starts to decrease greatly after 2 days, and the initial volume is reduced below 10 days later.
Overall, the peptides of the application, nectin-4/GAPDH, are able to decrease by at least more than 85% and are able to significantly inhibit tumor growth.
This demonstrates that the peptide compositions of the application can act against highly expressed Nectin-4, targeting cancer cells that highly express Nectin-4, and thus can targeted release drugs into cancer cells, resulting in no cell proliferation and even programmed apoptosis
Example 2:
the application prepares injection, which comprises the following components in weight ratio: the peptide composition of the application SEQ ID No.2:3%
Sodium chloride: 1%
Propylene glycol: 3%
Acetic acid: 1%
Sodium glacial acetate: 2%
The balance of water and ethanol (volume ratio 10:3).
Example 3:
the application prepares injection preparation, which comprises the following components in percentage by weight:
the peptide composition of the application SEQ ID No.3:3%
Glucose: 1%
Propylene glycol: 3%
Tween-80: 2%
Sodium acetate: 2%
Citric acid: 2%
The other is water and ethanol (volume ratio 5:2) solvent.
Example 4:
the application prepares injection preparation, which comprises the following components in percentage by weight:
the peptide composition of the application SEQ ID No.4:3%
Glucose: 1.5%
Mannitol: 3%
Tween-80: 1%
Acetic acid: 1%
Sodium acetate: 1%
The other is water and ethanol (volume ratio 5:2) solvent.
Example 5:
the application prepares injection, which comprises the following components in weight ratio: the peptide composition of the application SEQ ID No.5:3%
Sodium chloride: 2%
Mannitol: 3%
Citric acid: 1%
Sodium glacial acetate: 2%
The balance being water and ethanol (volume ratio 11:4).
Example 6:
the application prepares injection, which comprises the following components in weight ratio:
the peptide composition of the application SEQ ID No.6:3%
Glucose: 2%
Mannitol: 3%
Propylene glycol: 1%
Glacial acetic acid: 1%
Sodium glacial acetate: 2%
The balance being water and ethanol (volume ratio 11:3).
The above description of the specific embodiments of the present application has been given by way of example only, and the present application is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for the present application will occur to those skilled in the art, and are also within the scope of the present application. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present application without departing from the spirit and scope thereof.
Claims (7)
1. A peptide for targeted expression of Nectin-4 cells for the treatment of cancer, said peptide comprising the sequence of SEQ ID No. 1.
2. The peptide according to claim 1, characterized in that the first peptide is preferably one or several selected from the sequences of SEQ ID No.2-SEQ ID No.6:
SEQ ID No.1
Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.2
Ala-Val-Ala-Phe-Tyr-Ile-Pro-Asp-Gln-Ala-Thr-Leu-Leu-Arg-Gly-Trp-Thr-Arg-Le u-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.3
Ala-Val-Pro-Phe-Tyr-Leu-Pro-Glu-Gly-Gly-Ala-Asp-Asp-Val-Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.4
Ala-Ile-Ala-Tyr-Phe-Ile-Pro-Asp-Gln-Ala-Gln-Leu-Leu-Ala-Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.5
Ala-Val-Pro-Ile-Ala-Asn-Lys-Ser-Glu-Pro-His-Ser-Leu-Ser-Ser-Gly-Trp-Thr-Arg-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val
SEQ ID No.6
Ala-Val-Pro-Ser-Pro-Pro-Pro-Ala-Ser-Pro-Arg-Ser-Asn-Tyr-Asn-Gly-Trp-Thr-Ar g-Leu-Asp-Gly-Pro-Leu-Pro-Ser-Gly-Val-Arg-Val。
3. a medicament for the treatment of cancer, characterized in that it comprises a peptide according to claim 1, together with pharmaceutically acceptable excipients and/or other active ingredients.
4. A pharmaceutical product according to claim 3, wherein the pharmaceutically acceptable excipients and/or other active ingredients comprise: amino acid, polysaccharide, vitamin, solvent, dispersing agent, solubilizer, cosolvent, sustained-release agent, emulsifier, colorant, disintegrating agent, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, antiseptic, suspending agent, aromatic, anti-adhesive agent, integrating agent, penetration enhancer, pH regulator, buffer, surfactant, foaming agent, defoaming agent, absorbent, diluent, deflocculant, and release retarder.
5. A pharmaceutical product according to claim 3, wherein the pharmaceutical product is selected from one or more of a transdermal formulation and an injectable formulation.
6. A pharmaceutical product according to claim 3, wherein the pharmaceutical product is selected from the group consisting of: and (5) solution and freeze-dried powder.
7. A pharmaceutical product according to claim 3, wherein the cancer is selected from: cervical cancer, urothelial cancer, breast cancer, lung cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, pancreatic cancer, ovarian cancer, and bladder cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310774458.1A CN117143197A (en) | 2023-06-28 | 2023-06-28 | Peptides for targeted expression of Nectin-4 cells for treating cancers and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310774458.1A CN117143197A (en) | 2023-06-28 | 2023-06-28 | Peptides for targeted expression of Nectin-4 cells for treating cancers and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117143197A true CN117143197A (en) | 2023-12-01 |
Family
ID=88908826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310774458.1A Pending CN117143197A (en) | 2023-06-28 | 2023-06-28 | Peptides for targeted expression of Nectin-4 cells for treating cancers and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117143197A (en) |
-
2023
- 2023-06-28 CN CN202310774458.1A patent/CN117143197A/en active Pending
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