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RU-2861676-C2 - LONG-ACTING INSULIN COMPOUND

RU2861676C2RU 2861676 C2RU2861676 C2RU 2861676C2RU-2861676-C2

Abstract

FIELD: biotechnology; medicine. SUBSTANCE: invention discloses a novel compound which is a long-acting insulin. EFFECT: use for treating various metabolic diseases associated with disorders in carbohydrate metabolism, in particular type I diabetes, type II diabetes or gestational diabetes. 7 cl, 10 tbl, 9 ex

Inventors

  • ZHOU, Shuliang
  • WANG, PENG
  • DENG, Lan

Dates

Publication Date
20260507
Application Date
20230809
Priority Date
20220810

Claims (20)

  1. 1. A modified peptide for the treatment or prevention of diabetes, containing:
  2. (I) the amino acid sequence shown in formula I:
  3. Where:
  4. X 1 in formula I is selected from the group consisting of S, CH 2 , NH and CO;
  5. X 2 in formula I is selected from the group consisting of S, CH 2 , NH and CO;
  6. AA1 in formula I is selected from the group consisting of Asp, Glu and Ada;
  7. AA2 in formula I is selected from the group consisting of any encoded amino acid other than Cys and any non-encoded amino acid without an SH group, or is absent;
  8. AA3 in formula I is selected from the group consisting of His, Tyr and Phe;
  9. AA4 in formula I is selected from the group consisting of Asp, Glu and Ada;
  10. AA5 in formula I is selected from the group consisting of His, Tyr and Phe;
  11. AA6 in formula I is selected from the group consisting of any coding amino acid other than Cys and any non-coding amino acid without an SH group;
  12. AA7 in formula I is selected from the group consisting of any encoded amino acid other than Cys and any non-encoded amino acid without an SH group;
  13. AA8 in formula I is selected from the group consisting of any coding amino acid other than Cys and any non-coding amino acid without an SH group;
  14. AA9 in formula I is Thr, or absent;
  15. AA10 in formula I is selected from the group consisting of Lys, Dah, Orn, Dab and Dap, or is absent;
  16. R1 and R2 in formula I represent HO 2 C(CH 2 )n1CO-(γGlu)n2-(PEGn3(CH 2 )n4CO)n5-; and
  17. R1 and R2 in formula I are not present simultaneously;
  18. n1 is an integer chosen from 10-25;
  19. n2 is an integer chosen from 1-5;
  20. n3 is an integer chosen from 1-30;

Description

Cross-reference to related applications [0001] This application claims priority to Chinese Patent Application No. 202210956232.9, filed with the National Intellectual Property Administration of China on August 10, 2022, and entitled "Long-acting insulin compound", the disclosure of which is incorporated herein by reference in its entirety. State of the art [0002] The present invention relates to the field of pharmaceutical synthesis, in particular to a long-acting insulin compound. Field of technology Insulin is a protein hormone secreted by pancreatic B cells when stimulated by endogenous or exogenous substances such as glucose, lactose, ribose, arginine, and glucagon. Insulin is the only hormone in the body that lowers blood sugar levels and promotes the synthesis of glycogen, fat, and protein. Exogenous insulin is primarily used to treat diabetes. [0004] Unlike other recombinant protein therapeutics, insulin, as a hormone that regulates blood sugar levels, has a very narrow therapeutic window, and its blood concentration must be strictly controlled. If it is too high, hypoglycemia or even shock and death may occur, while if it is too low, hyperglycemia may develop. Therefore, insulin cannot be administered intravenously and can only be slowly released into the blood by subcutaneous injection. Furthermore, sugar consumption during three meals a day requires insulin regulation during meals, and basal blood sugar levels are regulated by basal insulin. Consequently, the physiological insulin curve is extremely complex, which determines the goal of developing rapid-acting and long-acting insulin. [0005] Insulin preparations are usually formulated as 100 IU/mL preparations, and at this concentration, insulin typically forms dimers and then hexamers. After subcutaneous injection of insulin, the hexamer gradually releases dimers and monomers, which enter the bloodstream to exert their effect. Since insulin takes 4-6 hours to act, which is longer than insulin produced during meals, hypoglycemia can easily occur 2 hours after a meal. Furthermore, its action period is too short compared to basal insulin. Protamine can bind to insulin and form a precipitate, resulting in slow dissolution and release of insulin after subcutaneous injection, and the time of action increases to more than 10 hours, so it is usually administered twice daily. Although protamine insulin has partially solved the problem, it is still far from the insulin secretion curve in physiological state, and it is a suspension due to its precipitation properties, which makes it difficult to ensure accurate dose control. [0006] Sanofi's insulin glargine has a similar sustained-release effect to protamine. The addition of two essential amino acids, arginine at the end of the B chain, changes the isoelectric point of insulin glargine from 5.4 to 6.7. After subcutaneous injection, insulin glargine is close to the isoelectric point and forms a precipitate that slowly dissolves and is released into the blood. However, insulin glargine must be in the form of an acidic preparation to be soluble as a result of the change in its isoelectric point. Asparagine at position A21 of the A chain, which is prone to deamidation, is mutated to glycine, which is also the reason for the name insulin glargine. The half-life of insulin glargine is 12 hours, its duration of action is 20-24 hours, and it is administered once daily. [0007] Novo Nordisk developed a new generation of long-acting insulin degludec, which was successfully launched in 2013. In insulin degludec, the threonine at position B30 is removed and the 16-carbon fatty acid chain is linked to lysine at position B29 via a glutamic acid-based linker. The fatty acid chain can bind to plasma albumin and prolong the half-life of insulin. This mechanism is the same as that of insulin detemir. In addition, by optimizing the ratio of linker, fatty acid chain, and zinc ions, insulin degludec is present in the formulation as a double hexamer. After subcutaneous injection, phenol diffuses, and insulin degludec undergoes a conformational change, rapidly converting from double hexamers to a linear multihexamer, typically more than several thousand molecules long. The multihexamer slowly releases the hexamer, dimer, and monomer, which enter the bloodstream to exert their effects. Thanks to these two mechanisms, insulin degludec has a half-life of up to 24 hours and a duration of action of up to 42 hours. [0008] Although the above-mentioned long-acting insulin achieves the goal of once-daily administration, it cannot achieve a longer duration of action, such as once-weekly administration. The essence of the invention [0009] In this regard, the present invention relates to a long-acting insulin compound. [0010] In order to achieve the above object, the present invention provides the following technical solution. [0011] The present invention relates to a compound comprising: [0012] (I) the amino acid sequence shown in formula I,