CN114452284A - Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter tract - Google Patents

Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter tract Download PDF

Info

Publication number
CN114452284A
CN114452284A CN202210063512.7A CN202210063512A CN114452284A CN 114452284 A CN114452284 A CN 114452284A CN 202210063512 A CN202210063512 A CN 202210063512A CN 114452284 A CN114452284 A CN 114452284A
Authority
CN
China
Prior art keywords
scarring
sting
inhibitor
preparation
application
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202210063512.7A
Other languages
Chinese (zh)
Other versions
CN114452284B (en
Inventor
乐融融
叶慧芳
邵旭
王庆
陆欣蕾
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eye Hospital of Wenzhou Medical University
Original Assignee
Eye Hospital of Wenzhou Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eye Hospital of Wenzhou Medical University filed Critical Eye Hospital of Wenzhou Medical University
Priority to CN202210063512.7A priority Critical patent/CN114452284B/en
Publication of CN114452284A publication Critical patent/CN114452284A/en
Application granted granted Critical
Publication of CN114452284B publication Critical patent/CN114452284B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/4045Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An application of a STING inhibitor in preparation of a medicine for treating filtering channel conjunctival scarring finds that H151 can inhibit fibrosis, proliferation and migration capabilities of HTF cells induced by angiotensin II, further inhibits activation of TBK1 and IRF3 mediated by STING and transcriptional activity of a transcription factor NF-kappa B, relieves filtering channel conjunctival sac fibrosis and filtering channel scarring, and improves long-term effective rate after glaucoma trabecular operation.

Description

Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter tract
Technical Field
The invention relates to the technical field of biological medicines, and in particular relates to application of a STING inhibitor in preparation of a therapeutic drug for resisting conjunctival scarring of a filter channel.
Background
Glaucoma is a disease caused by irreversible optic nerve degenerative change due to pathological intraocular pressure change, and is the first irreversible blindness-causing eye disease in the world. Glaucoma trabeculectomy is the most classical and widely used surgical method for treating various types of glaucoma at present, and can effectively reduce the elevated intraocular pressure of the glaucoma. According to previous researches, the early surgical success rate of trabeculectomy is as high as 83-92%, but the ratio is gradually reduced to 65-44% in the long-term follow-up process.
The main reason for failure after trabeculectomy is scarring of the conjunctiva of the filtering tract, resulting in reduction of effective filtering function and re-increase of intraocular pressure after the operation. At present, the pathogenesis of scar formation after glaucoma trabeculectomy is still not completely clear, and the traditional means of filtration bubble acupuncture separation, laser thread breakage or subconjunctival injection of cytostatic drugs and the like can only be adopted for treatment in the past, but the occurrence and the development of filter aisle scarring cannot be completely and effectively prevented. Therefore, the generation mechanism of the scar formation of the conjunctiva of the filtering passage after the trabeculectomy is clarified, a new drug target is searched, the development of targeted therapeutic drugs is facilitated, and the method has important scientific significance and clinical application value.
H151 is a potent, selective and covalent STING antagonist with significant anti-inflammatory activity in vitro and in vivo. H151 has the effects of resisting inflammation, inhibiting excessive immune response, relieving skin injury, protecting kidney and liver, and the like.
But scarring of the filter corridor after H-151 treatment for glaucoma trabeculectomy has not been reported.
Disclosure of Invention
In order to solve the technical defects in the prior art, the invention provides application of the STING inhibitor in preparing a medicament for treating the conjunctival scarring of the filtering channel.
The filtering channel conjunctiva scarring is glaucoma trabecular postoperative filtering channel conjunctiva scarring.
The STING inhibitor is STING inhibitor H151.
The structure of the STING inhibitor H151 is as follows:
Figure 610588DEST_PATH_IMAGE001
the concentration of the STING inhibitor H151 is 1 mug/ml.
The application of inhibitors of TBK1, IRF3 and transcription factor NF-kB signal channels in preparing medicaments for resisting filter channel conjunctiva scarring.
The inhibitor of the signal path of TBK1, IRF3 and transcription factor NF-kB is H151.
Use of STING inhibitor H151 for the preparation of a medicament for alleviating fibrosis, proliferation and migration of HTF cells.
The invention has the beneficial effects that: the invention provides application of a STING inhibitor in preparation of a medicine for treating filtering channel conjunctival scarring, and finds that H151 can inhibit fibrosis, proliferation and migration capabilities of HTF cells induced by angiotensin II, further inhibits activation of STING-mediated TBK1 and IRF3 and transcriptional activity of a transcription factor NF-kappa B, relieves filtering channel conjunctival sac fibrosis and filtering channel scarring, and improves long-term effective rate after glaucoma trabecular surgery.
Drawings
Figure 1 is H151 stabilizing post-trabeculectomy bleb morphology and alleviating post-operative filter tract fibrosis in mice.
Fig. 2 is a graph showing that H151 inhibits the fibrotic response induced by Ang II in HTF cells.
Fig. 3H 151 inhibits activation of the STING downstream signal path.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
Successfully constructs a filtering channel scarring model after trabeculectomy, the mode of trabeculectomy is referred to the prior literature report (Invest Ophthalmol Vis Sci, 2017, 58(9): 3432. 3439), the STING specific small molecule inhibitor H151 is injected into the conjunctiva sac after the operation for 2 weeks, and the photographing is carried out under an operation microscope after anesthesia for observing the conjunctiva bleb condition after the operation for 2 weeks.
The test process comprises the following steps: male C57BL/6 mice were obtained from a commercial animal laboratory center. Mice were housed in a constant temperature animal house with a circadian rhythm of 12-12h with standard rodent chow and water. Animals were grown environmentally adaptive one week prior to the start of the experiment. H151 used in the experiments was prepared as a DMSO-soluble formulation at a final concentration of 1 mg/kg. A trabeculectomy filter tract scarring mouse model was established, sham surgery was used as a control group, and the mice were sacrificed under anesthesia 2 weeks later. Sham is a Sham group; surgery is the trabeculectomy group; the Surgery + H151 group was a trabeculectomy in combination with H151 treatment group. (A) Filtration bleb status of mice by trabeculectomy after anesthesia before sacrifice; (B) post trabeculectomy filter aisle HE staining; (C, D) detecting the expression level of the alpha SMA in the filter channel of the mouse trabeculectomy by immunofluorescence; (E) real time qPCR detects mRNA levels of fibrinectin and CTGF. P < 0.01, Sham vs Surgery; # p < 0.01, # p < 0.001, and Surgery vs Surgery + H151.
The operation group can be seen under an operation microscope to show that the filtration bleb is limited and scar, the surface of the filtration bleb is congested, and the result of the operation combined with the H151 treatment group shows that the filtration bleb is formed well and the surface is pale, which is shown in figure 1A. To investigate the interfering effects of H151 on filter morphology change and fibrosis after trabeculectomy, we used HE staining and alpha SMA immunofluorescence observations, respectively. As shown in fig. 1B-D, HE staining showed significant increases in collagen deposition and α SMA expression in the filtered pathway of mice after trabeculectomy, with significant relief after H151 treatment. The RT-qPCR results showed that the levels of fibrinectin and CTGF mRNA were significantly increased in the filter membrane tissue of mice receiving trabecular surgery compared to the sham group, while the H151 treated group was decreased, as shown in fig. 1E, F.
Example 2
HTF cells are preincubated for 1H by using H151, and then the HTF cells are stimulated by Ang II (1 mu M) for 6 or 24 hours, and the effect of the H151 on Ang II resistance is detected by respectively adopting fluorescent staining, fluorescent quantitation, RT-qPCR, Western Blot, scratch experiment and the like.
The test process comprises the following steps: h151 (final concentration 1. mu.g/ml) preincubated HTF cells for 1 hour, Ang II (1. mu.M) stimulated for 6 or 24 hours. (A, B) detecting the expression level of alpha SMA in a filter channel of a mouse trabeculectomy by immunofluorescence; (C) western Blot for detecting the protein levels of fibrinectin and CTGF; (D, E) Real time qPCR to detect the mRNA levels of Fibronectin and CTGF; (F) detecting the migration capacity of the HTF cells by a migration scratch test; (G) CCK8 measures cell proliferative capacity. P < 0.01, Ctrl vs Ang II; # p < 0.01, # # # p < 0.001, Ang II vs Ang II + H151.
As shown in fig. 2A, B, H151 was found to inhibit Ang II-induced α SMA expression by immunofluorescence staining. As can be seen from FIGS. 2C-E, Ang II induced increased expression of Fibronectin and CTGF, which are factors involved in promotion of fibrosis, at protein and mRNA levels, whereas pre-incubation of H151 inhibited the expression of the factors involved in fibrosis induced by Ang II. Meanwhile, the cell scratch experiment suggests that the migration of the cells is remarkably accelerated under the stimulation of Ang II, the accelerated migration of the pre-incubated H151 group is relieved (fig. 2F), and the H151 can remarkably inhibit the proliferation of HTF cells caused by Ang II in the cell proliferation experiment (fig. 2G). The results show that the small molecule inhibitor H151 has a good relieving effect on the fibrosis, migration and proliferation of HTF cells caused by Ang II.
We used H151 pretreatment 1 hours later, then Ang II incubation 2 hours, using Western Blot detection of STING downstream signaling pathway TBK1, IRF3 and NF-. kappa.B-p 65 phosphorylation changes.
The test process comprises the following steps: h151 (final concentration 1. mu.g/ml) preincubated HTF cells for 1 hour, and Ang II (1. mu.M) for 2 hours. Western Blot was used to detect protein levels of p-TBK1, p-IRF3 and p-NF- κ B p 65.
As shown in FIG. 3, H151 significantly inhibited TBK1, IRF3 and NF-. kappa.B-p 65 phosphorylation. Therefore, the results suggest that the function of small molecule inhibitor H151 in regulating fibrosis is related to TBK1, IRF3 and NF- κ B signaling pathways.
The skilled person should understand that: although the invention has been described in terms of the above specific embodiments, the inventive concept is not limited thereto and any modification applying the inventive concept is intended to be included within the scope of the patent claims.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.

Claims (8)

  1. Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter tract.
  2. 2. The use of claim 1, wherein the filtering conjunctiva scarring is glaucoma trabecular post-surgery filtering conjunctival scarring.
  3. 3. The use of claim 1, wherein the STING inhibitor is STING inhibitor H151.
  4. 4. The use according to claim 1, wherein the STING inhibitor H151 has the structure:
    Figure 944851DEST_PATH_IMAGE001
  5. 5. the use according to claim 1, wherein the concentration of STING inhibitor H151 is 1 μ g/ml.
  6. The application of inhibitors of TBK1, IRF3 and transcription factor NF-kB signal pathways in preparing medicaments for resisting filter channel conjunctiva scarring.
  7. 7. The use of claim 6, wherein the inhibitor of the signaling pathway of TBK1, IRF3 and the transcription factor NF-. kappa.B is H151.
  8. Use of STING inhibitor H151 for the preparation of a medicament for alleviating fibrosis, proliferation and migration of HTF cells.
CN202210063512.7A 2022-01-20 2022-01-20 Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter Active CN114452284B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210063512.7A CN114452284B (en) 2022-01-20 2022-01-20 Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210063512.7A CN114452284B (en) 2022-01-20 2022-01-20 Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter

Publications (2)

Publication Number Publication Date
CN114452284A true CN114452284A (en) 2022-05-10
CN114452284B CN114452284B (en) 2023-09-01

Family

ID=81409572

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210063512.7A Active CN114452284B (en) 2022-01-20 2022-01-20 Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter

Country Status (1)

Country Link
CN (1) CN114452284B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1799540A (en) * 2005-11-16 2006-07-12 陈凤华 Use of okadaic acid in preparation of medicine for resisting glaucoma operation scar
CN102695511A (en) * 2009-04-17 2012-09-26 舒玛健康系统有限责任公司 Use of transforming growth factor-Beta receptor inhibitors to suppress ocular scarring

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1799540A (en) * 2005-11-16 2006-07-12 陈凤华 Use of okadaic acid in preparation of medicine for resisting glaucoma operation scar
CN102695511A (en) * 2009-04-17 2012-09-26 舒玛健康系统有限责任公司 Use of transforming growth factor-Beta receptor inhibitors to suppress ocular scarring

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
WEI GONG等: "The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction", 《AM J PHYSIOL RENAL PHYSIOL》 *
张典元等: "抗瘢痕形成药物在青光眼滤过术中的应用进展", 《中国中医眼科杂志》 *

Also Published As

Publication number Publication date
CN114452284B (en) 2023-09-01

Similar Documents

Publication Publication Date Title
Tanna et al. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension
Tokushige et al. Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys
Frucht-Pery et al. Single dosage of mitomycin C for prevention of recurrent pterygium: preliminary report
US6489350B1 (en) Methods for treating neuropathic pain using heteroarylmethanesulfonamides
Bech et al. Functional and morphologic alterations in mechanical, polymodal, and cold sensory nerve fibers of the cornea following photorefractive keratectomy
JPH0114204B2 (en)
CN101878026A (en) Pharmacological adjunctive treatment associated with glaucoma filtration surgery
Luna et al. Sodium channel blockers modulate abnormal activity of regenerating nociceptive corneal nerves after surgical lesion
Pitha et al. Sustained Dorzolamide Release Prevents Axonal and Retinal Ganglion Cell Loss in a Rat Model of IOP–Glaucoma
JP7542799B2 (en) Composition for inhibiting ocular tissue fibrosis
CN114452284A (en) Application of STING inhibitor in preparation of medicine for treating conjunctival scarring of filter tract
US20080051319A1 (en) Inhibiting JNK Signaling Promotes CNS Axon Regeneration
Nilsson et al. Effects of timolol on terbutaline-and VIP-stimulated aqueous humor flow in the cynomolgus monkey
Sakamoto et al. Electroporation and bleomycin in glaucoma-filtering surgery.
Hayes et al. Neuropathic pain in the perioperative period
JP2022009155A (en) Local and regional anesthesia and analgesia
JP7039606B2 (en) Treatment of myopia and its application in drug preparation
Waki et al. Effect of topically applied iganidipine dihydrochloride, a novel calcium antagonist, on optic nerve head circulation in rabbits
CA2442296C (en) Therapeutic agents for retinochoroidal disorders comprising steroids as active ingredients
Mokbel et al. Rho-Kinase Inhibitors as a novel medication for Glaucoma Treatment–A Review of the literature
TW200800261A (en) Compounds for the treatment of dryness of the ocular surface caused by photorefractive surgery
US10441566B2 (en) Use of butylidenephthalide
Bleau et al. Managing intraocular pressure: Innovation in glaucoma management
JP2024150780A (en) Composition for inhibiting ocular tissue fibrosis
EP1795193A1 (en) Suppressant for cerebral infarction attributed to long-time ischemia

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant