CN117414438A - Polypeptide coupling drug targeting M1 type macrophage and application thereof - Google Patents

Polypeptide coupling drug targeting M1 type macrophage and application thereof Download PDF

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CN117414438A
CN117414438A CN202311442601.3A CN202311442601A CN117414438A CN 117414438 A CN117414438 A CN 117414438A CN 202311442601 A CN202311442601 A CN 202311442601A CN 117414438 A CN117414438 A CN 117414438A
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tasquinimod
polypeptide
group
targeting
drug
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项红
尚东
陶旭锋
郭方悦
马殊荣
吴昱
孔馨
赵新亚
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First Affiliated Hospital of Dalian Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes

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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention discloses a polypeptide coupling drug targeting M1 type macrophages and application thereof, belonging to the technical field of polypeptide coupling drugs. The polypeptide coupling drug M1pep-Tasquinimod consists of a polypeptide targeting M1 type macrophages, a linker and a modified Tasquinimod, can reduce the toxicity of the Tasquinimod, inhibits M1 type polarization of macrophages by targeting pro-inflammatory M1 type macrophages, and reduces pancreatic tissue damage of acute pancreatitis mice, and provides a basis for using the M1pep-Tasquinimod as a novel drug for treating inflammatory diseases.

Description

Polypeptide coupling drug targeting M1 type macrophage and application thereof
Technical Field
The invention belongs to the technical field of polypeptide coupled drugs, and particularly relates to a polypeptide coupled drug targeting M1 type macrophages and application thereof.
Background
Acute Pancreatitis (AP) is a common digestive system disease. About 20% of AP patients continue to develop inflammation, which can progress to severe pancreatitis with mortality exceeding 30%. Imbalance of the response of proinflammatory cytokines and anti-inflammatory cytokines causes disturbance of the immune regulation system of the organism, induces inflammatory cascade reaction, and is a key factor for the severe of AP. Macrophages are used as the first immune defense line of a human body and play an important role in maintaining homeostasis, inflammation microenvironment and the like. In recent years, macrophage polarization has received extensive attention from the scientific community, and a variety of inflammation-related diseases have been demonstrated to be associated with macrophage polarization. Mature macrophages are highly plastic and are largely divided into different surface antigens and functions: a classical activated (M1) type with pro-inflammatory function and an alternate activated (M2) type with anti-inflammatory phenotype. Stimulation with interferon-gamma, lipopolysaccharide (LPS), granulocyte/macrophage colony-stimulating factor (G/M-CSF) or other toll-like receptor (TLR) ligand promotes macrophage M1-type polarization, and the polarized macrophages express a large number of pro-inflammatory cytokines (such as TNF-alpha, IL-1β and IL-6) and specific chemokines (such as CCL2-5, CCL8, CXCL-2, CXCL-4 and CXCL-9), inducing Th 1-type cellular immune responses, which are important drivers for AP-criticality. Thus, drug therapy targeting M1-type macrophages may become an important intervention in the inflammatory cascade.
S100A9 is a calbindin, mainly expressed in the mononuclear-macrophage cell line in a limited manner, with dual anti-inflammatory and pro-inflammatory effects. Our earlier studies found that S100A9 plays an important role in the development of pancreatitis. S100A9 and TLR4 are combined to activate NF-k B, so that the pro-inflammatory function of macrophages can be induced, and the polarization of M2 type macrophages can be inhibited. Taquinimod (CAS No. 254964-60-8) is an orally active quinoline-3-carboxamide, an experimental drug for the treatment of solid tumors currently under investigation. Tasquinimod acts as a small molecule oral inhibitor of S100A9, which inhibits the interaction between S100A9 and its late glycosylation end product ligand receptor and Toll-like receptor 4. However, tasquinimod has a certain toxicity, and a long-term administration of a large dose may cause irreversible injury to the human body. The success of antibody-conjugated drugs (ADCs) has opened the window of the "universal conjugated era". Compared with the ADC medicine, the polypeptide coupled medicine (PDC) has the advantages of small molecular weight, strong penetrability, low immunogenicity, low production cost and the like, and is expected to become a new generation of targeting medicine after the small molecular medicine, the monoclonal antibody and the ADC medicine. Current PDC studies focus on targeting antitumor drugs, and there is no related study on PDC targeting M1-type macrophages to treat inflammatory diseases.
Disclosure of Invention
In view of the above, the invention aims to provide a polypeptide coupled drug targeting M1 type macrophages and application thereof, which can inhibit M1 type polarization of macrophages by targeting pro-inflammatory M1 type macrophages and relieve sodium taurocholate-induced acute pancreatitis of mice.
The invention aims at realizing the following steps:
the invention provides a polypeptide coupling drug targeting M1 type macrophages, which consists of a polypeptide targeting M1 type macrophages, a linker and a modified Tasquinimod.
Based on the above technical scheme, further, the polypeptide is FSDDCYDCRIPR or VHAVPIRTIYYP.
Based on the technical scheme, further, the amino acid sequence of the linker is GGGSKKK.
Based on the above technical scheme, further, the structure of the modified Tasquinimod is as follows:
based on the technical scheme, further, the structure of the polypeptide coupling drug is as follows:
in another aspect, the invention provides a pharmaceutical composition comprising an effective amount of the polypeptide-conjugated drug described above and a pharmaceutically acceptable carrier.
Based on the technical scheme, the pharmaceutically acceptable carrier further comprises a filling agent, a diluting agent, an adhesive, a disintegrating agent, an emulsifying agent and a medicine carrying carrier without toxic or side effect.
The invention also provides application of the polypeptide coupling medicine and the medicine composition in preparing medicines for improving acute pancreatitis.
Based on the technical scheme, the dosage forms of the medicine comprise tablets, granules, oral liquid preparations, drops, injection preparations and capsule preparations.
Compared with the prior art, the invention has the following beneficial effects:
the invention adopts the polypeptide coupled drug M1pep-Tasquinimod targeting the M1 type macrophage to inhibit the polarization of the M1 type macrophage in vitro and treat an acute pancreatitis mouse model in vivo, proves that the M1pep-Tasquinimod can inhibit the polarization of the M1 type macrophage induced by LPS and lighten the pancreatic tissue lesion of the acute pancreatitis mouse, and provides a basis for using the M1pep-Tasquinimod as a novel drug for treating inflammatory diseases.
Drawings
In order to more clearly illustrate the embodiments of the present invention, the drawings to which the embodiments relate will be briefly described.
FIG. 1 is a block diagram of M1pep-Tasquinimod, where (a) is FSDDCYDCRIPRGGGSKK- [ K-modified Tasquinimod ], (b) is VHAVPIRTIYYPGGGSKK- [ K-modified Tasquinimod ], (c) is WEDYQWPVYKGWGGGSKK- [ K-modified Tasquinimod ].
FIG. 2 shows the flow cytometry detection of macrophage M1 polarization in different experimental groups, compared with LPS group,
**P<0.01; in contrast to the Tasquinimod group, ## P<0.01。
FIG. 3 shows qPCR detection of M1 type macrophage markers in different experimental groups, compared with LPS group,
**P<0.01; in contrast to the Tasquinimod group, # P<0.05， ## P<0.01。
FIG. 4 shows toxicity test results of mice after administration, wherein (a) HE staining is used for observing pathological damage of heart, liver, spleen, lung, kidney, pancreas and intestinal tissues, and (b) serum creatinine (Cre), urea nitrogen (Bun), ALT and AST contents are shown.
Fig. 5 shows pancreatic HE staining patterns (a, image magnification 200 x) and histopathological scoring results (b) of mice after treatment administration, P <0.01 compared to the AP group; # P <0.01 compared to Tasquinimod-15 group.
FIG. 6 shows serum amylase and lipase detection results of mice after treatment with drug, compared to the AP group<0.01，**P<0.01; in contrast to the Tasquinimod-15 group, ## P<0.01。
Detailed Description
The following detailed description of the invention is provided in connection with examples, but the implementation of the invention is not limited thereto, and it is obvious that the examples described below are only some examples of the invention, and that it is within the scope of protection of the invention to those skilled in the art to obtain other similar examples without inventive faculty.
Example 1
Tasquinimod structural modification, the reaction formula is as follows:
the method comprises the following steps:
(1) In a single-neck flask, concentrated hydrochloric acid (3 mL) with the mass fraction of 38% is slowly added into glacial acetic acid (9 mL), then a compound 1Cas:248282-13-5 (1 g,1 eq) is added, then the mixture is heated to 70 ℃ for reaction for 18 hours, LCMS monitors the generation of a product, and after the raw material disappears, the reaction solution is cooled to room temperature. The solid formed was filtered and washed with ethanol (20 mL). Oven drying to give compound 2 (0.6 g,66% yield) as a white solid;
(2) In a one-necked flask, HATU (1.83 g,2 eq), DIPEA (0.94 g,3 eq) were added sequentially to a solution of compound 2 (0.6 g,1 eq) in DMF (10 mL)/THF (10 mL) and stirred at room temperature for 10min, then compound 2a (0.48 g,1.2 eq) was added and then stirred at 50℃for 2 hours. LCMS monitored product formation and starting material disappeared. Adding dilute hydrochloric acid to adjust pH to 6-7, concentrating, purifying with 4.6*150mm,kromasil C18-5 liquid chromatographic column (20% -55% MeCN,0.1% TFA), concentrating, and lyophilizing to obtain yellow oily compound 3 (0.5 g,52.6% yieldd);
(3) To a single-necked flask, 5mL of an aqueous solution of KOH (0.21 g,3 eq) was added a solution of Compound 3 (0.5 g,1 eq) in THF (10 mL) and stirred at 50℃for 4 hours. LCMS monitors the product formation, the material disappeared, adding dilute hydrochloric acid to adjust pH to 5-6, concentrating, pouring out water, adding 5ml of anhydrous methanol into the yellow viscous substance at the bottom, carrying out ultrasonic treatment, filtering, and drying to obtain white solid compound 4 (0.2 g,41.5% yield);
(4) DCC (0.13 g,1.2 eq) was added to a suspension of compound 4 (0.2 g,1 eq) in DMF (5 mL) followed by sequential addition of compound 4a (90 mg,1.5 eq), DMAP (6.4 mg,0.1 eq) and stirring at 50℃for 2 hours. Filtration, purification of the filtrate by 4.6*150mm,kromasil C18-5 liquid chromatography (20% -50% MeCN,0.1% tfa), concentration and lyophilization gave the white solid modification tasquinimod (0.12 g,48% yield,97.8% purity, m+h+= 480.1).
M1pep-Tasquinimod chemical Synthesis
(1) Swelling of the resin: weighing resin, putting into a reaction column, adding DCM into the reaction column, oscillating for 30min, and activating for later use. (2) ligating the first amino acid: the DCM solvent was filtered off with sand core suction, the first amino acid was added, 10 times the molar amount of DIEA was added, and finally a small amount of DMF was added for dissolution and shaking for 1 hour. After the reaction was completed, the reaction mixture was washed with DMF and DCM alternately 6 times. (3) deprotection: 20% piperidine/DMF solution was added, after 5min, the solution was removed, and then 20% piperidine/DMF solution was added and the mixture was shaken for 15min. (4) detection: pumping off piperidine solution, taking more than ten resin particles, washing with ethanol for three times, adding ninhydrin, pyridine and phenol into the resin particles, heating the mixture for 5 minutes at the temperature of 105-110 ℃ respectively, turning into blue positive, continuing to connect the next amino acid, and carrying out deprotection again if no color change exists, and if no color change exists, the reaction is negative. (5) first cleaning: sequentially washing twice with DMF, methanol and DMF respectively. (6) condensation: the amino acid with protecting group, condensing agent HBTU, was added and dissolved in a small amount of DMF, DIEA was added immediately and reacted for 30min. (7) second cleaning: sequentially washing twice with DMF, methanol and DMF respectively. (8) detection: extracting solvent, collecting more than ten resin, washing with ethanol for three times, adding ninhydrin, pyridine and phenol, heating at 105-110deg.C for 5min, and condensing again if blue. (9) extension of peptide chain: repeating the above steps, and sequentially grafting the rest amino acids. (10) grafting an activated small molecule: 2% hydrazine hydrate/DMF solution was added, the mixture was withdrawn after 5min, the operation was repeated 2 times, the above-mentioned activated molecule of Tasquinimod was added, dissolved in a small amount of DMF, DIEA was immediately added, and the reaction was carried out for 30min. (11) detection: the solvent is pumped out, more than ten resin particles are taken, ethanol is used for three times, ninhydrin, pyridine and phenol are added, one drop of each of the ninhydrin, the pyridine and the phenol is heated for 5 minutes at the temperature of 105-110 ℃, the colorless positive reaction is realized, and the recondensing is needed if the colorless positive reaction is blue. (12) shrinkage of peptide chain: after the last amino acid is grafted, the synthesis of the whole peptide is completed, the final shrinkage stage is entered, the DMF washing reaction is performed for 3 times, the DCM washing reaction is performed for 3 times, the methanol washing reaction is performed for 3 times, and finally the peptide resin is pumped down. (13) deprotection of amino acid side chain and cleavage of resin: 15mL of cutting fluid is prepared, wherein the volume ratio of each component is as follows: TFA (94.5%), water (2%), EDT (2.5%), TIS (1%). The resin was placed in a flask and shaken at constant temperature (30 ℃) for 2 hours. The lysate was dried with nitrogen as much as possible, then poured into a centrifuge tube and slowly poured into diethyl ether. Sealing and centrifuging in a centrifuge for 5min, pouring out supernatant, and collecting white solid below. Washing with diethyl ether for 6 times, and volatilizing at normal temperature to obtain crude peptide.
Three crude peptide samples were obtained in this example, the specific structure of which is shown in FIG. 1, (a) is
FSDDCYDCRIPRGGGSKK- [ K modifies Tasquinimod ], i.e., M1pep1-Tasquinimod; (b) Modification of Tasquinimod for VHAVPIRTIYYPGGGSKK- [ K ], i.e., M1pep10-Tasquinimod; (c) Tasquinimod was modified for WEDYQWPVYKGWGGGSKK- [ K (control drug), i.e., NCpep-Tasquinimod.
Example 2
In this example, raw264.7 cells were inoculated into 6-well plates for culture for 24 hours, and were divided into a control group, a model group, and a drug treatment group (divided into a high-dose group and a low-dose group, each of which includes Taq uinimod group, M1pep1-Tasquinimod, M pep10-Tasquinimod, and NCpep-Tasquinimod group), medium was added to the control group, 1 μg/mL LPS+20ng/mL IFN-gamma medium was added to the model group and the drug treatment group, incubation was performed for 24 hours, medium was aspirated, medium was added, and 20 μM Taq uinimod, M1pep1-Tasquinimod, M1pep10-Tasquinimod, NCpep-Tasquinimod were respectively added to the treatment group, and incubation was performed in an incubator for 24 hours. And collecting cell sediment for subsequent flow cytometry detection, qPCR and other experiments.
Flow cytometry detection: each group of cells was collected in a centrifuge tube, centrifuged at 1000rpm for 5min, the supernatant was discarded, washed once with PBS, and checked on the machine.
qPCR experiment: each group of cell RNAs was extracted using trizol, and reverse transcribed to cDNA using Taq-HS according to the All-in-One First-Strand Synthesis MasterMix (with dsDNase) kit instructionsGreen qPCR Premix (Universal) kit prepares a qPCR system and performs on-machine detection.
As shown in fig. 2-3, the Tasquinimod group significantly reduced the M1 polarization ratio of raw264.7 cells compared to the lps+ifn- γ group (LPS in fig. 2), inhibited M1 macrophage marker iNOS, CD86, TNF- α gene expression, and the M1pep-Tasquinimod group inhibited macrophage M1 polarization better compared to the Tasquinimod group, while the NCpep-Tasquinimod group did not significantly change compared to the Tasquinimod group, suggesting that M1pep-Tasquinimod enhanced the drug effect of Tasquinimod.
Example 3
This example is an in vivo experiment in mice, and a mouse model of acute pancreatitis was induced by retrograde injection of sodium taurocholate into the pancreatic bile duct according to the method reported in the literature (doi: 10.1038/nprot.2009.243). 54C 57BL/6 mice were randomized into model groups, drug treatment groups (into high and low dose groups, each of which included Taq uinimod groups, M1pep1-Tasquinimod, M pep10-Tasquinimod and NCpep-Tasquinimod groups), with 6 mice per group. The specific operation is as follows: mice were fasted for 12h without water deprivation prior to the experiment and isoflurane was inhaled for anaesthesia. After the anesthesia is successful, the patient takes the supine position and fixes the head and the limbs. The incision is made in the middle of the upper abdomen under aseptic operation, the operative field is fully exposed, and the duodenum is lifted and flattened. The bile duct close to the hepatic portal was clamped to prevent drug infusion into the bile duct, the syringe pump was connected with a 31G needle (diameter 0.25 mm), and the operation was performed under a small animal microscope, the needle penetrated the pancreatic bile duct junction, and 30 μl of 5% sodium taurocholate solution was slowly infused in reverse. After the injection is completed, the needle is withdrawn, the pancreas is carefully reset, and the abdomen is closed by suturing layer by layer. After operation, keep warm, fasted and drink water freely. After the control group had been opened in the same way, the pancreatic bile duct was retrograde injected with an equal amount of sterile saline. The drug treatment groups were intraperitoneally injected with Taq uinimod (15 mg/kg,30 mg/kg) and M1pep1-Tasquinimod 2 hours after the end of the surgery, respectively: FSDDCYDCRIPRGGGSKK- [ K-modified Tasquinimod ] (15 mg/kg,30 mg/kg), M1pep10-Tasquinimod: VHAVPIRTIYYPGGGSKK- [ K modified Tasquinimod ] (15 mg/kg,30 mg/kg), NCpep-Tasquinimod:
WEDYQWPVYKGWGGGSKK- [ K modification Tasquinimod ] (15 mg/kg,30 mg/kg); the model group was given an equal volume of physiological saline. 24h after administration, isoflurane was inhaled into anesthetized mice, serum was collected and stored at-80 ℃. Pancreatic, heart, liver, spleen, lung, kidney and part of intestinal tissues are respectively placed in paraformaldehyde tissue fixing solution so as to carry out HE staining to observe pathological changes of the tissues.
HE staining observed pathological lesions of heart, liver, spleen, lung, kidney and intestine, alpha-amylase and lipase assay kits detect serum amylase and lipase levels, creatinine (Cre), urea nitrogen (Bun), ALT and AST assay kits detect serum Cre, bun, ALT and AST levels.
Toxicity test results As shown in FIG. 4, the Taq uinimod group (15 mg/kg,30 mg/kg), the NCpep-Tasquinimod group (15 mg/kg,30 mg/kg), both showed glomerular immobilization and structural failure, suggesting renal toxicity, whereas the M1pep1-Tasquinimod group and the M1pep10-Tasquinimod group showed glomerular injury at a dose of only 30mg/kg, compared to the model group. Compared with the NCpep-Tasquinimod group (30 mg/kg), the Tatuimod group (30 mg/kg) and the NCpep-Tasquinimod group (30 mg/kg) show that immune cells of the spleen are increased, immune hyperfunction occurs, and the Bun content is obviously higher than that of the model group.
HE staining observed pathological lesions of pancreatic tissue, as shown in fig. 5, showed that the tamanimod group (15 mg/kg,30 mg/kg) showed a significant improvement in pancreatic tissue lesions of mice compared to the model group, while the NCpep-tamanimod group (15 mg/kg,30 mg/kg) showed no significant change in pancreatic tissue lesions of mice compared to the tamanimod group (15 mg/kg,30 mg/kg). The results show that Taruinimod has an improving effect on the acute pancreatitis of mice, and M1 pep-Tasequinmod has better treatment effect than Taruinimod alone.
As shown in FIG. 6, the serum amylase and lipase detection results showed that the serum amylase and lipase levels were significantly reduced in mice in the Tasquinimod group (15 mg/kg,30 mg/kg), the M1pep-Tasquinimod group (15 mg/kg,30 mg/kg), and the NCpep-Tasquinimod group (15 mg/kg,30 mg/kg) compared to the model group.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (9)

1. The polypeptide coupling medicine for targeting the M1 type macrophage is characterized by comprising a polypeptide for targeting the M1 type macrophage, a linker and a modified Tasquinimod.
2. The polypeptide-conjugated drug according to claim 1, wherein the polypeptide is FSDDCYDCRIPR or VHAVPIRTIYYP.
3. The polypeptide-conjugated drug according to claim 1, wherein the amino acid sequence of linker is GGGSKKK.
4. The polypeptide-conjugated drug of claim 1, wherein the modified Tasquinimod has the structure:
5. the polypeptide-conjugated drug according to claim 1, wherein the structure of the polypeptide-conjugated drug is as follows:
6. a pharmaceutical composition comprising an effective amount of the polypeptide conjugate of any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable carrier comprises a filler, a diluent, an adhesive, a disintegrant, an emulsifier, and a drug carrier without toxic or side effects.
8. Use of a polypeptide conjugated drug according to any one of claims 1-5, a pharmaceutical composition according to claim 6 or 7 for the manufacture of a medicament for ameliorating acute pancreatitis.
9. The use according to claim 8, wherein the pharmaceutical dosage form comprises tablets, granules, oral liquid preparations, drops, injectable preparations and capsule preparations.
CN202311442601.3A 2023-11-01 2023-11-01 Polypeptide coupling drug targeting M1 type macrophage and application thereof Pending CN117414438A (en)

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