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CN-122011102-A - Cyclic peptide ligand of target asialoglycoprotein receptor, pharmaceutically acceptable salt thereof and application and pharmaceutical composition thereof

CN122011102ACN 122011102 ACN122011102 ACN 122011102ACN-122011102-A

Abstract

The invention relates to the technical field of liver targeting compounds, in particular to a cyclopeptide ligand of a target asialoglycoprotein receptor, a pharmaceutically acceptable salt thereof, an application thereof and a pharmaceutical composition thereof. The invention provides a cyclopeptide ligand of a target asialoglycoprotein receptor, pharmaceutically acceptable salts thereof, application thereof and a pharmaceutical composition. The cyclopeptide ligand has better endocytosis activity.

Inventors

  • TENG PENG
  • ZHANG JIANING
  • ZHOU RUHONG
  • XU YICHEN
  • GUO ZHITAO
  • LI WENJUAN
  • SHEN YUTAO

Assignees

  • 浙江大学

Dates

Publication Date
20260512
Application Date
20260212

Claims (10)

  1. 1. A cyclic peptide ligand targeting an asialoglycoprotein receptor and pharmaceutically acceptable salts thereof, wherein the cyclic peptide ligand has a structure represented by formula I: A formula I; Wherein in formula I, -S-R 0 -S-is-S-S-or ; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 are independently glycine, L-arginine, L-alanine, L-leucine, L-phenylalanine, L-proline, L-aspartic acid, L-lysine, L-glutamine, L-asparagine, L-histidine, L-glutamic acid, L-isoleucine, L-valine, L-methionine, L-tryptophan, L-serine, L-threonine, L-tyrosine or R-cysteine; a. b, c, d, e, f, g and h are independently integers of 0-3; R 13 is-NH 2 、-OH、-NHR 14 OR-OR 14 , R 14 in-NHR 14 and-OR 14 are independently- (CH 2 ) y CH 3 OR- (CH 2 ) y COOH), and y in- (CH 2 ) y CH 3 OR- (CH 2 ) y COOH) is independently an integer between 6 and 20; L 1 is- (NH- (CH 2 ) n ) -CO-or- (NH- (CH 2 CH 2 O) m –CO) p ) -wherein the broken bond at the-NH-position in L 1 is connected with carbonyl in formula I, the broken bond at the-CO-position in L 1 is connected with imino in formula I, n in L 1 is an integer between 1 and 8, m is an integer between 1 and 8, and p is an integer between 0 and 3; l 2 is- (CH 2 ) z -, wherein z is an integer between 0 and 12; L 3 is -CO-(CH 2 ) q -NH-、-(CO-(CH 2 CH 2 O) t -NH) w -、-CO-(CH 2 ) q -NH-CO-(CH 2 CH 2 O) t -NH- or-CO- (CH 2 CH 2 O) t -NH-CO-(CH 2 ) q -NH-, wherein the bond at-CO-in L 3 is connected with imino in formula I, the bond at-NH-in L 3 is connected with X in formula I, q in the -CO-(CH 2 ) q -NH-、-CO-(CH 2 ) q -NH-CO-(CH 2 CH 2 O) t -NH- and-CO- (CH 2 CH 2 O) t -NH-CO-(CH 2 ) q -NH-are independently integers of 6-18, t in the -(CO-(CH 2 CH 2 O) t -NH) w -、-CO-(CH 2 ) q -NH-CO-(CH 2 CH 2 O) t -NH- and-CO- (CH 2 CH 2 O) t -NH-CO-(CH 2 ) q -NH-are independently integers of 1-8, and w in the- (CO- (CH 2 CH 2 O) t -NH) w -is a positive integer of 1-6); x is an isotopic chelator, an oligonucleotide, a binding agent for an extracellular protein or a fluorescent dye.
  2. 2. The cyclopeptide ligand of claim 1, and pharmaceutically acceptable salts thereof, wherein the isotopic chelator comprises 、 Or (b) 。
  3. 3. The cyclic peptide ligand as defined in claim 1, and pharmaceutically acceptable salts thereof, wherein the oligonucleotide comprises ASO, shRNA, miRNA, siRNA or a DNA/RNA hybrid molecule of the sense strand and DNA of interest.
  4. 4. The cyclic peptide ligand and pharmaceutically acceptable salt thereof according to claim 1, wherein the extracellular protein binding agent comprises a membrane protein binding agent, a secreted protein binding agent, or a nucleic acid drug.
  5. 5. The cyclic peptide ligand and pharmaceutically acceptable salt thereof according to claim 1, wherein the fluorescent dye comprises 5FAM, FITC, cy, cy5, cy5.5, or Cy7.
  6. 6. The cyclic peptide ligand as defined in any one of claims 1-5, and pharmaceutically acceptable salts thereof, wherein the cyclic peptide ligand has a structure according to any one of formula I-1 to formula I-4: A formula I-1, A formula I-2, Of formula I-3 or Formula I-4; x in the formulas I-1 to I-4 is independently an isotope chelating agent, an oligonucleotide or a binding agent of extracellular proteins.
  7. 7. The cyclic peptide ligand as defined in any one of claims 1-5, and pharmaceutically acceptable salts thereof, wherein the cyclic peptide ligand is: A formula 1, A formula 2, 3(S), 4 (V), 5, 6 (V), 7, 8 (V), 9. A step of, 10. A, Formula 11, 12, Formula 13, Formula 14, 15, 16. A, 17 (V), 18, Formula 19, 20 Parts of, 21. A third part, Formula 22, 23 Or Equation 24.
  8. 8. The use of a cyclic peptide ligand as defined in any one of claims 1 to 7, and pharmaceutically acceptable salts thereof, in the preparation of RNAi drugs or LYTAC protein degrading agents for degrading extracellular proteins.
  9. 9. The use of claim 8, wherein the RNAi agent comprises a LYTAC protein degrading agent.
  10. 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a cyclic peptide ligand and pharmaceutically acceptable salts thereof; The cyclopeptide ligand and pharmaceutically acceptable salt thereof are the cyclopeptide ligand according to any one of claims 1 to 7 and pharmaceutically acceptable salt thereof.

Description

Cyclic peptide ligand of target asialoglycoprotein receptor, pharmaceutically acceptable salt thereof and application and pharmaceutical composition thereof Technical Field The invention relates to the technical field of liver targeting compounds, in particular to a cyclopeptide ligand of a target asialoglycoprotein receptor, a pharmaceutically acceptable salt thereof, an application thereof and a pharmaceutical composition thereof. Background The liver is the largest metabolic organ of the human body and is involved in the synthesis and metabolism of various chemical substances in the body. Liver-targeted delivery of drugs is a particularly attractive strategy for the treatment of metabolic, cardiovascular and other liver diseases. The asialoglycoprotein receptor (ASGPR) is a well-defined lysosomal targeting receptor, responsible for the clearance of glycoproteins by endocytosis and lysosomal degradation pathways of clathrin reception, and is highly expressed in the liver. Its unique expression pattern, the well-defined binding ligand N-acetylgalactosamine (GalNAc), and the rapid rate of recycling make ASGPR the most effective ligand molecule in liver-specific targeted protein degradation agents as well as liver-targeted drug delivery technologies. The tri-GalNAc glycoligand targeting ASGPR receptor is one of the most important lysosomal mediated endocytosis targeting molecules at present, occupying a central role in lysosomal targeting chimeric (LYTAC) design and drug targeted delivery. GalNAc-induced ASGPR receptors also provide an ideal pathway for the targeted delivery of drug molecules or imaging agents to liver tissue. Further studies have shown that LYTAC molecules designed based on ASGPR ligands are a hotspot in the study of extracellular protein-targeted degradants and have shown unique biological activity and potential drug development. Currently, both Lytac drugs BHV1300 and BHV1400 designed based on tri-GalNac ligand have completed clinical primary experiments. Although clinical results are encouraging, there is still a great room for improvement in the degradation efficiency of target proteins, and a large number of clinical demands are not satisfied. Therefore, the development of novel ASGPR ligand molecules with better endocytic activity and the improvement of drug delivery such as small nucleic acid and the efficiency of degrading pathological extracellular proteins by novel LYTAC drugs are core key technologies which are urgently needed to be solved at present. Disclosure of Invention In view of the above, the present invention aims to provide a cyclic peptide ligand targeting asialoglycoprotein receptor, and pharmaceutically acceptable salts, applications and pharmaceutical compositions thereof. The cyclopeptide ligand has better endocytosis activity. In order to achieve the above object, the present invention provides the following technical solutions: the invention provides a cyclic peptide ligand of a target asialoglycoprotein receptor and pharmaceutically acceptable salts thereof, wherein the cyclic peptide ligand has a structure shown in a formula I: A formula I; Wherein in formula I, -S-R 0 -S-is-S-S-or ; R 1、R2、R3、R4、R5、R6、R7 and R 8 are independently glycine, L-arginine, L-alanine, L-leucine, L-phenylalanine, L-proline, L-aspartic acid, L-lysine, L-glutamine, L-asparagine, L-histidine, L-glutamic acid, L-isoleucine, L-valine, L-methionine, L-tryptophan, L-serine, L-threonine, L-tyrosine or R-cysteine; a. b, c, d, e, f, g and h are independently integers of 0-3; R 13 is-NH 2、-OH、-NHR14 OR-OR 14, R 14 in-NHR 14 and-OR 14 are independently- (CH 2)yCH3 OR- (CH 2)y COOH), and y in- (CH 2)yCH3 OR- (CH 2)y COOH) is independently an integer between 6 and 20; L 1 is- (NH- (CH 2)n) -CO-or- (NH- (CH 2CH2O)m–CO)p) -wherein the broken bond at the-NH-position in L 1 is connected with carbonyl in formula I, the broken bond at the-CO-position in L 1 is connected with imino in formula I, n in L 1 is an integer between 1 and 8, m is an integer between 1 and 8, and p is an integer between 0 and 3; l 2 is- (CH 2)z -, wherein z is an integer between 0 and 12; L 3 is -CO-(CH2)q-NH-、-(CO-(CH2CH2O)t-NH)w-、-CO-(CH2)q-NH-CO-(CH2CH2O)t-NH- or-CO- (CH 2CH2O)t-NH-CO-(CH2)q -NH-, wherein the bond at-CO-in L 3 is connected with imino in formula I, the bond at-NH-in L 3 is connected with X in formula I, q in the -CO-(CH2)q-NH-、-CO-(CH2)q-NH-CO-(CH2CH2O)t-NH- and-CO- (CH 2CH2O)t-NH-CO-(CH2)q -NH-are independently integers of 6-18, t in the -(CO-(CH2CH2O)t-NH)w-、-CO-(CH2)q-NH-CO-(CH2CH2O)t-NH- and-CO- (CH 2CH2O)t-NH-CO-(CH2)q -NH-are independently integers of 1-8, and w in the- (CO- (CH 2CH2O)t-NH)w -is a positive integer of 1-6); x is an isotopic chelator, an oligonucleotide, a binding agent for an extracellular protein or a fluorescent dye. Preferably, the isotopic chelant comprises、Or (b)。 The cyclopeptide ligand and the pharmaceutically acceptable salt thereof can target ASGPR by utilizing a GalNAc modified cy