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CN-121974815-A - Lipid compound for enhancing immune response level and preparation method and application thereof

CN121974815ACN 121974815 ACN121974815 ACN 121974815ACN-121974815-A

Abstract

The invention discloses a lipid compound for enhancing immune response level, a preparation method and application thereof. The lipid compounds of the present invention have symmetrical tail carbon chains comprising formula I A compound represented by X. The invention also provides lipid nanoparticles, drug delivery systems, and pharmaceutical compositions comprising the lipid compounds. The lipid compound disclosed by the invention can promote the activation of cell mitochondria and enhance the cell metabolism level, so that the immune response is obviously improved, and the lipid compound has a wide application prospect in the fields of mRNA vaccine, protein vaccine, CAR-T cell treatment and the like.

Inventors

  • XIA YUFEI
  • YAN YUMENG
  • MA GUANGHUI
  • HUANG XIAONAN
  • Ming Yali
  • MA YISHAN

Assignees

  • 中国科学院过程工程研究所

Dates

Publication Date
20260505
Application Date
20260407

Claims (10)

  1. 1. A lipid compound for enhancing immune response level, characterized in that the lipid compound comprises a main chain and tail branches positioned at two ends of the main chain, wherein the main chain and the tail branches are covalently connected through carbonyl-containing groups, the main chain has a bilateral symmetry structure along the center, the tail branches comprise a first branched chain and a second branched chain with the same structure, the first branched chain and the second branched chain are carbon chains with 6-16 carbon atoms, the structure of the main chain is shown as a formula I-a, the structure of the carbonyl-containing groups is shown as a formula I-b, The compounds of the formula I-a, Formula I-b; Wherein R 1 and R 2 are the same and have a carbon chain of 5 to 8 carbon atoms, R 3 is a carbon chain of 4 to 6 carbon atoms and the end contains a hydroxyl group, and R 4 and R 5 are independently selected from a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, a methylene group, a methine group or an imino group.
  2. 2. A lipid compound for enhancing the level of an immune response according to claim 1, selected from the group consisting of compounds represented by formulas I-X: The compound of the formula I, The compound of the formula II is shown in the specification, The compound of the formula III, The compound of the formula IV, The characteristic of the V-shaped alloy is that, A compound of the formula VI, The compound of the formula VII, The catalyst of formula VIII, The composition of the material IX, Formula X.
  3. 3. A process for the preparation of a lipid compound for enhancing the level of immune response, characterized in that the lipid compound is selected from the group consisting of compounds of the formulae I-X as defined in claim 2, wherein, The compounds of formula I are prepared by the following method: reacting carboxylic acid compounds and bromoalkane in an organic solvent at 10-30 ℃ for 1-5 h to obtain an intermediate I-1; (I-2) reacting said intermediate I-1 with an amino alcohol in an organic solvent at 50-70 ℃ in the presence of a catalyst for 10-20 h to obtain a compound of formula I; The compound of formula II is prepared by the following method: (II-1) reacting a bromoamine compound with an activated ester compound in an organic solvent at 10-30 ℃ for 2-10 h to obtain a carbamate intermediate II-1; (II-2) reacting the carbamate intermediate II-1 with a dialkylamine compound in an organic solvent at 70-100 ℃ for 10-20 h to obtain intermediate II-2; (II-3) reacting said intermediate II-2 with an amino alcohol in an organic solvent at 50-90 ℃ in the presence of a catalyst for 10-20 h to obtain a compound of formula II; the compound of formula III is prepared by the following method: (III-1) reacting a secondary alcohol compound and an imidazole derivative in an organic solvent at 40-80 ℃ for 2-8 h to obtain an intermediate III-1; (III-2) reacting the intermediate III-1 with a halohydrin compound in an organic solvent at 10-40 ℃ for 10-20 h to obtain intermediate III-2; (III-3) reacting said intermediate III-2 with an amino alcohol in an organic solvent at 60-100 ℃ in the presence of a catalyst for 10-20 h to give a compound of formula III; the compound of formula IV is prepared by the following method: (IV-1) reacting a triamine compound and a carbonate in an organic solvent at 10-30 ℃ for 5-15 h to obtain an aminocarbonate intermediate; (IV-2) reacting an amino alcohol compound with a carbonic ester, and then reacting with a sulfonyl chloride compound in an organic solvent at 10-30 ℃ for 1-10 h to obtain a sulfonate intermediate; (IV-3) reacting the sulfonate intermediate with the aminocarbonate intermediate in an organic solvent at 70-100 ℃ for 36-48 h to provide a carbamate intermediate; (IV-4) reacting the carbamate intermediate with a carboxylic acid compound in an organic solvent at 10-30 ℃ for 1-5 h to obtain a triamine intermediate; (IV-5) reacting the triamine intermediate with an activated carboxylic acid compound in an organic solvent at 10-30 ℃ for 5-15 h to obtain a compound of formula IV; the compound of formula V is prepared by the following method: (V-1) reacting a triamine compound with an amino alcohol compound in an organic solvent at 10-30 ℃ for 5-15 h to obtain a triamine intermediate V-1; (V-2) reacting an alcohol compound and a carbonate compound in an organic solvent at-25 ℃ to-15 ℃ for 0.5-2 h, and continuing to react at 10-30 ℃ for 1-5 h to obtain an active carbonate intermediate V-2; (V-3) reacting said intermediate V-1 and said intermediate V-2 in an organic solvent at 10-30 ℃ for 5-15 h to give a compound of formula V; the compound of formula VI is prepared by the following method: (VI-1) reacting a bromoacid compound and an acyl chloride compound in an organic solvent at 10-30 ℃ for 1-6 h to obtain an acyl chloride intermediate; (VI-2) reacting a thiol compound and the acid chloride intermediate in an organic solvent at 10-30 ℃ for 5-15 h to obtain a bromosulfate intermediate; (VI-3) reacting the bromothioester intermediate with an amino alcohol in an organic solvent at 70-100 ℃ for 24-36 h to provide a thioester intermediate; (VI-4) reacting said thioester intermediate with said bromosulfate intermediate in an organic solvent at 70-100 ℃ for 36-48 h to provide a compound of formula VI; Formula VII is prepared by the following method: (VII-1) reacting an alkyl alcohol compound and an acyl chloride reagent in an organic solvent at 10-30 ℃ under alkaline conditions for 1-5 h to obtain chloroformate; (VII-2) reacting the chloroformate and bromoalcohol compound in an organic solvent at 10-30 ℃ for 5-15 h to give a 5-bromopentylcarbonate intermediate; (VII-3) reacting the 5-bromopentylcarbonate intermediate with an amino alcohol compound in an organic solvent at 70-100 ℃ for 36-47 h to give a compound of formula VII; formula VIII is prepared by the following method: (VIII-1) reacting an alkyl alcohol compound and an acyl chloride reagent in an organic solvent at 10-30 ℃ for 1-5 h under alkaline conditions to obtain chloroformate; (VIII-2) reacting the chloroformate and bromoalcohol compound in an organic solvent at 10-30 ℃ for 5-15 h to obtain a 5-bromopentylcarbonate intermediate; (VIII-3) reacting the 5-bromopentylcarbonate intermediate with an amino alcohol compound in an organic solvent at 70-100 ℃ for 48-59 h to give a compound of formula VIII; Formula IX is prepared by the following method: (IX-1) reacting an alkyl alcohol compound and an acyl chloride reagent in an organic solvent at 10-30 ℃ under alkaline conditions for 1-5 h to obtain chloroformate; (IX-2) reacting the chloroformate and bromoalcohol compounds in an organic solvent at 10-30 ℃ for 5-15 h to give a 5-bromopentylcarbonate intermediate; (IX-3) reacting the 5-bromopentylcarbonate intermediate with an amino alcohol compound in an organic solvent at 70-100 ℃ for 60h to give a compound of formula IX; Formula X is prepared by the following method: (X-1) reacting an alkyl alcohol compound and an acyl chloride reagent in an organic solvent at 10-30 ℃ under alkaline conditions for 1-5 h to obtain chloroformate; (X-2) reacting the chloroformate and bromoalcohol compound in an organic solvent at 10-30 ℃ for 5-15 h to obtain a 5-bromopentylcarbonate intermediate; (X-3) reacting the 5-bromopentylcarbonate intermediate with an amino alcohol compound in an organic solvent at 70-100 ℃ for 61-72 h to give a compound of formula X.
  4. 4. The method for producing a lipid compound for enhancing an immune response level according to claim 3, wherein the organic solvent comprises at least one of methylene chloride, N-dimethylformamide, toluene, acetonitrile, N-hexane and tetrahydrofuran, and the catalyst comprises at least one of an alkali metal halide and an organic base.
  5. 5. Lipid nanoparticle, characterized in that it comprises a lipid compound according to claim 1 or 2.
  6. 6. A drug delivery system, characterized in that it comprises a lipid compound according to claim 1 or 2 or a lipid nanoparticle according to claim 5.
  7. 7. A pharmaceutical composition, characterized in that it comprises a lipid compound according to claim 1 or 2, a lipid nanoparticle according to claim 5 or a drug delivery system according to claim 6.
  8. 8. Use of a lipid compound or a lipid nanoparticle according to claim 1 or 2 for the preparation of a drug delivery system, wherein the lipid compound is a lipid compound according to claim 5.
  9. 9. Use of a lipid compound, a lipid nanoparticle or a drug delivery system for the preparation of a pharmaceutical composition, characterized in that the lipid compound is a lipid compound according to claim 1 or 2, the lipid nanoparticle is a lipid nanoparticle according to claim 5, and the drug delivery system is a drug delivery system according to claim 6.
  10. 10. A method of enhancing the level of an immune response in a cell in vitro, comprising the step of contacting the cell in vitro with a lipid compound according to claim 1 or 2, a lipid nanoparticle according to claim 5 or a drug delivery system according to claim 6.

Description

Lipid compound for enhancing immune response level and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicine, and particularly relates to a lipid compound for enhancing immune response level, and a preparation method and application thereof. Background Treatment and prevention strategies based on messenger ribonucleic acid (mRNA), such as mRNA vaccines and chimeric antigen receptor T cell (CAR-T) therapies, have shown great potential in the treatment of infectious diseases, cancer and genetic diseases. The core of these techniques is the efficient and safe delivery of nucleic acid molecules encoding specific antigens or CARs into target cells (e.g., dendritic cells or T cells). Lipid nanoparticles (Lipid Nanoparticles, LNPs) play a key role in protecting nucleic acids from degradation, promoting cellular uptake and endosomal escape as one of the most advanced, most mature non-viral delivery systems currently. Among the components LNPs, ionizable lipids are core functional ingredients. The mechanism of action is positively charged at acidic pH, thereby condensing negatively charged nucleic acid molecules (e.g., mRNA) and facilitating endosomal escape. Currently, the most commonly used ionizable lipids, such as ALC-0315 and SM-102, employ asymmetric tail structure designs. However, this design is mainly focused on achieving efficient encapsulation of nucleic acids by coulomb forces and by virtue of their ionizable nature, protonation occurs in the acidic environment of the endosome, thus destroying the endosome membrane and releasing the nucleic acids. That is, the design of existing ionizable lipids is primarily focused on improving the delivery efficiency itself, whose function is generally limited to being a structural component. Such lipids lack the ability to actively regulate the functional state of immune cells, and it is difficult to synergistically enhance the level of an immune response of an organism against a particular antigen while delivering antigen information. Thus, there is a need for lipid compounds for enhancing immune response levels and methods of preparing the same. Disclosure of Invention To solve at least part of the technical problems in the prior art, the invention provides a lipid compound for enhancing immune response level, and a preparation method and application thereof. Specifically, the present invention includes the following. In a first aspect of the present invention, there is provided a lipid compound for enhancing the level of immune response, the lipid compound comprising a main chain and tail branches located at both ends of the main chain, and the main chain and the tail branches are covalently linked through carbonyl-containing groups, wherein the main chain has a bilateral symmetry structure along the center, and the tail branches comprise a first branch and a second branch having the same structure, the first branch and the second branch are carbon chains having 6 to 16 carbon atoms, the structure of the main chain is as shown in formula I-a, the structure of the carbonyl-containing groups is as shown in formula I-b, The compounds of the formula I-a,Formula I-b; Wherein R 1 and R 2 are the same and have a carbon chain of 5 to 8 carbon atoms, R 3 is a carbon chain of 4 to 6 carbon atoms and the end contains a hydroxyl group, and R 4 and R 5 are independently selected from a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, a methylene group, a methine group or an imino group. In certain embodiments, a lipid compound for enhancing the level of an immune response according to the present invention, wherein the lipid compound is selected from the group consisting of compounds represented by formulas I-X: The compound of the formula I, The compound of the formula II is shown in the specification, The compound of the formula III, The compound of the formula IV, The characteristic of the V-shaped alloy is that, A compound of the formula VI, The compound of the formula VII, The catalyst of formula VIII, The composition of the material IX, Formula X. In a second aspect of the present invention, there is provided a process for producing a lipid compound represented by the formula I-X, wherein, The compounds of formula I are prepared by the following method: reacting carboxylic acid compounds and bromoalkane in an organic solvent at 10-30 ℃ for 1-5 h to obtain an intermediate I-1; (I-2) reacting said intermediate I-1 with an amino alcohol in an organic solvent at 50-70 ℃ in the presence of a catalyst for 10-20 h to obtain a compound of formula I; The compound of formula II is prepared by the following method: (II-1) reacting a bromoamine compound with an activated ester compound in an organic solvent at 10-30 ℃ for 2-10 h to obtain a carbamate intermediate II-1; (II-2) reacting the carbamate intermediate II-1 with a dialkylamine compound in an organic solvent at 70-100 ℃ for 10-20 h to obtain