CN116889620A - 内源性蛋白trf在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用 - Google Patents
内源性蛋白trf在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用 Download PDFInfo
- Publication number
- CN116889620A CN116889620A CN202310606508.5A CN202310606508A CN116889620A CN 116889620 A CN116889620 A CN 116889620A CN 202310606508 A CN202310606508 A CN 202310606508A CN 116889620 A CN116889620 A CN 116889620A
- Authority
- CN
- China
- Prior art keywords
- maculopathy
- trf
- retinal
- atral
- visual
- 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.)
- Pending
Links
- 208000002780 macular degeneration Diseases 0.000 title claims abstract description 29
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 title claims abstract description 26
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 208000035719 Maculopathy Diseases 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 238000006471 dimerization reaction Methods 0.000 title abstract description 6
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 claims abstract description 18
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 claims abstract description 17
- 208000011325 dry age related macular degeneration Diseases 0.000 claims abstract description 16
- 230000004382 visual function Effects 0.000 claims abstract description 10
- 210000001525 retina Anatomy 0.000 claims abstract description 9
- 201000007737 Retinal degeneration Diseases 0.000 claims abstract description 6
- 230000004258 retinal degeneration Effects 0.000 claims abstract description 6
- 230000002776 aggregation Effects 0.000 claims abstract description 5
- 238000004220 aggregation Methods 0.000 claims abstract description 5
- 102000004338 Transferrin Human genes 0.000 claims description 40
- 108090000901 Transferrin Proteins 0.000 claims description 40
- 239000012581 transferrin Substances 0.000 claims description 36
- 210000000608 photoreceptor cell Anatomy 0.000 claims description 7
- 230000001737 promoting effect Effects 0.000 claims description 6
- 210000004027 cell Anatomy 0.000 claims description 5
- 230000004083 survival effect Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000003902 lesion Effects 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000002207 retinal effect Effects 0.000 claims description 2
- 230000000007 visual effect Effects 0.000 abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 238000011161 development Methods 0.000 abstract description 5
- 239000000539 dimer Substances 0.000 abstract description 5
- BOMUADPKDXMXIH-UHFFFAOYSA-M 1,3-bis(1-methylquinolin-1-ium-6-yl)urea;methyl sulfate Chemical compound COS([O-])(=O)=O.COS([O-])(=O)=O.C[N+]1=CC=CC2=CC(NC(=O)NC=3C=C4C=CC=[N+](C4=CC=3)C)=CC=C21 BOMUADPKDXMXIH-UHFFFAOYSA-M 0.000 abstract 2
- 241000699670 Mus sp. Species 0.000 description 15
- 101100338246 Mus musculus Hsd17b6 gene Proteins 0.000 description 11
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 10
- 108091008695 photoreceptors Proteins 0.000 description 9
- NCYCYZXNIZJOKI-IOUUIBBYSA-N 11-cis-retinal Chemical compound O=C/C=C(\C)/C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-IOUUIBBYSA-N 0.000 description 8
- 206010064930 age-related macular degeneration Diseases 0.000 description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 102000004330 Rhodopsin Human genes 0.000 description 5
- 108090000820 Rhodopsin Proteins 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- NCYCYZXNIZJOKI-HPNHMNAASA-N 11Z-retinal Natural products CC(=C/C=O)C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-HPNHMNAASA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 102000010175 Opsin Human genes 0.000 description 3
- 108050001704 Opsin Proteins 0.000 description 3
- 208000027073 Stargardt disease Diseases 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000004438 eyesight Effects 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 150000003726 retinal derivatives Chemical class 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 102100026663 All-trans-retinol dehydrogenase [NAD(+)] ADH7 Human genes 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- 102100024844 Retinol dehydrogenase 8 Human genes 0.000 description 2
- 208000000208 Wet Macular Degeneration Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 210000005157 neural retina Anatomy 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 108010035291 retinol dehydrogenase Proteins 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 208000003569 Central serous chorioretinopathy Diseases 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 101000687592 Homo sapiens Retinol dehydrogenase 8 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 208000002367 Retinal Perforations Diseases 0.000 description 1
- 101710189258 Retinol dehydrogenase 8 Proteins 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940100609 all-trans-retinol Drugs 0.000 description 1
- 239000011717 all-trans-retinol Substances 0.000 description 1
- 235000019169 all-trans-retinol Nutrition 0.000 description 1
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- -1 iron ions Chemical class 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- 210000004880 lymph fluid Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 208000029233 macular holes Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 208000027653 severe early-childhood-onset retinal dystrophy Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
Classifications
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了内源性蛋白TRF在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用。视觉循环紊乱介导游离的atRAL在视网膜上聚集，其在黄斑病变尤其是干性AMD和STGD1的发生发展中发挥了至关重要的作用。本发明发现TRF能够将视觉循环紊乱产生的游离的atRAL转化为二聚体，可减轻视网膜变性、改善视觉功能，为逆转黄斑病变尤其是干性AMD和STGD1提供了一种全新而更加有效的解决途径。
Description
技术领域
本发明属于医药技术领域，具体涉及内源性蛋白转铁蛋白TRF的应用。
背景技术
黄斑是视网膜上一个区域的名字，位于视神经的颞侧稍下方0.35厘米处，富含叶黄素，呈黄色的小凹，属于眼睛的正常解剖结构之一，为视物最清晰的位置。黄斑部位的疾病统称为“黄斑病变”，包括年龄相关性黄斑变性(AMD)、中心性浆液性脉络膜视网膜病变、黄斑裂孔、常染色体隐性Stargardt病(STGD1)等。黄斑病变能够引发视力减退、视物变小、变形、变色、眼前暗影等症状，是主要的致盲性眼病之一。以AMD为例，它是50岁以上人群视力不可逆性严重下降和失明的首要原因。流行病学调查显示，AMD致盲者约占全球盲人的8.7％。干性AMD是较为常见的类型，占AMD患者总数的88％。临床观察发现干性AMD可能转化为湿性AMD，因此抗干性AMD治疗可以阻止其进展至湿性AMD，并在AMD的发生、发展及转归中起着重要的作用。相对而言，STGD1是最常见的遗传性青少年黄斑营养不良眼病，全球患病率约为1/6578。干性AMD和STGD1至今尚无有效的治疗方法。虽然干性AMD和STGD1属于两种不同类型的黄斑病变，但是它们却有着非常相似的临床病理特征，如光感受器/RPE细胞死亡等。
视网膜上运行的视觉循环(也称之为“视黄素代谢”)是人类视觉形成的基础。视觉信号的传导需要将光信号转换为神经冲动，视觉循环在这个过程中起到了关键的作用。在光感受器细胞中，11-顺式-视黄醛与视蛋白上的第296位赖氨酸基团通过质子化希夫碱键相连形成视紫红质。捕获一个光子后，11-顺式-视黄醛异构化成为全反式视黄醛(atRAL)，进而激活视紫红质，转导素传递光信号使其成为神经冲动，沿着视神经传到大脑皮层的视觉中枢形成视觉。视紫红质分解为视蛋白和atRAL，后者经由转运蛋白ABCA4从光感受器细胞外节盘膜腔进入胞质中，在视黄醇脱氢酶(RDHs)特别是视黄醇脱氢酶8(RDH8)作用下还原成全反式视黄醇(维生素A)，然后维生素A从光感受器细胞进入视网膜色素上皮(RPE)细胞中，经过一系列酶促反应再生成11-顺式-视黄醛，其返回光感受器细胞中与视蛋白结合重新形成视紫红质，从而维持正常的视觉功能。
视觉循环紊乱介导游离的atRAL在视网膜上聚集，其在黄斑病变尤其是干性AMD和STGD1的发生发展中发挥了至关重要的作用。因此，有必要对atRAL进一步研究。
发明内容
本发明的目的在于提供了内源性蛋白TRF在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用。
如前所述，游离的atRAL是光感受器和RPE细胞死亡的刽子手。本发明的技术思路在于，及时地将视觉循环紊乱产生的游离的atRAL转化为无害/低毒物质，可能是更为有效地治疗黄斑病变的方法。
本发明经研究，获得了促使视觉循环紊乱“良性”转化的内源性蛋白---转铁蛋白(TRF)。TRF是人体内源性合成的一种转运蛋白，含有679个氨基酸残基，分子量约为79kD。该分子由19个链内二硫键稳定，并受到三个碳水化合物侧链的保护，其中两个是N连接的(Asn-413和Asn-611)，第三个是O连接的(Ser-32)。TRF分子由两个进化相关的叶组成，称为N叶(336个氨基酸)和C叶(343个氨基酸)，它们由短间隔序列连接。每个叶包含两个结构域，其相互作用形成一个深的、亲水的金属离子结合位点，结合位点需要由碳酸盐分子提供的两个氧分子来稳定铁原子。周围的氨基酸残基(N端叶上的Gly-65、Glu-83、Tyr-85、Arg-124、Lys-206、Ser-248和Lys-296)被认为可以进一步稳定金属结合位点，它们在铁释放中起着至关重要的作用。例如，已经证明位于N端叶的相对结构域上的Lys-206和Lys-296以“闭合”氢键形式与铁离子相结合。当pH值降低时，该氢键被破坏，使域旋转形成“开放”构象，促进铁释放。TRF主要由肝细胞合成，分布在血浆、胆汁、羊水、脑脊液、淋巴液、母乳等各种体液中。TRF的血浆浓度从出生开始就很稳定，范围从2到3g/L，体内半衰期为8天。TRF的水平对于健康生长很重要，含量低于0.1g/L可增加感染、生长迟缓和贫血的发生率。但既往没有TRF在视觉循环、黄斑病变等领域的报道。
本发明经研究发现，利用TRF能够“原位”干预视觉循环紊乱产生的游离atRAL，使其转化为低毒的atRAL二聚体，再通过日常光照降解为无毒的碎片分子，进而达到减少游离atRAL水平的目的，可为逆转黄斑病变尤其是干性AMD和STGD1提供一种全新而更加有效的解决途径。
本发明解决其技术问题所采用的技术方案之一是：
转铁蛋白(transferrin，TRF)在制备治疗黄斑病变的药物中的应用。
优选地，所述黄斑病变包括干性AMD(年龄相关性黄斑变性)。
优选地，所述黄斑病变包括STGD1(常染色体隐性Stargardt病)。
优选地，所述应用包括促进光感受器细胞存活。
优选地，所述应用包括促进RPE(视网膜色素上皮)细胞存活。
优选地，所述应用包括改善视网膜变性，维持视网膜组织结构的正常形态。
优选地，所述应用包括改善视觉功能。
本发明解决其技术问题所采用的技术方案之二是：
转铁蛋白在制备减少游离全反式视黄醛在视网膜上聚集的抑制剂中的应用。
本发明解决其技术问题所采用的技术方案之三是：
转铁蛋白在制备全反式视黄醛的二聚化的转化剂中的应用，所述应用具体指的是介导全反式视黄醛二聚化形成二聚体。
优选地，所述TRF单独使用，或作为活性成分与其他辅料共同使用。优选地，所述药物中除TRF外，还包括至少一种药学上可接受的辅料或载体，即TRF不但可以单独制备成药物进行使用，还可以作为活性成分与药学上可接受的辅料或载体共同制备成药物进行使用。所述辅料包括但不限于稀释剂、溶剂、赋形剂、吸收剂、润湿剂、黏合剂、崩解剂、润滑剂、增溶剂、乳化剂、助悬剂、表面活性剂、成膜剂、抛射剂、抗氧剂、矫味剂、芳香剂、杀菌剂、防腐剂等；所述载体指能够担载化合物，并且具有改变化合物进入人体的方式和在体内的分布，控制释放速度达到控释或缓释，靶向输送至靶器官等作用的体系，包括但不限于脂质体、微球、微囊、固体分散体、胶束、微乳液、凝胶、缓释型载体、控释型载体、靶向型载体、纳米颗粒材料等。进一步地，TRF可以直接采用药学上可接受的工艺，或者与上述的药学上可接受的辅料或载体混合共同采用药学上可接受的工艺，制备成为具体的药物剂型。
本发明所涉及的设备、试剂、工艺、参数等，除有特别说明外，均为常规设备、试剂、工艺、参数等，不再作实施例。
本发明所列举的所有范围包括该范围内的所有点值。
本技术方案与背景技术相比，它具有如下优点：
本发明发现转铁蛋白TRF能够使视觉循环紊乱产生的游离atRAL转化为低毒的atRAL二聚体，能够减轻视网膜变性、改善视觉功能，为逆转黄斑病变尤其是干性AMD和STGD1提供了一种全新而更加有效的解决途径。
附图说明
图1用于说明TRF挽救了光暴露Abca4–/–Rdh8–/–小鼠的视觉功能。
图2用于说明TRF减轻了光暴露Abca4–/–Rdh8–/–小鼠的视网膜变性。
图3用于说明TRF提高了光暴露Abca4–/–Rdh8–/–小鼠眼球中atRAL-dimer的含量。
具体实施方式
下面结合附图和实施例对本发明作进一步说明。
实施例
药物信息：转铁蛋白transferrin基因ID:Human(7018)分子量：76～81kDa
动物模型：STGD1是遗传性青少年黄斑变性，由Abca4基因突变引发。同时，以往的研究表明Abca4和Rdh8是干性AMD发生的易感基因。Abca4–/–Rdh8–/–小鼠光感受器中atRAL水平显著上升，并且产生了一系列与干性AMD和STGD1相似的表型：光感受器/RPE细胞死亡等，从而使其成为研究干性AMD和STGD1病理及其药物开发的重要动物模型，同时为视觉循环紊乱是干性AMD和STGD1病因的研究提供了更为坚实的理论基础；再者，光照可促使视紫红质快速释放大量atRAL，能够恶化因ABCA4和RDH8功能缺失导致的atRAL聚集并加速光感受器退化，故光暴露Abca4–/–Rdh8–/–小鼠可以作为干性AMD和STGD1分子机理及其药物开发研究的急性动物模型。
实验设计：转铁蛋白(TRF)溶解于生理盐水中配成50毫克/毫升溶液。选择4周龄的Abca4–/–Rdh8–/–双敲小鼠作为实验对象，TRF实验组小鼠按照每只眼睛2微升进行玻璃体下腔注射，对照组按照等量的溶剂进行玻璃体下腔注射。注射后4小时，小鼠从麻醉中苏醒，托吡卡胺滴眼液对小鼠眼睛进行散瞳处理，10,000-lx LED白光对小鼠进行光照1小时。光照后第5天通过视网膜电图(ERG)对小鼠视觉功能进行分析：
如图1所示：溶剂处理组Abca4–/–Rdh8–/–小鼠的视觉功能在10000-lx LED光照射后明显受损，然而在TRF处理组，小鼠的视觉功能有显著的恢复，表明TRF处理对光暴露Abca4–/–Rdh8–/–小鼠视觉功能具有明显的改善作用。
如图2所示：溶剂处理组Abca4–/–Rdh8–/–小鼠的视网膜在10000-lx LED光照射后明显受损，表现整体神经视网膜、光感受器细胞内外节和内外核层的厚度明显变薄，并且伴随细胞核变少、变小及其紧密度增加，然而在TRF处理组，小鼠视网膜的组织结构退化有明显的恢复，整体神经视网膜、光感受器细胞内外节和内外核层呈现了正常的形态，说明TRF处理对光暴露Abca4–/–Rdh8–/–小鼠视网膜退化具有明显的改善作用。
如图3所示：通过组织提取和高效液相色谱检测，发现玻璃体下腔注射TRF使得光暴露Abca4–/–Rdh8–/–小鼠眼球中atRAL-dimer的含量明显增加，从而证实了TRF在视觉循环紊乱中起到促进atRAL二聚化的作用。
光感受器/RPE细胞死亡是黄斑病变最主要的病理特征。视觉循环紊乱诱发游离的atRAL在视网膜上聚集，是黄斑病变中光感受器/RPE细胞死亡的关键原因。TRF通过特异性“原位”干预视觉循环紊乱，使得高毒atRAL“良性”转化为低毒atRAL-dimer，促进光感受器/RPE细胞存活，进而从根源上解决了视觉循环紊乱导致的黄斑病变。由于TRF在动物实验中治疗效果明显，且给药安全，无毒副作用，因此TRF在治疗黄斑病变疾病的药物开发中具有广阔的前景。
以上所述，仅为本发明较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。
Claims (9)
1.转铁蛋白在制备治疗黄斑病变的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述黄斑病变包括干性AMD。
3.根据权利要求1所述的应用，其特征在于：所述黄斑病变包括STGD1。
4.根据权利要求1所述的应用，其特征在于：所述应用包括促进光感受器细胞存活。
5.根据权利要求1所述的应用，其特征在于：所述应用包括促进RPE细胞存活。
6.根据权利要求1所述的应用，其特征在于：所述应用包括改善视网膜变性或维持视网膜组织结构的正常形态。
7.根据权利要求1所述的应用，其特征在于：所述应用包括改善视觉功能。
8.转铁蛋白在制备减少游离全反式视黄醛在视网膜上聚集的抑制剂中的应用。
9.转铁蛋白在制备全反式视黄醛的二聚化的转化剂中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310606508.5A CN116889620A (zh) | 2023-05-26 | 2023-05-26 | 内源性蛋白trf在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310606508.5A CN116889620A (zh) | 2023-05-26 | 2023-05-26 | 内源性蛋白trf在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116889620A true CN116889620A (zh) | 2023-10-17 |
Family
ID=88309935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310606508.5A Pending CN116889620A (zh) | 2023-05-26 | 2023-05-26 | 内源性蛋白trf在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116889620A (zh) |
-
2023
- 2023-05-26 CN CN202310606508.5A patent/CN116889620A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Verkman | Mammalian aquaporins: diverse physiological roles and potential clinical significance | |
| US6207190B1 (en) | Dosage forms for the treatment of the chronic glaucomas | |
| US11123412B2 (en) | Method of treating macular degeneration using botulinum toxin-based pharmaceuticals | |
| RU2598339C2 (ru) | Нейропротекторное и ретинопротекторное средство n-ацетил-dl-лейцин | |
| KR20060127043A (ko) | 녹내장성 망막병증 및 시각신경병증의 치료용 약제 | |
| EP2646010B1 (en) | Folic acid - ramipril combination: cellprotective, neuroprotective and retinoprotective ophtalmologic compositions | |
| Waszczykowska et al. | Effect of treatment with silver (I) complex of metronidazole on ocular rosacea: Design and formulation of new silver drug with potent antimicrobial activity | |
| JP2009501725A (ja) | 糖尿病の眼科合併症の予防及び治療 | |
| US20180085359A1 (en) | Use of chelators of divalent cations to promote nerve regeneration | |
| KR20040063943A (ko) | 안과 질환 및 질병의 치료를 위한 과산화물 디스뮤타제모방체 | |
| EP2578215A1 (en) | Use of oxaloacetate in the treatment of ischaemia | |
| CN114948935B (zh) | 一种没食子酸衍生物纳米药物、制备方法及应用 | |
| CN116889620A (zh) | 内源性蛋白trf在介导全反式视黄醛二聚化及制备治疗黄斑病变的药物中的应用 | |
| US20060194874A1 (en) | Use of propionyl l-carnitine for the preparation of a medicament for the treatment of glaucoma | |
| CN100563628C (zh) | 一种苄达赖氨酸眼用凝胶制剂及其制备方法 | |
| CA3156220A1 (en) | Anti-c5 agent for treatment of dry age-related macular degeneration (amd) or geographic atrophy secondary to dry amd | |
| CN107530319B (zh) | 用于治疗眼疾的化合物 | |
| RU2362554C2 (ru) | Регенерирующее противовоспалительное средство и способы лечения с помощью этого средства | |
| RU2268689C9 (ru) | Способ создания депо лекарственных веществ в офтальмологии | |
| WO1998022129A1 (fr) | Agent therapeutique pour maladies ophtalmiques | |
| RU2733392C1 (ru) | Комбинированное офтальмологическое средство | |
| RU2318534C2 (ru) | Способ лечения туберкулезных увеитов | |
| US20060172977A1 (en) | Method and composition for preventing, reducing and reversing ocular ischemic neuronal damage | |
| RU2188021C2 (ru) | Способ лечения увеитов | |
| CN117982516A (zh) | Skq1在抑制线粒体自噬和制备抑制线粒体自噬相关产品中的应用 |
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 |