WO2024104197A1 - Hydrogel peptidique, son procédé de préparation et son utilisation en traitement - Google Patents

Hydrogel peptidique, son procédé de préparation et son utilisation en traitement Download PDF

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WO2024104197A1
WO2024104197A1 PCT/CN2023/129629 CN2023129629W WO2024104197A1 WO 2024104197 A1 WO2024104197 A1 WO 2024104197A1 CN 2023129629 W CN2023129629 W CN 2023129629W WO 2024104197 A1 WO2024104197 A1 WO 2024104197A1
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peptide
hydrogel
host defense
solution
peptide hydrogel
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Chinese (zh)
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闫学海
邢蕊蕊
沈桂芝
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中国科学院过程工程研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to a biomimetic host defense peptide hydrogel, a preparation method and an application thereof.
  • the biomimetic host defense peptide hydrogel has a ⁇ -folded fiber structure and can selectively and specifically regulate the body's immune response through conformational conversion under lipid membrane conditions.
  • the present invention relates to the application of the biomimetic host defense peptide hydrogel in autoimmune diseases, indications or syndromes caused by cancer chemotherapy, radiotherapy and immunotherapy, including related manifestations such as immune inflammation of various organs and mucosal damage and ulcers of the skin, oral cavity and digestive tract system, and belongs to the field of biomaterials.
  • HDPs host defense peptides
  • immune regulatory cells promote the degradation of arginine through the expression of the catabolic enzyme arginase 1 (ARG1). Therefore, providing arginine-containing materials and/or preventing arginine degradation in tumor-associated macrophages (TAMs) can re-stimulate T cell-mediated and NK cell-mediated immune responses.
  • AMG1 arginase 1
  • HDPs In addition, the actual application efficacy of natural HDPs is often strongly affected by environmental components. For example, many natural HDPs lose their direct anti-inflammatory effects in the presence of physiological salt concentrations (e.g., high salt content, especially divalent cations) or certain host factors (such as anionic polysaccharides, apolipoproteins, DNA, F-actin, and glycosaminoglycans). Coupled with problems such as poor absorption, biodistribution, metabolism, and excretion characteristics, HDPs have failed to demonstrate sufficient efficacy in in vitro clinical trials. Secondly, naturally occurring HDPs may also exhibit other functions that are not desirable for drug development, such as the ability to induce mast cell degranulation, the release of histamine and prostaglandins, and the activation of complement factors.
  • physiological salt concentrations e.g., high salt content, especially divalent cations
  • certain host factors such as anionic polysaccharides, apolipoproteins, DNA, F-actin,
  • the present invention aims to provide a peptide hydrogel suitable for autoimmune diseases, indications or syndromes caused by cancer chemotherapy, radiotherapy and immunotherapy, including related manifestations such as immune inflammation of various organs and mucosal damage and ulcers of the skin, oral cavity and digestive system, and an amphipathic peptide that can form the peptide hydrogel.
  • Host defense peptides can participate in the regulation of innate immunity and adaptive immunity by regulating immune effector cells. Studies have found that host defense peptides can affect the entire signal network of immune response. It is expressed throughout the body and mediates a wide range of physiological reactions, making it associated with various inflammatory diseases and autoimmune diseases.
  • the general formula (1) is Cm-IDR-Z or a physiologically acceptable salt thereof.
  • isomers or diastereomers thereof including L-isomers, D-isomers, or isomers, stereoisomers, and isomers mixed with L-isomers and D-isomers.
  • the "physiologically acceptable salt” refers to a salt prepared from a non-toxic base or acid, non-toxic alkali metal, alkaline earth metal, ammonium salts including sodium, potassium, lithium, calcium, magnesium, barium, ammonium, protamine zinc salts; non-toxic acid salts include but are not limited to hydrochlorides, ethanolamine salts, trifluoroacetates, maleates, malates, benzenesulfonates, acetates, tartrates, sulfates, lactates, oxalates, phosphates, etc.; particularly useful are acetate, hydrochloride and phosphate forms.
  • C m is a C 8 to C 18 acyl group, wherein C 8 to C 18 contains a straight chain or branched alkyl group;
  • n is the number of times the peptide sequence is repeated, and is independently any integer from 2 to 5 in each case.
  • Z is a C-capping group, each occurrence of which is independently selected from -COOH or -CONH 2 ;
  • biomimetic host defense peptide of general formula (2) is provided,
  • the general formula (2) is C m -(X 1 X 2 RR) n X 3 -Z;
  • R represents arginine
  • K represents lysine
  • X1 , X2 , and X3 are amino acids
  • X1 is selected from any one of alanine (Ala or A), valine (Val or V), leucine (Leu or L), isoleucine (Ile or I), and phenylalanine (Phe or F)
  • X2 is selected from any one of alanine (Ala or A), valine (Val or V), leucine (Leu or L), isoleucine (Ile or I), proline (Pro or P), and phenylalanine (Phe or F)
  • X3 is selected from any one of Any one of alanine (Ala or A), valine (Val or V), leucine (Leu or L), isoleucine (Ile or I), phenylalanine (Phe or F), tyrosine (Tyr or Y) or tryptophan (Trp or W);
  • biomimetic host defense peptide of formula (3) is provided,
  • the general formula (3) is C m -X 1 X 2 RKX 1 X 2 KRX 3 -Z;
  • biomimetic host defense peptide of general formula (4) is provided,
  • the general formula (4) is C m -X 1 X 2 KRX 1 X 2 RKX 3 -Z;
  • the bionic host defense peptide is an assembly unit for forming a bionic host defense peptide hydrogel.
  • the special secondary structure allows the bionic host defense peptide molecule to further form a three-dimensional structure that can be used as a molecular recognition and enhance the spatial topological structure response.
  • biomimetic host defense peptide is selected from the following sequences:
  • the present invention provides a biomimetic host defense peptide hydrogel, characterized in that it is a hydrogel assembled in a physiologically acceptable medium by structures of general formula (1), general formula (2), general formula (3) or general formula (4) as described in the first aspect.
  • the biomimetic host defense peptide hydrogel Compared with the biomimetic host defense peptide that has not formed a hydrogel, the biomimetic host defense peptide hydrogel has reduced the non-specific hemolytic side effects of membrane damage and enhanced immunomodulatory ability, including the ability to produce a net inhibition of potentially harmful pro-inflammatory responses, and has multi-pathway immunomodulatory ability (regulating pro-inflammatory and anti-inflammatory responses), therefore, it can act as an immunomodulator for both innate and adaptive immune responses.
  • hydrophobic structures such as the plasma membrane, it can spontaneously transform from a ⁇ -folded structure to an ⁇ -helical structure.
  • bionic host defense peptide hydrogel After the bionic host defense peptide hydrogel is formed, it has better chemical stability, improved safety (increased specificity, reduced hemolysis rate), and enhanced pharmacological properties (such as half-life, absorption and efficacy, etc.) than previous bionic host defense peptides.
  • the presence of the above-mentioned biomimetic host defense peptide hydrogel leads to the polarization of macrophages from the pro-inflammatory M1 phenotype to the M2 phenotype, altering the differentiation of DC cells and thus promoting enhanced adaptive immunity.
  • the present invention provides a method for preparing a biomimetic host defense peptide hydrogel as described in the second aspect.
  • the method mainly comprises the following steps:
  • a biomimetic host defense peptide is dispersed in an aqueous medium solution at a certain concentration, and the temperature is increased or ultrasonicated until it is dissolved.
  • the certain concentration in step (1) means that the concentration of the host defense peptide is 0.1-100 mg/mL, preferably 0.5-20 mg/mL, and more preferably 1-10 mg/mL;
  • the aqueous medium solution can be pure water, physiological saline, glucose, PBS solution or Tris buffer solution, etc.;
  • the heating temperature should be controlled at 50-95°C;
  • the ultrasound time is 0.5-30min;
  • step (2) the pH of the solution is adjusted to 4-10, preferably 5.5-8;
  • Increasing the ionic strength of the solution in step (2) refers to adding one or more of physiologically commonly used metal ion salts, such as sodium salts, potassium salts, iron salts and calcium salts, to mix.
  • physiologically commonly used metal ion salts such as sodium salts, potassium salts, iron salts and calcium salts
  • the static aging time is 0.1-72h, preferably 1-24h;
  • the present invention provides an application of the above hydrogel, wherein the application includes the application in the prevention and treatment of oral diseases, autoimmune diseases, inflammatory diseases, wound infections and the like.
  • biomimetic host defense peptide hydrogel of the present invention is used to treat infectious diseases caused by microorganisms, including but not limited to periodontitis, oral mucosal healing disorders, etc.
  • the human body surface is primarily covered by an epithelial layer, which serves as a physical barrier that acts as a first line of defense against invading pathogens and a response to commensal microbiota.
  • epithelial layer serves as a physical barrier that acts as a first line of defense against invading pathogens and a response to commensal microbiota.
  • the oral mucosa is an exception, as the tooth is actually a transmucosal organ, and the interface between each tooth and the mucosa lacks the integrity of tight junctions, making it susceptible to infection by oral bacteria. Periodontitis is considered one of the most common infectious diseases. Therefore, unlike the microbiota in other mucosal sites, such as the gut and skin, the oral microbiota may have a direct and unique impact on the immune system and the health and well-being of the host.
  • the biomimetic host defense peptide hydrogel of the present invention is used to treat inflammatory diseases and inflammatory disorders.
  • Such inflammatory disorders include certain forms of arthritis, including but not limited to osteoarthritis, rheumatoid arthritis, septic arthritis, TNF receptor-associated periodic syndromes, and inflammatory bowel disease, including Crohn's disease and ulcerative colitis.
  • Such diseases include certain forms of inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, irritable bowel syndrome, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, infectious colitis, and indeterminate colitis.
  • inflammatory bowel disease such as Crohn's disease, ulcerative colitis, irritable bowel syndrome, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, infectious colitis, and indeterminate colitis.
  • the autoimmune disease is caused by a disorder or abnormality of the autoimmune system, including but not limited to systemic syndromes such as systemic lupus erythematosus, Sjögren's syndrome, psoriasis, ankylosing spondylitis, scleroderma, rheumatoid arthritis and polymyositis, or a syndrome that affects only one local body system, such as the endocrine system (type 1 diabetes, Hashimoto's thyroiditis, Addison's disease, etc.), skin system (pemphigoid vulgaris), blood system (autoimmune hemolytic anemia), or nervous system (multiple sclerosis).
  • systemic syndromes such as systemic lupus erythematosus, Sjögren's syndrome, psoriasis, ankylosing spondylitis, scleroderma, rheumatoid arthritis and polymyositis
  • a syndrome that affects only one local body system
  • the present invention provides a method for treating immune activation in the case of immunosuppression, which can be administered through conventional intravenous, subcutaneous or intramuscular injection delivery systems due to the high stability and safety of the ⁇ -folded structure under physiological conditions, and may also include but are not limited to oral delivery systems, nasal delivery systems and transmucosal delivery systems.
  • biomimetic host defense peptide and its hydrogel provided by the present invention show great prospects as low-cost and effective anti-inflammatory preparations. They have at least one, multiple or all of the following beneficial effects:
  • the hydrogel of the present invention has good biocompatibility and small toxic and side effects
  • the hydrogel of the present invention has multi-pathway immunomodulatory capabilities (regulating pro-inflammatory and anti-inflammatory responses), which can regulate the dual effects of innate immunity and adaptive immunity, thereby accelerating the healing of the body;
  • the hydrogel of the present invention has good in vivo stability and resistance to enzymatic degradation, and can exert a more lasting effect;
  • the hydrogel of the present invention can be prepared on a large scale through solid phase synthesis, and the cost and quality are controllable.
  • amino acid residues have their conventional meanings as given in the Manual of Patent Examining Procedure, 8th edition, Chapter 2400.
  • alanine is “Ala” or A
  • valine is “Val” or V
  • leucine is “Leu” or L
  • isoleucine is “Ile” or I
  • phenylalanine is “Phe” or F
  • proline is “Pro” or P
  • tyrosine is “Tyr” Y
  • tryptophan is "Trp” or W, etc.
  • Inflammatory disease or "inflammatory condition” means a disease characterized in part by inflammatory mechanisms, such as specific T lymphocyte responses or antibody-antigen interactions leading to the recruitment of inflammatory cells and endogenous mediator chemicals, including but not limited to cytokines, including but not limited to one or more of increased NF- ⁇ B activity, increased TNF- ⁇ production, increased IL-1 ⁇ production, and increased IL-6 production.
  • cytokines including but not limited to one or more of increased NF- ⁇ B activity, increased TNF- ⁇ production, increased IL-1 ⁇ production, and increased IL-6 production.
  • biomimetic host defense peptides of the present invention can be synthesized by solid phase synthesis and purified according to methods known in the art. Any well-known procedures using various resins and reagents can be used to prepare the biomimetic host defense peptides of the present invention.
  • Solid phase peptide synthesis methods are well known and practiced in the art.
  • the synthesis of the biomimetic host defense peptides of the present invention can be carried out according to the general principles of solid phase methods by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain.
  • beta-sheet tendency parameters and hydrophobicity parameters of each amino acid in the peptide sequence are cited from: An algorithm for protein secondary structure prediction based on class prediction, Protein Engineering 1: 289-294 (1987); and Analysis of membrane and surface protein sequences with the hydrophobic moment plot, J Mol Biol. 1984 Oct 15; 179 (1): 125-142.
  • the reference values of each amino acid are shown in Table 1:
  • the hydrophobicity parameter value of the peptide sequence is the sum of the hydrophobicity parameters corresponding to each amino acid in the peptide sequence. The average value after
  • the ⁇ -folding tendency parameter value of the peptide sequence is the average value of the sum of the ⁇ -folding tendency parameter values corresponding to each amino acid in the peptide sequence.
  • Table 3 ⁇ -folding tendency parameter values of host defense peptides involved in the present invention
  • the simulation data summarize that the hydrophobicity parameters and the ⁇ -folding tendency parameters can form a fiber structure of a ⁇ -sheet structure within a certain range.
  • the results show that the bionic host defense peptide of the present invention has a high tendency to form a ⁇ -sheet structure, which is conducive to further forming a hydrogel structure.
  • biomimetic host defense peptide hydrogels of the present invention can be tested using a variety of test systems and animal models to determine structure, functional status and efficacy.
  • IBD Inflammatory bowel disease
  • innate immune cells neutrils, macrophages, dendritic cells, and natural killer T cells
  • adaptive immune cells T cells and B cells
  • TNF- ⁇ interleukin-1 ⁇
  • IL-6 interleukin-6
  • IFN- ⁇ interferon- ⁇
  • cytokines of the interleukin-23-Th17 pathway IL-1 ⁇
  • IL-6 interleukin-6
  • IFN- ⁇ interferon- ⁇
  • the proinflammatory cytokine TNF- ⁇ plays a key role in the inflammatory cascade that causes chronic inflammation observed in IBD. Elevated levels of circulating IL-6 are found in a variety of inflammatory diseases, including Crohn's disease. IL-6 is a key regulator of the inflammatory response. Influencing the production of this cytokine can alter the balance of effector CD4+ T cell subsets and induce B cell antibody production. While IL-6 is mostly produced by innate cells such as neutrophils, macrophages, and mast cells, IL-6 is a bridge between the innate and adaptive immune systems.
  • the MTT method was used to detect cell viability, evaluate the safety of the host defense peptide hydrogel and eliminate the impact of subsequent experiments.
  • the human intestinal epithelial cell line Caco-2 cells, the test concentration of the host defense peptide hydrogel was 0.5mg/mL or 1ug/mL LPS treatment, and the operation was carried out according to the standard MTT procedure.
  • the in vitro inflammatory model of IBD was prepared by stimulating human intestinal epithelial cell line Caco-2 cells transformed by lipopolysaccharide (LPS) to evaluate the effect of host defense peptide hydrogel.
  • LPS lipopolysaccharide
  • LPS has been considered to be a powerful, rapid and continuous stimulator of pathological inflammation and apoptosis of intestinal epithelial cells, which can aggravate intestinal epithelial barrier dysfunction and weaken the defense function of the mucosa against pathogens.
  • low-level expression of epithelial cell TLR4 can limit the recognition of LPS signals and participate in the low responsiveness of normal mucosa to intestinal bacteria.
  • LPS intervention experimental method The grouped cells were inoculated into a 96-well plate, and the cells were pre-cultured with the sample to be tested (0.5 mg/mL) for 2 hours, and then stimulated with LPS at a concentration of 1 ug/mL for 48 hours. The normal blank group was only given an equal volume of PBS solution.
  • the culture supernatant was aspirated and the levels of cytokines TNF- ⁇ , IL-6, and PGE2 secreted by the cells were measured by ELISA according to the standard procedure of the kit.
  • nitric oxide (NO) in the supernatant of each group were measured.
  • LPS or T cells in vivo activate macrophages and polymorphonuclear leukocytes, a large amount of inducible nitric oxide synthase (NOS) and superoxide anion free radicals can be produced, thereby synthesizing a large amount of NO and H 2 O 2 play a very important role in killing invading bacteria, fungi and other microorganisms and tumor cells, organic foreign matter and in inflammatory damage.
  • NOS inducible nitric oxide synthase
  • H 2 O 2 superoxide anion free radicals
  • Oxidative stress damage in the intestine has a promoting effect on the onset and progression of IBD.
  • the amount of ROS generated in the intestinal mucosal tissue of patients with Crohn's disease (CD) is significantly increased, and the upregulated oxidative stress response in the intestinal tissue will damage the barrier function of intestinal epithelial cells and increase their permeability.
  • Detection of cellular ROS content Digest and collect Caco-2 cells after host defense peptide hydrogel/LPS intervention, wash twice with serum-free DMEM medium, and determine the cellular ROS content according to the instructions of the Bio-Tech reagent.
  • Western blot was used to determine the expression levels of inflammation-related proteins and apoptosis-related proteins, including COX-2 (an inducible synthase responsible for the production of inflammatory mediators), TLR4, and NF- ⁇ B.
  • COX-2 an inducible synthase responsible for the production of inflammatory mediators
  • TLR4 apoptosis-related proteins
  • RAW264.7 The host defense peptide hydrogel-induced differentiation of mouse macrophages RAW264.7 can be used to analyze its mechanism in the treatment of inflammatory diseases.
  • the classical method is to use iNOS, CD86 and CD40 to identify M1 macrophages, and MR, CD206 and Arg I to identify M2 macrophages.
  • the sample to be tested (0.5mg/mL) was added for co-incubation for 48h, and then fixed with 4% paraformaldehyde.
  • the cells were incubated with primary antibodies against CD68 (1:200, pan-macrophage marker), CD86 (1:100, M1 marker) or CD206 (1:100, M2 marker) at 4°C overnight and then incubated with the corresponding fluorescent-labeled secondary antibodies for 30 min.
  • the mRNA expression of M1 and M2 macrophage markers in RAW264.7 under each condition was evaluated by qRT-PCR quantitative analysis.
  • mice Female BALB/c mice, 6-8 weeks old, weighing about 25 g, were housed for 3 days at room temperature of 25°C in an animal room with alternating light/dark cycles every 12 h. They were fasted for 24 h before the experiment and had free access to water.
  • the ulcerative colitis model was induced by DSS. DSS-induced inflammation causes vascular and mucosal damage by destroying the epithelial barrier and exposing the lamina intestinal to luminal contents and bacterial antigens. This exposure triggers the activation of inflammatory pathways, leading to increased production of inflammatory cytokines, TNF- ⁇ , IL-1 ⁇ , IL-6, IL-10, IL-12, and IFN- ⁇ .
  • the DSS-induced colitis mouse model was used to evaluate the effect of biomimetic host defense peptide hydrogel.
  • TNBS Trinitrobenzene sulfonic acid
  • TNBS TNBS dissolved in 50% ethanol can produce intestinal lesions, manifested as shortened colon, intestinal bleeding, epithelial necrosis leading to crypt destruction, and increased Th1/Th17 immune response in the colon leading to transmural inflammation, which is similar to Crohn's disease (CD) and is used to study the efficacy of CD.
  • the acute periodontitis model of rats was first established by ligature induction. Six-week-old Wistar rats weighing about 200 g were selected. After intraperitoneal injection of 10% chloral hydrate (3.5 mL/kg) to anesthetize the rats, the rats were fixed on the operating table in a supine position. The upper and lower teeth of the rats were expanded with a spreader. The oral cavity of the rats was disinfected with 75% ethanol. Then, a 0.25 mm orthodontic ligature wire was wrapped around the neck of the left maxillary second molar of the rats.
  • the rats were examined according to the clinical diagnostic criteria of periodontitis: (1) gingival color, shape, and texture; (2) bleeding during periodontal probing; (3) periodontal probing to see whether deep periodontal pockets were formed; (4) whether there was attachment loss.
  • the formation of attachment loss is an indicator to distinguish periodontitis from gingivitis. If the above four criteria were met, the modeling was successful, and then the wire was removed and grouped.
  • Figure 1 is a macroscopic photo and TEM photo of the hydrogel prepared in Example 1
  • Figure 2 is a macroscopic photo and TEM photo of the hydrogel prepared in Example 2
  • Figure 3 is a macroscopic photo and TEM photo of the hydrogel prepared in Example 7
  • FIG. 4 shows the CD spectra of the hydrogel prepared in Example 1 and Comparative Example 1.
  • FIG5 is the CD spectra of the hydrogels prepared in Example 2, Example 3, Example 4, Example 5, Example 6 and Example 7.
  • FIG6 is the CD spectra of the hydrogels prepared in Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5, Comparative Example 6 and Example 7 in SDS solution.
  • FIG. 7 is the rheological curves of the hydrogels prepared in Example 7, Example 8, and Example 9.
  • FIG8 is a graph showing the self-healing and shear-thinning characteristic curves of the hydrogels prepared in Examples 8 and 9.
  • FIG. 9 shows the effect of host defense peptide hydrogel on LPS-induced cell survival rate.
  • Figure 10 shows the effects of host defense peptide hydrogel on the secretion levels of inflammatory factors A) TNF- ⁇ , B) IL-8, C) PGE 2 and D) NO in Caco-2 cells induced by LPS.
  • FIG. 11 shows the effect of host defense peptide hydrogel on the ROS secretion level of Caco-2 cells induced by LPS.
  • FIG. 12 shows the effect of host defense peptide hydrogel on LPS-induced differentiation of mouse macrophages RAW264.7M1/M2.
  • FIG. 13 is a photograph of the colon obtained after dissection after treatment of DSS-induced enteritis.
  • FIG. 14 shows the changes in colon length after treatment of DSS-induced enteritis.
  • FIG. 15 shows the effect of host defense peptides on body weight of animals in DSS-induced experimental colitis model.
  • FIG. 16 shows the DAI scores of host defense peptides on experimental colitis model animals at day 7 of DSS intervention.
  • FIG. 17 shows the changes in colon index after treatment of TNBS-induced enteritis.
  • Figure 18 is a three-dimensional reconstruction of the left maxillary molars of rats in each group, wherein a is a blank group, b is a periodontitis control group, c is a comparative example treatment group, and d is an example treatment group.
  • Figure 19 shows the trabecular microstructure parameters BV/TV, Tb.N, Tb.Sp. and Tb.Th. of each group. ### indicates p ⁇ 0.001 compared with the blank group; *p ⁇ 0.05, **p ⁇ 0.001 compared with the periodontitis group.
  • Figure 20 is an analysis of alveolar bone resorption.
  • A. The marked line is the distance from the cementoenamel junction to the alveolar bone crest (CEJ-ABC).
  • Figure 21 shows the levels of inflammatory factors TNF- ⁇ and IL-1 ⁇ in the serum of rats in each group of the Example, wherein ### indicates p ⁇ 0.001 compared with the blank group; **p ⁇ 0.01 compared with the periodontitis group.
  • peptide refers to the peptide compound in the present invention. It should be noted that the amino acid sequence of the peptide used in the embodiment of the present invention is as recorded in the sequence table, but the peptide used also includes a hydrophobic chain, so its specific structure is as described in the previous text of the present specification.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 1 was dispersed in 0.01 M Hepes buffer at a concentration of 5 mg/mL and heated in a water bath at 85°C for 2 hours until it was completely dissolved.
  • the obtained hydrogel is transparent (Figure 1a), and the TEM characterization results (Figure 1b) show that it is composed of a fiber network.
  • the secondary structure of the hydrogel fiber is further analyzed by CD spectroscopy. As shown in Figure 4, it has a typical characteristic peak of ⁇ -sheet at 220nm.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 2 was dispersed in an aqueous solution at a concentration of 20 mg/mL and heated in an 80°C water bath for 2 hours until it was completely dissolved.
  • Disodium hydrogen phosphate and sodium dihydrogen phosphate (mass ratio 5:1) were added to the above system, wherein the concentration of the sodium salt solution was 10 mM, and the system was naturally cooled to room temperature and aged for 12 h to obtain a bionic host defense peptide hydrogel capable of inverted self-support.
  • the obtained hydrogel is transparent (Figure 2a), and the TEM characterization results (Figure 2b) show that it is composed of a fiber network. Its CD spectrum is shown in Figure 5a, which has typical characteristic peaks of ⁇ -sheet.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 3 was dispersed in 0.01 M Hepes buffer at a concentration of 10 mg/mL and heated in a water bath at 85°C for 2 hours until it was completely dissolved.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 4 was dispersed in 0.01 M Hepes buffer at a concentration of 5 mg/mL and heated in a water bath at 85°C for 2 hours until it was completely dissolved.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 5 was dispersed in 0.01 M Hepes buffer at a concentration of 1 mg/mL and sonicated until it was completely dissolved.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 6 was dispersed in 0.01 M Hepes buffer at a concentration of 5 mg/mL and heated in an 80°C water bath for 2 hours until it was completely dissolved.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 7 was dispersed in water at a concentration of 5 mg/mL and placed at 85°C Heat in a water bath for 0.5 hours until completely dissolved.
  • the obtained hydrogel is transparent (Figure 3a), and the TEM characterization results (Figure 3b) show that it is composed of a fiber network.
  • Its CD spectrum is shown in Figure 5f, which has the typical characteristic peaks of ⁇ -sheet. It is dissolved in 1% SDS solution and left to stand for 24 hours. Its CD spectrum is shown in Figure 6f, which has the typical characteristic peaks of ⁇ -helix.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 8 was dispersed in 0.01 M Hepes buffer at a concentration of 3 mg/mL and heated in a 75°C water bath for 2 hours until it was completely dissolved.
  • biomimetic host defense peptide with the sequence of SEQ ID No. 9 was dispersed in a 0.01 M sodium chloride solution at a concentration of 2.5 mg/mL and sonicated until it was completely dissolved.
  • biomimetic host defense peptide with the sequence of SEQ ID No. 10 was dispersed in 0.01 M Tris-HCl buffer at a concentration of 5 mg/mL and heated in a 65°C water bath for 2 hours until it was completely dissolved.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 11 was dispersed in 0.01 M Hepes buffer at a concentration of 5 mg/mL and heated in a 70°C water bath for 2 hours until it was completely dissolved.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 12 was dispersed in 0.01 M Hepes buffer at a concentration of 15 mg/mL and heated in a 65°C water bath for 2 hours until it was completely dissolved.
  • the concentration of ferric chloride in the solution is 1 mM, naturally cooling to room temperature, and aging for 24 hours to obtain a bionic host defense peptide hydrogel that can stand upside down and support itself.
  • the prepared hydrogel was used for evaluation in a mouse skin abscess model, and the results are shown in FIG16 .
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 33 was dispersed in 0.01 M saline at a concentration of 5 mg/mL and heated in a 75°C water bath for 2 hours until it was completely dissolved.
  • the biomimetic host defense peptide with the sequence of SEQ ID No. 24 was dispersed in 0.01 M glucose solution at a concentration of 5 mg/mL and heated in a 55°C water bath for 2 hours until it was completely dissolved.
  • biomimetic host defense peptide with the sequence of SEQ ID No. 35 was dispersed in 0.01 M Tris buffer at a concentration of 2.5 mg/mL and heated in a 65°C water bath for 1 hour until it was completely dissolved.
  • Example 1 The host defense peptide in Example 1 was dispersed in a 1% SDS solution and allowed to stand for 24 hours to obtain Comparative Example 1. Its CD spectrum is shown in FIG5b , which has typical characteristic peaks of ⁇ -helix.
  • Example 2 The host defense peptide in Example 2 was dispersed in a 1% SDS solution and allowed to stand for 24 hours to obtain Comparative Example 2. The spectrum is shown in Figure 6a, which has typical characteristic peaks of ⁇ -helix.
  • Example 3 The host defense peptide in Example 3 was dispersed in a 1% SDS solution and allowed to stand for 24 hours to obtain Comparative Example 3. Its CD spectrum is shown in FIG6b , which has typical characteristic peaks of ⁇ -helix.
  • Example 4 The host defense peptide in Example 4 was dispersed in a 1% SDS solution and allowed to stand for 24 hours to obtain Comparative Example 4. Its CD spectrum is shown in FIG6c , which has typical characteristic peaks of ⁇ -helix.
  • Example 5 The host defense peptide in Example 5 was dispersed in a 1% SDS solution and allowed to stand for 24 hours to obtain Comparative Example 5. Its CD spectrum is shown in FIG6d , which has typical characteristic peaks of ⁇ -helix.
  • Example 6 The host defense peptide in Example 6 was dispersed in a 1% SDS solution and allowed to stand for 24 hours to obtain Comparative Example 6. Its CD spectrum is shown in FIG6e , which has typical characteristic peaks of ⁇ -helix.
  • Example 4 and Example 5 hydrogels and their corresponding Comparative Examples 3, Comparative Example 4 and Comparative Example 5 was evaluated using an LPS-induced in vitro inflammation model, and the results are shown in Figures 10-11. From the analysis of the results in Figure 10, in each experimental group, the cytokines THF- ⁇ , IL-8, PGE 2 and NO were significantly reduced compared with the inflammation model group (LPS group), showing an anti-inflammatory effect. The hydrogel effect in each embodiment is stronger than that in the comparison group, indicating that the host defense peptide hydrogel can enhance the anti-inflammatory effect.
  • Figure 11 is an evaluation of the ability of different treatment groups to scavenge ROS. The results show that the hydrogel group has better ROS scavenging ability and can more effectively protect cells from oxidative damage.
  • Example 7 According to the method described in 5.1.3, the induction of macrophage M1/M2 differentiation by Example 7, Example 12 and Example 16 was evaluated, and the results are shown in Figure 12.
  • the host defense peptide hydrogel prepared in each example can significantly inhibit M1 subtype macrophages and promote the differentiation of M2 macrophages, which shows that it has the potential to inhibit inflammatory diseases.
  • the Disease Activity Index (DAI) score table was used to evaluate and score patients from three aspects, namely body weight, stool viscosity, and fecal occult blood.
  • the DAI score was the sum of the three indicators.
  • mice with consistent DAI scores were selected for grouping and subsequent experiments.
  • the mice with successful modeling were divided into 6 groups, namely the control group, the model group, and Example 1, with 5 mice in each group.
  • the control group and the model group were gavaged with normal saline (10 mg/kg); the other groups of mice were given 10 mg/kg of the biomimetic host defense peptide gel sample.
  • the improvement of DSS-induced inflammatory bowel disease by Examples 1-4 and Comparative Examples 1-4 was evaluated according to the above method.
  • One week after administration the anesthetized mice were killed and dissected, and the colon of the mice was taken, photographed and the length measured. The results are shown in Figures 13 and 14.
  • the colon length of the normal group mice was 8.0 ⁇ 0.2cm, while the colon length of the colitis model group mice was 5.6 ⁇ 0.1cm, which was significantly increased compared with the normal group mice (p ⁇ 0.01).
  • the length of the colon was significantly reduced compared with the model group, and the colon length of the hydrogel group was lower than that of the group without hydrogel formation, indicating that the hydrogel better reduced the degree of inflammation.
  • the improvement of DSS-induced inflammatory bowel disease in Examples 8-11 was evaluated according to the above method. After administration, the weight of mice was detected every day, and after 7 days of treatment, the DAI scores of each group of mice were evaluated again, and the evaluation DAI scores of each group were calculated. As shown in Figure 15, the weight of mice in the normal group showed a gradual upward trend, while the weight of mice in the colitis model group continued to decrease. After 7 days, the weight loss was nearly 80%. After administration of bionic host defense peptides and their hydrogels, the weight loss trend was significantly alleviated compared with the model group. The corresponding DAI scores (as shown in Figure 16) also showed the same results, indicating that the hydrogel can effectively reduce the symptoms of colitis.
  • TBS Trinitrobenzene sulfonic acid
  • Rats with consistent DAI scores were selected for grouping and subsequent experiments.
  • the rats with successful modeling were divided into 6 groups, namely, control group, model group, and Example 1, with 5 rats in each group.
  • the control group and the model group were gavaged with normal saline (10 mg/kg); the other groups of rats were given 10 mg/kg of biomimetic host defense peptide gel samples.
  • the body weight of the rats was measured every day, and after 7 days of administration, the DAI scores of the mice in each group were evaluated again, and the evaluated DAI scores of each group were calculated.
  • the colon index measurement results of each group of rats after being given different bionic host defense peptide hydrogels The colon index of the normal group of rats was 6.45 ⁇ 0.47 mg/g, while the colon index of the colitis model group of rats was 15.9 ⁇ 0.32 mg/g, which was significantly higher than that of the normal group of rats (p ⁇ 0.01).
  • the colon index was significantly reduced compared with the model group, and the colon index of the hydrogel group was lower than that of the group without hydrogel formation, indicating that the hydrogel better reduced the degree of inflammation.
  • Table 7 The specific data are shown in Table 7 below:
  • the periodontitis animal model was established. Grouping and drug administration: 5 rats without any treatment were used as the blank group; the rats with successful modeling were randomly divided into three groups, with 5 rats in each group.
  • Blank group 50uL of normal saline was injected into the gums of the model teeth;
  • Control group 50uL of normal saline was injected into the gums of the model teeth of periodontitis model mice;
  • Example 1 50uL of Example 1 was injected into the gums of the model teeth of periodontitis model mice;
  • Control Example 1 50uL of Control Example 1 was injected into the gums of the model teeth of periodontitis model mice.
  • the drug was administered once a week for 4 consecutive weeks.
  • Micro-computed tomography was used to examine the alveolar bone of rats.
  • the specific method was as follows: the alveolar bone of rats in each group was scanned with Micro-CT. To ensure the consistency of the measurement standard, the viewing angle of all images was adjusted so that all tooth cusps were located on the same plane and the occlusal plane was not visible from the buccal and palatal sides. Three-dimensional images were reconstructed to quantify the degree of bone destruction. In each sample, the alveolar bone around the maxillary first molar was selected as the region of interest (ROI) for study.
  • ROI region of interest
  • the anterior boundary of the ROI was the mesial part of the mesial root of the left maxillary first molar of the rat; the posterior boundary was the distal part of the distal root of the left maxillary first molar; the upper boundary was the line connecting the bottom of the root bifurcation of the first molar; and the lower boundary was the line connecting the mesial and distal root tips of the first molar.
  • the following bone microstructure parameters were analyzed in the ROI: Bone Volume per Trabecular Volume (BV/TV) is the most commonly used parameter for measuring bone mass in clinical and basic research.
  • trabecular microarchitecture parameters are direct indicators for evaluating bone quality, such as trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular spacing (Tb.Sp).
  • Alveolar bone loss (ABL) was measured along the long axis of the root of the maxillary left first molar.
  • the vertical distance from the cementum enamel junction (CEJ) to the alveolar bone crest (ABC) represented the degree of alveolar bone loss.
  • the distances of six anatomical sites were measured, including three sites on the palate (mesial, middle, and distal) and three sites on the buccal (mesial, middle, and distal).
  • SPSS statistical software was used to perform statistical analysis on the experimental data. The results were expressed as mean ⁇ standard deviation (Mean ⁇ SD). Variance analysis was used for comparison among multiple groups. p ⁇ 0.05 was considered statistically different, and p ⁇ 0.01 was considered significantly different.
  • biomimetic host defense peptide hydrogel has anti-inflammatory activity, significantly reduces the levels of TNF- ⁇ and IL-8, and has good therapeutic effects in chronic inflammatory diseases such as gastrointestinal inflammatory diseases.
  • biomimetic host defense peptide hydrogel has the dual effects of anti-inflammatory and promoting healing, so it has significant therapeutic effects when both infection and inflammation are present. When there is no infection, it can be used to treat inflammation; when there is infection, the hydrogel can be used to prevent inflammation. At the same time, the hydrogel can interrupt the prevention of the potential vicious cycle between chronic bacterial colonization, inflammation and epithelial damage.
  • the present invention illustrates the detailed method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed method, that is, it does not mean that the present invention must rely on the above-mentioned detailed method to be implemented.
  • Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

L'invention concerne un hydrogel peptidique et un peptide amphiphile qui peut former l'hydrogel peptidique. Le peptide amphiphile est un sel qui est acceptable de formule générale (1) Cm-IDR-Z ou un sel physiologiquement acceptable par les tissus de celui-ci, IDR représentant une séquence peptidique ayant au moins deux charges positives, Cm étant un groupe acyle en C8 à C18, et Z étant un groupe de coiffage C. L'hydrogel peptidique a un pic caractéristique positif dans la plage de 190 à 210 nm et un singulet négatif dans la plage de 210 à 230 nm dans un spectre CD ; et après que l'hydrogel peptidique ait été dispersé dans une solution de SDS (laurylsulfate de sodium) 1%, le spectre CD a un pic caractéristique positif dans la plage de 190-200 nm et un doublet négatif dans la plage de 200-210 nm et 215-230 nm.
PCT/CN2023/129629 2022-11-18 2023-11-03 Hydrogel peptidique, son procédé de préparation et son utilisation en traitement WO2024104197A1 (fr)

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