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CN-122011112-A - Anti-cancer short peptide designed based on threonine and analogues thereof and application thereof

CN122011112ACN 122011112 ACN122011112 ACN 122011112ACN-122011112-A

Abstract

The invention discloses an anticancer short peptide designed based on threonine and analogues thereof and application thereof, wherein the anticancer short peptide is obtained by replacing amino acids at different positions with hydroxyl-containing threonine or analogues thereof based on KLLKKLLKKLLKW and then amidating the C-terminal, the structural general formula is KXmLKKLLKKLLKW-NH 2 , wherein X= T, pT, F, Y or pY and p represent phosphorylation, and m is 2, 3, 6,7, 10, 11 or 13 positions. The anticancer short peptide has the advantages of high efficiency, low toxicity, short sequence and the like. The in vitro anti-tumor activity and toxicity experiment result shows that the compound has strong killing effect on various tumor cells, and has low hemolytic toxicity and high therapeutic index. Serum stability experiments further show that the enzyme has higher enzymolysis stability. Scanning electron microscope experiments show that the anticancer short peptide can rapidly kill tumor cells through an effective membrane rupture mechanism. Therefore, the novel high-efficiency low-toxicity polypeptide anticancer drug has good application prospect in the aspects of researching novel high-efficiency low-toxicity polypeptide anticancer drugs, resisting multi-drug resistance and preparing anticancer drugs.

Inventors

  • NI JINGMAN
  • WANG RUI
  • ZHANG YUN
  • WANG YUXIA
  • LIU LINFENG

Assignees

  • 兰州大学

Dates

Publication Date
20260512
Application Date
20251114

Claims (6)

  1. 1. The anti-cancer short peptide is characterized by being obtained by replacing amino acids at different positions with threonine containing hydroxyl groups or analogues with similar hydrophobicity based on KLLKKLLKKLLKW serving as a structural basis and then carrying out C-terminal amidation, wherein the structural general formula is as follows: KXmLKKLLKKLLKW-NH 2 , labeled mX; wherein x= T, pT, F, Y or pY, the pT is phosphorylated threonine, pY is phosphorylated tyrosine, m is a substitution site, m=2, 3, 6, 7, 10, 11 or 13.
  2. 2. The threonine and analog-based designed anti-cancer short peptide of claim 1, wherein said anti-cancer short peptide is: 2T, the amino acid sequence of which is shown as SEQ ID No. 1; Or 2pT with the amino acid sequence KPTLKKLLKKLLKW-NH 2 ; Or 2F, the amino acid sequence of which is shown as SEQ ID No. 2; or 2Y, the amino acid sequence of which is shown as SEQ ID No. 3; Or 2pY, the amino acid sequence of which is KPYLKKLLKKLLKW-NH 2 ; or 3T, the amino acid sequence of which is shown as SEQ ID No. 4; or 6T, the amino acid sequence of which is shown as SEQ ID No. 5; Or 7T, the amino acid sequence of which is shown as SEQ ID No. 6; Or 10T, the amino acid sequence of which is shown as SEQ ID No. 7; or 11T, the amino acid sequence of which is shown as SEQ ID No. 8; or 13T, the amino acid sequence of which is shown as SEQ ID No. 9.
  3. 3. The threonine-and analog-based design of claim 2, wherein said anticancer oligopeptide is 2T, 11T, or 2pT.
  4. 4. The threonine-and analog-based design of claim 3, wherein said anticancer oligopeptide is 2pT.
  5. 5. The use of the threonine and its analogues-based anti-cancer short peptides of any of claims 1-4 for the manufacture of a clinical anti-cancer medicament.
  6. 6. The use of the designed anti-cancer short peptides based on threonine and its analogues according to any of claims 1-4 for anti-tumor multi-drug resistance.

Description

Anti-cancer short peptide designed based on threonine and analogues thereof and application thereof Technical Field The invention belongs to the technical field of biological medicines, relates to a high-efficiency low-toxicity anti-cancer short peptide based on threonine and analogues thereof, and simultaneously relates to application of the anti-cancer short peptide in preparation of clinical anti-tumor medicines and multi-medicine resistance to tumors. Background Cancer is a complex disease that is mainly caused by malignant proliferation and spread of cells, and is medically called malignant tumor, and is one of the major public Health problems worldwide, and its death rate is about one sixth of the total death rate worldwide [ IEEE J. Biomed. Health 2025, 29 (3): 1564-1566]. At present, the common clinical tumor treatment modes are radiotherapy, chemotherapy, operation treatment and combined treatment of operation and chemotherapy [ Nature Rev. Clin. Oncol. 2020, 17 (2): 91-10]. Although the combination therapy of the chemotherapeutic agent and the surgery exhibits a good therapeutic effect, it has no specificity, and thus has strong side effects on normal tissue cells and is costly [ Nature Rev. Clin. Oncol. 2020, 17 (2): 91-10]. Thus, there is an urgent need for a new class of anticancer drugs that have low toxicity and are effective against tumor multidrug resistance. Anticancer peptides (ACPs) are a class of bioactive peptides with broad spectrum antitumor activity and low drug resistance, typically consisting of 10-50 amino acids. Studies show that the cationic amphiphilic anticancer peptide can combine with an anionic cancer cell membrane through electrostatic adsorption and hydrophobic interaction and perturb the cancer cell membrane, thereby exerting high-efficiency anti-tumor activity, has lower cytotoxicity to normal tissues and better selectivity [ IEEE J. Biomed. Health 2025, 29 (3): 1714-1725; curr. Pharm. Biotechnol 2025, 12:1153-1165]. In addition, compared with the traditional anticancer drugs, the anticancer peptide has the characteristics of lower drug resistance and drug resistance and effective resistance to multiple drugs due to the membrane cleavage effect [ Mini-Rev. Med. Chem. 2015, 15:73-81 ]. However, the existing anticancer peptide still has a series of problems of long sequence, high toxicity, poor stability and the like, and limits the clinical application and development of the existing anticancer peptide. Disclosure of Invention The invention aims at providing an anticancer short peptide which has a brand new structure, short sequence, low manufacturing cost, high antitumor activity and low toxicity and is designed based on threonine and analogues thereof. The second purpose of the invention is to provide the application of the anticancer short peptide in preparing clinical anticancer drugs. The invention also provides the application of the anticancer short peptide in resisting tumor multi-drug resistance. In order to achieve the above purpose, the present invention adopts the following technical scheme: 1. structural design of anticancer short peptide based on threonine and analogue thereof The invention provides an anticancer short peptide designed based on threonine and analogues thereof, which is obtained by replacing amino acids at different positions with threonine or analogues with similar hydrophobicity based on KLLKKLLKKLLKW, and then carrying out C-terminal amidation, wherein the structural general formula is as follows: KXmLKKLLKKLLKW-NH 2, labeled mX; wherein x= T, pT, F, Y or pY, the pT is phosphorylated threonine, pY is phosphorylated tyrosine, m is a substitution site, m=2, 3, 6, 7, 10, 11 or 13. Specifically, the structural formula of the anti-cancer short peptide designed based on threonine and the analogues thereof is as follows: LysXmLeuLysLysLeuLeuLysLysLeuLeuLysTrp-NH 2, labeled mX; As the preferable scheme of the invention, the anticancer short peptide is as follows: 2T with the amino acid sequence KTLKKLLKKLLKW-NH 2 as shown in SEQ ID No. 1; or 2pT with the amino acid sequence KPTLKKLLKKLLKW-NH 2; Or 2F, the amino acid sequence of which is KFLKKLLKKLLKW-NH 2, as shown in SEQ ID No. 2; or 2Y, the amino acid sequence of which is KYLKKLLKKLLKW-NH 2, as shown in SEQ ID No. 3; Or 2pY, the amino acid sequence of which is KPYLKKLLKKLLKW-NH 2; or 3T with the amino acid sequence KLTKKLLKKLLKW-NH 2 shown in SEQ ID No. 4; or 6T with the amino acid sequence KLLKKTLKKLLKW-NH 2 shown in SEQ ID No. 5; Or 7T, the amino acid sequence of which is KLLKKLTKKLLKW-NH 2, as shown in SEQ ID No. 6; Or 10T, the amino acid sequence of which is KLLKKLLKKTLKW-NH 2, as shown in SEQ ID No. 7; Or 11T with the amino acid sequence KLLKKLLKKLTKW-NH 2 shown in SEQ ID No. 8; or 13T, the amino acid sequence of which is KLLKKLLKKLLKT-NH 2, as shown in SEQ ID No. 9. The anticancer short peptide is more preferably 2T, 11T or 2pT with low hemolytic toxicity, and most preferably 2pT with hi