WO2023035950A1 - 视网膜变性的治疗方法 - Google Patents

视网膜变性的治疗方法 Download PDF

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WO2023035950A1
WO2023035950A1 PCT/CN2022/114540 CN2022114540W WO2023035950A1 WO 2023035950 A1 WO2023035950 A1 WO 2023035950A1 CN 2022114540 W CN2022114540 W CN 2022114540W WO 2023035950 A1 WO2023035950 A1 WO 2023035950A1
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formula
optionally substituted
parts
antibiotics
alkyl
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PCT/CN2022/114540
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French (fr)
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魏来
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珠海岐微生物科技有限公司
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Priority to KR1020247011733A priority Critical patent/KR20240058917A/ko
Priority to AU2022343302A priority patent/AU2022343302A1/en
Priority to CA3231217A priority patent/CA3231217A1/en
Priority to IL311428A priority patent/IL311428A/en
Priority to CN202280061741.3A priority patent/CN117940129A/zh
Publication of WO2023035950A1 publication Critical patent/WO2023035950A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • 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

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to a method for treating retinal degeneration and the application of microbial inhibitors or killing agents in the preparation of medicines for treating retinal degeneration.
  • IRD Inherited retinal degeneration
  • microorganisms can activate the complement system and induce drusen-like lesions in rhesus monkeys when administered in a live state. Furthermore, killing or inhibiting the growth of such microorganisms, such as by intravitreal administration of the antibiotic vancomycin, resulted in a reduction in the size of drusen-like lesions in retinal tissue of rhesus monkeys compared to controls, killing such microorganisms such as Bacillus megaterium or agents that inhibit their growth are useful in the treatment of age-related macular degeneration.
  • microbial inhibitors or killers can be used as drugs to treat retinal degeneration.
  • the present invention firstly establishes eye disease models or eye disease model carriers, especially retinal degeneration models or model carriers, and verifies that microbial inhibitors or killing agents can be used as drugs to treat retinal degeneration.
  • the present invention firstly provides a treatment method for retinal degeneration, said method comprising administering microorganism inhibitors or killing agents to the patient's eyes or gastrointestinal tract.
  • the retinal degeneration is progressive retinal degeneration; more preferably, the retinal degeneration is hereditary retinal degeneration; more preferably, hereditary retinal degeneration includes congenital amaurosis (LCA), retinitis pigmentosa (RP), Premature Rod-Cone Dystrophy, Rod-Rod Dystrophy, Congenital Stationary Night Blindness and Color Blindness, and Stargardt Disease.
  • LCA congenital amaurosis
  • RP retinitis pigmentosa
  • Premature Rod-Cone Dystrophy Rod-Rod Dystrophy
  • Congenital Stationary Night Blindness and Color Blindness and Stargardt Disease.
  • the microorganism is one or a combination of two or more of bacteria, archaea, protists, fungi or viruses.
  • the microorganisms are bacteria selected from the group consisting of: Anearostipes, Bifidobacterium, Megamonas, Nitrosomonas, Oscillibacter, Tatum (Tatumella), Thiobacillus sp., Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Platts Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella Klebsiella, Porphyromonas, Azospira, Aquimarina, Achromobacter, Acidithiobacillus, Burke Burkholderia, Marinobacter, Treponema, Actinosporangium, Vibrio, Ruminococcus, Methanobacillus One or more
  • the bacterium is selected from: Anearostipeshadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp.Is79A3, Oscillibactervalericigenes, Tatumella sp.TA1, Megamonasfuniformis, Thiobacillus denitrificans, Akkermansiamucinphila.
  • the microbial inhibitors or killing agents include compounds, polypeptides, polynucleotides, natural plants or natural plant extracts.
  • the microorganism inhibitor or killing agent is an antibiotic
  • the antibiotic is a ⁇ -lactam antibiotic; an aminoglycoside antibiotic; a tetracycline antibiotic; a chloramphenicol antibiotic; Antibiotics; glycopeptide antibiotics; quinolone antibiotics; nitroimidazole antibiotics; rifamycin antibiotics; echinocandin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; One or two or more of other antibiotics.
  • antibiotics may include one or more of the following: ⁇ -lactam antibiotics, including penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacancilin, carbenicillin, Xacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pimacillin, pimacillin, ticarcillin, cephalosporins such as cefacetonitrile, Cefadroxil, cephalexin, cefalaxine, cefuroxime, cefotaxime, cephalothin, cefapirin, ceftriaxone, cefazolin, cefoxizone, cefazolin, cefradine, cefoxadin, ceftezole , Cefaclor, Cefamandole, Cefmetazole, Cefdinir, Cefotet
  • penicillins e
  • the antibiotic may be selected from the group consisting of amikacin, amoxicillin, ampicillin, arsenamin, azithromycin, azlocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefixime Lo, cefadroxil, cephalexin, cephalothin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil , ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, Colistin, cycloserine, dalfopristin, dapsone, dap
  • the microorganism inhibitor or killing agent is formula I (for example, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5), formula II (for example, Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula II-5, Formula II-6, Formula II-7, Formula II-8, Formula II-9, Formula II-10) , formula III (for example, formula III-1, formula III-2, formula III-3), formula IV-1 or IV-2 (for example, formula IV-3, formula IV-4, formula IV-5, formula IV -6), a compound of glycoside (for example, formula V), or a pharmaceutically acceptable salt or ester thereof, wherein the aglycon of the glycoside is a phenolic compound, a flavonoid, a coumarin, a benzoic acid or a sterol, wherein
  • the formulas I, II, III, IV-1, IV-2, V and their subformulas are defined as follows.
  • compounds of the invention can be characterized by having Formula I, or a pharmaceutically acceptable salt or ester thereof:
  • the cyclic structure Cy 1 is connected to another cyclic structure Cy 2 through two linkers L and L ' , the two cyclic structures may be the same or different, and the two connecting The group forms an additional ring structure between Cy 1 and Cy 2 . It should be understood that both Cy 1 and Cy 2 are ring structures independent of L and L ' , respectively.
  • Cy 1 and Cy 2 are each independently an optionally substituted cycloalkyl ring (e.g., a C3-7 cycloalkyl ring), an optionally substituted heterocycle such as an optionally substituted 4-7 membered heterocycle ring (for example, having one or two ring heteroatoms independently selected from N, O, and S), an optionally substituted aryl ring (for example, a C 6-10 aryl ring (for example, phenyl)), or any Optionally substituted heteroaryl rings such as optionally substituted 5-10 membered heteroaryl rings (e.g., 5 or 6 membered heteroaryl rings having one or two ring heteroaryl rings independently selected from N, O and S atom);
  • an optionally substituted cycloalkyl ring e.g., a C3-7 cycloalkyl ring
  • an optionally substituted heterocycle such as an optionally substituted 4-7 membered heterocycle ring (for example, having one or two ring heteroatom
  • L and L ' are each independently empty or a linker (eg, as described herein); as used herein, the term "linker” is not limited to any particular type of linker.
  • the linker can also form a ring structure with a moiety to which it is attached, for example, L and Cy 1 can form a ring structure independently of Cy 2 ;
  • L 2 is empty, optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 2-6 alkenylene, optionally substituted C 2-6 Alkynylene, optionally substituted C 3-6 cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene or optionally substituted 4-7 membered heterocyclylene;
  • W is -OR1 ; -COR2 ; -COOR1a ; -OCOOR1a ; -NR3R4 ; -CONR3aR4a ; -OCONR3bR4b ; -SO2NR3cR4c ; -OSO2NR3dR 4d ; -SR5 ; -SO2R5a ; -OCOR2a ; -OSO2R5a or
  • R and R are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted A heteroaryl or optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently hydrogen, -COR 2b , -SO 2 R 5b , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4-7 membered heterocyclyl, or R 3 and R 4 together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclyl;
  • R 2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , optionally substituted C 1-6 alkyl, optionally substituted C 2- 6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy Base, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; and
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl, optionally C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d or R 3e and R 4e together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclic group.
  • Cy 1 and Cy 2 in Formula I may be aromatic or non-aromatic ring systems, and may contain heteroatoms in some cases.
  • at least one of Cy 1 and Cy 2 in formula I is an aryl or heteroaryl ring, such as an optionally substituted C 6-10 aryl ring, or an optionally substituted 5- 10 membered heteroaryl ring.
  • Cy 1 and Cy 2 are such that the core structure of Formula I, that is, exhibits no optional substituents
  • the structure of can be any of the following:
  • L2 -W can be attached to the left ring or the right ring, where L and L ' can be any of those described herein, and suitable substituents for the rings are described herein.
  • Cy 1 and Cy 2 in Formula I can both be aryl or heteroaryl rings.
  • a compound of Formula I may have Formula I-1:
  • Ar1 and Ay2 in Formula I-1 are each independently an optionally substituted C6-10 aryl ring, or an optionally substituted 5-10 membered heteroaryl ring.
  • Ar 1 and Ar 2 in Formula I-1 are each independently an optionally substituted phenyl ring or a 5- or 6-membered heteroaryl ring.
  • Ar and Ar in Formula I-1 are each independently an optionally substituted phenyl ring, an optionally substituted thienyl ring, an optionally substituted furyl ring, an optionally substituted A pyridyl ring or an optionally substituted pyrimidinyl ring.
  • Formula I-1 generally has a polycyclic core structure.
  • Ar 1 and Ar 2 are such that the core structure of formula I-1, i.e., exhibits no optional substituents
  • L2 -W can be attached to the left or right ring, wherein L and L ' are defined herein and suitable substituents for the rings are described herein.
  • compounds of Formula I may have Formula I-2:
  • n 0, 1, 2 or 3
  • R 10 at each occurrence is independently halogen, L 2' -W ' , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkyne Base, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclic group; or two adjacent R 10 , or one R 10 and L or L ' together with the atoms they are bound to form an optional substitution cycloalkyl, heterocyclyl, aryl or heteroaryl ring;
  • L 2' is independently empty at each occurrence, optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 2-6 alkenylene, Optionally substituted C 2-6 alkynylene, optionally substituted C 3-6 cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene or optionally substituted 4-7 membered and W ' is independently at each occurrence -OR 1 ; -COR 2 ; -COOR 1a ; -OCOOR 1a ; -NR 3 R 4 ; -CONR 3a R 4a ; -OCONR 3b R 4b ; -SO 2 NR 3c R 4c ; -OSO 2 NR 3d R 4d ; -SR 5 ; -SO 2 R 5a ; -OCOR 2a ; -OSO 2 R 5a or where R 1 , R 1a , R 2 , R 2a , R 2b , R 3
  • each instance of the structural units -L 2' -W ' and -L 2 -W is independently selected and may be the same or different.
  • Cy in Formula I-2 is an optionally substituted phenyl ring, an optionally substituted thienyl ring, an optionally substituted furyl ring, an optionally substituted pyridyl ring, or an optionally substituted the pyrimidinyl ring.
  • Cy in formula I-2 is an optionally substituted C3-6 cycloalkyl ring or an optionally substituted 4-7 heterocycle having a ring independently selected from N, O and 1 or 2 ring heteroatoms of S.
  • Cy 1 is such that the core structure of formula 1-2 can be any of the following:
  • L and L ' are defined herein, and suitable substituents for the ring are described herein.
  • Cy 1 and Cy 2 in formula I are both phenyl rings.
  • a compound of Formula I-2 may have Formula I-3:
  • L, L ' , L2 , W, R10 and m are defined herein, see for example formula I-2,
  • n 0, 1, 2 or 3
  • R 1 1 independently at each occurrence is halogen, -L 2' -W ' , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally Substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclic group; or two adjacent R 11 , or one R 11 and L or L ' together with the atoms they are bound to form any A substituted cycloalkyl, heterocyclyl, aryl or heteroaryl ring; wherein L 2' and W ' are defined herein, see for example as defined for formula I-2, and -L 2' -W ' in each The first occurrence is chosen independently.
  • L and L ' in Formula I can independently be empty or a linker.
  • L and L ' in Formula I are each independently empty, -C(O)-, optionally substituted C 1-4 alkylene, optionally substituted C 2-4 alkenylene , -O-, -S-, -NR 100 -, -S(O)-, -SO 2 -, -X 1 -G 1 -, -X 2 -G 2 -X 2a -or -CR 101 R 102 -,
  • X 1 , X 2 and X 2a are independently optionally substituted C 1-4 alkylene, optionally substituted C 2-4 alkenylene, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a -;
  • G 1 and G 2 are independently optionally substituted C 1-4 alkylene, optionally substituted C 2-4 alkenylene, -C(O)-, -NR 100a -, -S(O)- , -SO 2 - or -CR 101a R 102a -;
  • -X 1 -G 1 - or -X 2 -G 2 -X 2a - does not contain ON, SS, SN (except SO 2 -N) or -C(O)-S bonds ;
  • R 100 and R 100a are each independently a lone pair (when applicable), hydrogen, COR 2c , —SO 2 R 5c , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, Optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4-7 or R 100 or R 100a and R 10 or R 11 groups form an optionally substituted heterocyclic or heteroaryl ring;
  • R 101 , R 101a , R 102 and R 102a when present, are each independently hydrogen, -OH, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkoxy, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4-7-membered heterocyclic group, or R 101 and R 102 , or R 101a and R 102a with their The atoms joined together form an optionally substituted 3-7 membered cycloalkyl or heterocyclyl ring; or one of R 101 and R 102 , or one of R 101a and R 102a together with an R 10 or R 11 group forms an optionally substituted cycloalkyl or heterocyclyl
  • R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1 -6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally substituted 5 or 6 membered heteroaryl; or an optionally substituted 4-7 membered heterocyclyl.
  • linker L or L ' forms a double bond with one of the ring carbons, it cannot be CR 101 R 102 where both R 101 and R 102 are present, because the valence of the carbon will exceed 4. In such cases, it is understood that one of R 101 and R 102 is absent, and L or L ' is CR 101 or CR 102 as defined herein.
  • L or L ' forms a double bond with one of the ring carbons, it can be NR 100 , where R 100 is usually a lone pair. Similarly, other similar situations in this disclosure should be understood.
  • L and L ' in Formula I are each independently empty, -O-, -C(O)-, -S-, -NR 100 -, -S(O)-, -SO 2 -or-CR 101 R 102- .
  • the compound of formula I has a formula according to any one of I-4 to I-5:
  • X 3 , X 4 and X 5 are each independently empty, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a -; and
  • R 10 , R 11 , R 100a , R 101a , R 102a , W, L 2 , m and n are defined herein.
  • the compound has Formula I-4, wherein X 3 and X 4 are each independently -O-, -C(O)-, -S-, -NR 100a -, or -SO 2 -. In some embodiments, the compound has Formula I-5, wherein X 5 is -O-, -C(O)-, -S-, -NR 100a -, or -SO 2 -. In some embodiments, R 100a is hydrogen or optionally substituted C 1-4 alkyl.
  • L2 in Formula I is typically empty, ie, the W group is directly attached to Cy2 .
  • L in Formula I can also be C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, or C 1-4 heteroalkylene.
  • the W group can be attached to Cy2 through a methylene or vinyl group.
  • each occurrence of the W group is independently -OH, -NH 2 , -SO 2 NH 2 , -SO 2 NH(C 1-4 alkyl), -SO 2 NH(C 1-4 alkanoyl), -COOH, -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl) -, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl), wherein each C 1-4 alkyl is independently optionally independently selected from C 1 -4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and 1-3 substituents of fluorine.
  • W in Formula I is -OH
  • L 2' -W ' may in some embodiments be selected as a substituent for Cy 1 or Cy 2 such as for Ar 1 or Ar 2 .
  • L 2' in Formula I may independently be empty at each occurrence, ie, the W ' group is directly attached to Cy 1 or Cy 2 , such as for Ar 1 or Ar 2 (when applicable), or C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene or C 1-4 heteroalkylene.
  • the W ' group may be attached to Cy 1 or Cy 2 through a methylene or vinyl group, such as for Ar 1 or Ar 2 .
  • W ' in Formula I may independently at each occurrence be -OH, -NH2 , -SO2NH 2.
  • each instance of W ' in Formula I may be -OH, -NH2 , -SO2NH2 , -SO2NH (acetyl), -COOH, or -OC(O) -CH3 .
  • each of R 10 and R 11 may independently at each occurrence be F; Cl; -OH; -NH 2 ; -SO 2 NH 2 ; 4 alkyl); -SO 2 NH (C 1-4 alkanoyl); -COOH; -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl) -; -O-(CO)-(C 1-4 alkyl); optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and fluorine C 1-4 alkyl substituted by 1-3 substituents; optionally 1-3 independently selected from C 1-4 alkyl, C 1-4 alkoxy,
  • each of R 10 and R 11 may independently at each occurrence be -OH; -NH 2 ; -SO 2 NH 2 ; -SO 2 NH(C 1-4 alkyl) ; -SO 2 NH(C 1-4 alkanoyl); -COOH; -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl) -; -O-(CO)-(C 1-4 alkyl); C 1-4 alkyl; or C 1-4 alkoxy.
  • one or more instances of R 10 and/or one or more instances of R 11 can be independently selected L 2′ -W ′ as described herein.
  • n is 0, 1 or 2 where applicable; preferably, it is 1.
  • n is 0, 1, 2 or 3 as applicable; preferably, it is 1 or 2.
  • the compounds herein can be characterized by having Formula II, or a pharmaceutically acceptable salt or ester thereof:
  • Cy 10 and Cy 11 are each independently optionally substituted cycloalkyl ring (e.g., C 3-7 cycloalkyl ring), optionally substituted heterocycle (e.g., 4-7 membered heterocycle), optionally substituted Aryl ring (for example, C 6-10 aryl ring), optionally substituted heteroaryl ring (for example, 5-10 membered heteroaryl ring), or optionally substituted cycloalkyl ring or heterocycle containing and a ring structure of an aryl or heteroaryl ring, wherein the ring structure may be fused or otherwise linked;
  • cycloalkyl ring e.g., C 3-7 cycloalkyl ring
  • optionally substituted heterocycle e.g., 4-7 membered heterocycle
  • Aryl ring for example, C 6-10 aryl ring
  • optionally substituted heteroaryl ring for example, 5-10 membered heteroaryl ring
  • L 10 is empty or linker
  • L 11 is empty, optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 2-6 alkenylene, optionally substituted C 2-6 Alkynylene, optionally substituted C 3-6 cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene or optionally substituted 4-7 membered heterocyclylene,
  • W 10 is -OR 1 ; -COOR 1a ; -OCOOR 1a ; -COR 2 ; -NR 3 R 4 ; -CONR 3a R 4a ; -OCONR 3b R 4b ; -SO 2 NR 3c R 4c ; R 4d ; -SR 5 ; -SO 2 R 5a ; -OCOR 2a ; -OSO 2 R 5a ; or
  • R and R are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted A heteroaryl or optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently hydrogen, -COR 2b , -SO 2 R 5b , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4-7 membered heterocyclyl, or R 3 and R 4 together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclyl;
  • R 2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , optionally substituted C 1-6 alkyl, optionally substituted C 2- 6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy Base, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; and
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl, optionally C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d or R 3e and R 4e together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclic group.
  • Cy 10 and Cy 11 is an optionally substituted C 6-10 aryl ring or an optionally substituted 5-10 membered heteroaryl ring.
  • Cy is an optionally substituted C6-10 aryl ring or an optionally substituted 5-10 membered heteroaryl ring.
  • Cy 11 is a bicyclic or polycyclic aryl or heteroaryl ring, L 10 -Cy 10 and L 11 -W 10 can be independently connected to Cy 11 through any ring.
  • Cy 11 may have a fused ring structure comprising an aryl or heteroaryl ring and a cycloalkyl or heterocyclic structure.
  • Cy 11 may be linked to L 10 -Cy 10 and L 11 -W 10 through any of an aryl or heteroaryl ring and a cycloalkyl or heterocyclic structure; or alternatively, One of L 10 -Cy 10 and L 11 -W 10 is connected to Cy 11 through an aryl or heteroaryl ring, while the other of L 10 -Cy 10 and L 11 -W 10 is connected to Cy 11 through a cycloalkyl or heterocycle The structure is linked to Cy 11 .
  • the compound of formula II has at least one phenyl ring, which can have the following core structure as Cy 10 -L 10 -Cy 11 :
  • Cy 10 can be either the left ring or the right ring in the above diagram, i.e., the diagram is not limited to a particular orientation, where L 11 -W 10 can be connected to either of the left or right ring, both Each ring can be optionally substituted.
  • the compound of Formula II may have the following core structure as Cy 10 -L 10 -Cy 11 :
  • Cy 10 can be either the left ring or the right ring in the above diagram, i.e., the diagram is not limited to a particular orientation, where L 11 -W 10 can be connected to either of the left or right ring, both Each ring can be optionally substituted.
  • Cy 10 and Cy 11 in Formula II are both aryl or heteroaryl rings.
  • the compound of Formula II has Formula II-1:
  • Ar 10 and Ar 11 are each independently an optionally substituted C 6-10 aryl ring or an optionally substituted 5-10 membered heteroaryl ring.
  • Ar 10 and Ar 11 in Formula II-1 are each independently an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heteroaryl ring.
  • Ar 10 and Ar 11 in Formula II-1 are each independently an optionally substituted phenyl ring, an optionally substituted thienyl ring, an optionally substituted furyl ring, an optionally substituted pyridine A base ring or an optionally substituted pyrimidinyl ring.
  • one of Ar 10 and Ar 11 in Formula II-1 is a bicyclic aryl or a bicyclic heteroaryl ring, each of which is optionally substituted, for example, in some embodiments, Ar 11 Can be an optionally substituted bicyclic aryl or bicyclic heteroaryl ring.
  • Cy 11 in Formula II is a phenyl ring.
  • the compound of Formula II has Formula II-2:
  • n 0, 1, 2 or 3
  • R 20 independently at each occurrence is halogen, -L 11' -W 10' , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally Substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclic group; or two adjacent R 20 , or one R 20 and L 10 or L 11 are formed together with the atoms to which they are bound Optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl rings;
  • L independently at each occurrence is empty, optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 2-6 alkenylene , optionally substituted C 2-6 alkynylene, optionally substituted C 3-6 cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted 4-7 and W 10' is independently at each occurrence -OR 1 ; -COR 2 ; -COOR 1a ; -OCOOR 1a ; -NR 3 R 4 ; -CONR 3a R 4a ; 4b ;-SO 2 NR 3c R 4c ;-OSO 2 NR 3d R 4d ;-SR 5 ;-SO 2 R 5a ;-OCOR 2a ;-OSO 2 R 5a or where R 1 , R 1a , R 2 , R 2a , R 2b , R 3 , R 4 , R 3a , R 3b , R
  • Cy 11 in Formula II is a benzofused ring.
  • the compound of Formula II has Formula II-3:
  • n 0, 1, 2 or 3
  • R 20 independently at each occurrence is halogen, -L 11' -W 10' , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally Substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclic group; or two adjacent R 20 , or one R 20 and L 10 or L 11 are formed together with the atoms to which they are bound Optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl rings;
  • L 11' and W 10' are defined herein, see e.g. formula II-2, and -L 11' -W 10' are independently selected at each occurrence;
  • Ring B is a 4-7 membered cycloalkyl ring, a 4-7 membered heterocyclic ring, a phenyl ring, a 5 or 6 membered heteroaryl ring, each of which is optionally substituted.
  • Cy 11 in Formula II is a benzo-fused bicyclic aryl or heteroaryl ring.
  • Cy 11 in Formula II can have the following core structure:
  • L 10 -Cy 10 and L 11 -W 10 can be independently connected to Cy 11 through any one of the two rings, wherein the phenyl ring can be optionally substituted by 1-3 R 20 groups as defined herein .
  • L 10 -Cy 10 may be attached to the thiophene ring, while L 11 -W 10 may be attached to the phenyl ring, and vice versa, and in some cases In this case, both L 10 -Cy 10 and L 11 -W 10 may be attached to the same ring, such as a phenyl ring.
  • compounds of Formula II can have any of the following structures:
  • Cy 10 , L 10 , R 20 , m, R 21 , n, R 100a , L 11 and W 10 are defined herein, see eg formula II and sub-formulas herein, such as formula II-3.
  • Cy 10 is Ar 10 as defined for formula II-3.
  • a compound of Formula II-3 may have Formula II-4:
  • Ar 10 , L 10 , R 20 , m, L 11 and W 10 are defined herein, see for example formula II-3,
  • n 0 or 1
  • R 21 independently at each occurrence is halogen, oxo, -L 11' -W 10' , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl ; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; wherein L 11' and W 10' are defined herein, see for example formula II-2, and -L 11' -W 10' selects independently at each occurrence;
  • X 10 and X 11 are each independently empty, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a -;
  • R 100a is a lone pair (when applicable), hydrogen, COR 2c , -SO 2 R 5c , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6-membered heteroaryl, or optionally substituted 4-7-membered heterocyclyl; or R 100a and R 20 or R 21 groups form an optionally substituted heterocyclic or heteroaryl ring;
  • R 101a and R 102a when present, are each independently hydrogen, -OH, halogen; optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkyne group, optionally substituted C 3-6 cycloalkyl group, optionally substituted C 1-6 alkoxy group, optionally substituted C 3-6 cycloalkoxy group, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4-7-membered heterocyclyl; or R 101a and R 102a together with the atoms to which they are bound form an optionally substituted 3-7 a membered cycloalkyl or heterocyclyl ring; or one of R 101a and R 102a together with R 20 or R 21 groups form an optionally substituted cycloalkyl or heterocyclyl ring; and
  • R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1 -6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally substituted 5 or 6 membered heteroaryl; Or an optionally substituted 4-7 membered heterocyclyl;
  • X 10 or X 11 forms a double bond with one of the ring carbons, it cannot be CR 101a R 102a where both R 101a and R 102a are present, because the valence of the carbon will exceed 4. In such cases, it is understood that one of R 101a and R 102a is absent, and X 10 or X 11 is CR 101a or CR 102a as defined herein.
  • X 10 or X 11 forms a double bond with one of the ring carbons, it can be NR 100a , where R 100a is usually a lone pair.
  • the compound of Formula II has Formula II-5:
  • Ar 10 , L 10 , R 20 , m, R 21 , n, L 11 and W 10 are defined herein, see eg formula II-4.
  • Cy 10 and Cy 11 in Formula II may be linked directly or via various groups.
  • L 10 in Formula II eg, Formulas II-1 to II-5 is empty, -C(O)-, optionally substituted C 1-4 alkylene, optionally Substituted C 2-4 alkenylene, optionally substituted C 3-6 cycloalkylene, optionally substituted 4-7 membered heterocyclylene, optionally substituted phenylene, optionally substituted 5 or 6-membered heteroarylene, -O-, -S-, -NR 100 -, -S(O)-, -SO 2 -, -X 1 -G 1 -, -X 2 -G 2 -X 2a - , -X 12 -G 10 -, -X 13 -G 11 -X 13a - or -CR 101 R 102 -,
  • X 1 , X 2 and X 2a are independently optionally substituted C 1-4 alkylene, optionally substituted C 2-4 alkenylene, optionally substituted C 3-6 cycloalkylene, optionally Substituted 4-7 membered heterocyclylene, optionally substituted phenylene, optionally substituted 5 or 6 membered heteroarylene, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a -;
  • G 1 and G 2 are independently optionally substituted C 1-4 alkylene, optionally substituted C 2-4 alkenylene, optionally substituted C 3-6 cycloalkylene, optionally substituted 4 -7-membered heterocyclylene, optionally substituted phenylene, optionally substituted 5- or 6-membered heteroarylene, -C(O)-, -NR 100a -, -S(O)-, -SO 2 - or - CR 101a R 102a -;
  • -X 1 -G 1 - or -X 2 -G 2 -X 2a - does not contain ON, SS, SN (except SO 2 -N bond) or -C(O)-S key;
  • X 12 , X 13 and X 13a are independently optionally substituted C 1-4 alkylene, optionally substituted C 2-4 alkenylene, optionally substituted C 3-6 cycloalkylene, optionally Substituted 4-7 membered heterocyclylene, optionally substituted phenylene, optionally substituted 5 or 6 membered heteroarylene, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a -;
  • G 10 and G 11 are independently -X 1 -G 1 - or -X 2 -G 2 -X 2a -;
  • -X 12 -G 10 - or -X 13 -G 11 -X 13a - does not contain OO, ON, SS, SN (except SO 2 -N bonds), or -C(O )-S bond or three (or more) consecutive heteroatoms, except for O-SO 2 -O, O-SO 2 -N and N-SO 2 -N;
  • R 100 and R 100a are each independently a lone pair (when applicable), hydrogen, COR 2c , —SO 2 R 5c , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, Optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4-7 membered heterocyclyl;
  • R 101 , R 101a , R 102 and R 102a are each independently hydrogen, -OH, halogen; optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2 -6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkoxy, optionally substituted amino, Optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4-7-membered heterocyclic group; or R 101 and R 102 , or R 101a and R 102a combined with them The atoms are taken together to form an optionally substituted 3-7 membered cycloalkyl or heterocyclyl ring.
  • L 10 in Formula II may be empty, and Cy 10 is directly linked to Cy 11 .
  • L 10 in Formula II can be empty, -O-, -C(O)-, -S-, -NR 100 -, -S(O)-, -SO 2 -, or -CR 101 R 102 -.
  • L 10 in Formula II may be -X 1 -G 1 - or -X 2 -G 2 -X 2a -, wherein: X 1 , X 2 and X 2a are independently -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 -, or -CR 101a R 102a -; and G 1 and G 2 are independently -C(O)- , -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a -.
  • L 10 in Formula II may be -X 12 -G 10 -.
  • X 12 is optionally substituted C 2-4 alkenylene, preferably
  • G 10 is -X 1 -G 1 -or -X 2 -G 2 -X 2a -; wherein: X 1 , X 2 and X 2a are independently -O-, -C(O)-, -S- , -NR 100a -, -S(O)-, -SO 2 -, or -CR 101a R 102a -; and G 1 and G 2 are independently -C(O)-, -NR 100a -, -S(O )-, -SO 2 - or -CR 101a R 102a -.
  • L in formula II may be
  • compounds of Formula II may have the following core structure:
  • L 11 -W 10 can be directly attached to either ring, preferably to one of the two phenyl rings or to the only phenyl ring, wherein each ring can optionally be surrounded by one or more -OH; -NH 2 ; -SO 2 NH 2 ; -SO 2 NH ( C 1-4 alkyl ); -SO 2 NH(C 1-4 alkanoyl); -COOH; -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl) -; -O-(CO)-(C 1-4 alkyl); optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and fluorine C 1-4 alkyl substituted by 1-3 substituents; optionally 1-3 independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH, -
  • L 11 -W 10 is NH 2 or NH(C 1-4 alkanoyl), which is attached to one of the two phenyl rings or to the only phenyl ring, while the other The ring is optionally substituted with 1 or 2 substituents selected from methyl and methoxy.
  • the compound of formula II has a formula according to formula II-6 or II-7:
  • L 11 , W 10 , R 20 and m are defined herein, see for example formula II-3,
  • p 0, 1, 2, 3 or 4,
  • R 22 independently at each occurrence is halogen, -L 11' -W 10' , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally Substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclic group; or two adjacent R 22 together with their bonded atoms form an optionally substituted cycloalkyl, heterocyclic group , aryl or heteroaryl ring;
  • L 11' and W 10' are defined herein, see eg formula II-2, and -L 11' -W 10' are independently selected at each occurrence.
  • L 11 in formula II (eg, any sub-formula, such as formulas II-1 to II-7) is typically empty, ie, when applicable, the W 10 group is directly attached to Cy 11 .
  • L 11 in Formula II can also be C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, or C 1-4 heteroalkylene.
  • a W 10 group may be attached to Cy 11 through a methylene or vinyl group.
  • each occurrence of the W 10 group is independently -OH, -NH 2 , -SO 2 NH 2 , -SO 2 NH(C 1-4 alkyl); -SO 2 NH( C 1-4 alkanoyl), -COOH, -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl) -, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl), wherein each C 1-4 alkyl is independently optionally independently selected from C 1 -4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and 1-3 substituents of fluorine.
  • the W 10 group in Formula II is -OH, -OMe, -NH 2 , -SO 2 NH 2 , -SO 2 NH(acetyl), -COOH, or -OC(O) -CH3 .
  • L 11' -W 10' may in some embodiments be selected as substituents for Cy 10 or Cy 11 such as for Ar 10 or Ar 11 .
  • L 11' in Formula II may independently be empty at each occurrence, ie, the W 10' group is directly Attached to Cy 10 or Cy 11 , such as for Ar 10 or Ar 11 (when applicable), or C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene or C 1-4 heteroalkylene.
  • a W 10' group may be attached to Cy 10 or Cy 11 through a methylene or vinyl group, such as for Ar 10 or Ar 11 (where applicable).
  • W 10' in Formula II may independently at each occurrence be -OH, -NH 2 , -SO 2 NH 2 , -SO 2 NH(C 1-4 alkyl), -SO 2 NH(C 1-4 alkanoyl), -COOH, -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl) -, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl), wherein each C 1-4 alkyl is independently optionally independently selected from C 1 -4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and 1-3 substituents of fluorine.
  • each instance of W 10' in Formula II may be -OH, -OMe, -NH2 , -SO2NH2 , -SO2NH (acetyl), -COOH or -OC(O) -CH3 .
  • each of R 20 , R 21 , and R 22 may independently at each occurrence be F; Cl; —OH; —NH 2 ; —SO 2 NH 2 ; —SO 2 NH( C 1-4 alkyl); -SO 2 NH (C 1-4 alkanoyl); -COOH; -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl) -; -O-(CO)-(C 1-4 alkyl); optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and fluorine C 1-4 alkyl substituted by 1-3 substituents; optionally 1-3 independently selected from C 1-4 alkyl,
  • each of R 20 , R 21 , and R 22 may independently at each occurrence be F; Cl; —OH; —NH 2 , —SO 2 NH 2 , —SO 2 NH( C 1-4 alkyl), -SO 2 NH (C 1-4 alkanoyl), -COOH; -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl) -; -O-(CO)-(C 1-4 alkyl); -O-(C 1-6 alkyl); -O-(C 2-6 alkenyl); optionally independently selected from C 1-4 alkyl, C 1-6 alkoxy, -OH, -NH 2 and 1-3 substituents of fluorine substituted C 1-6 alkyl; or optionally independently selected from C 1 C 2-6 alkenyl substituted with 1-3 substituents of -4 alky
  • each occurrence of R 20 , R 21 and R 22 may independently be -OH, C 1-4 alkyl, C 2-6 alkenyl, or -O-(C 1-4 alkyl). In some embodiments, each occurrence of R 20 , R 21 , and R 22 may independently be —OH, —OMe, or In some embodiments, one or more instances of R 20 , one or more instances of R 21 and/or one or more instances of R 22 may be independently selected as L 11 ' -W as described herein 10' .
  • n and p are 0, 1, 2 or 3 as applicable; preferably, 1 or 2.
  • n is 0, 1 or 2 as applicable; preferably, it is 0 or 1 .
  • the compound of Formula II can have a formula according to any one of Formulas II-8 to II-10:
  • R 20 , R 22 , m and p are defined herein.
  • m is 1 or 2 and p is 1, 2 or 3.
  • each occurrence of R 20 and R 22 is, independently at each occurrence, F; Cl; -OH; -NH 2 , -SO 2 NH 2 , -SO 2 NH(C 1-4 Alkyl), -SO 2 NH (C 1-4 alkanoyl), -COOH; -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl) -; -O-(CO)-(C 1-4 alkyl); -O-(C 1-6 alkyl); -O-(C 2-6 alkenyl); optionally independently selected from C 1-4 alkyl, C 1-6 alkoxy, -OH, -NH 2 and 1-3 substituents of fluorine substitute
  • the structural unit in any applicable formula II can be selected from
  • the compound of formula II can be:
  • the compounds herein can be characterized by having Formula III, or a pharmaceutically acceptable salt or ester thereof:
  • Ar is an optionally substituted aryl ring (for example, a C 6-10 aryl ring) or an optionally substituted heteroaryl ring (for example, a 5-10 membered heteroaryl ring);
  • L 20 is empty, optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 2-6 alkenylene, optionally substituted C 2-6 Alkynylene, optionally substituted C 3-6 cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene or optionally substituted 4-7 membered heterocyclylene,
  • W 20 is -OR 1 ; -COR 2 ; -COOR 1a ; -OCOOR 1a ; -NR 3 R 4 ; -CONR 3a R 4a ; -OCONR 3b R 4b ; R 4d ; -SR 5 ; -SO 2 R 5a ; -OCOR 2a ; -OSO 2 R 5a ; or
  • R and R are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted A heteroaryl or optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently hydrogen, -COR 2b , -SO 2 R 5b , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4-7 membered heterocyclyl, or R 3 and R 4 together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclyl;
  • R 2 , R 2a , R wb , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , optionally substituted C 1-6 alkyl, optionally substituted C 2- 6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy Base, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; and
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl, optionally C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d or R 3e and R 4e together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclic group.
  • Ar 20 in Formula III is an optionally substituted phenyl ring or an optionally substituted 5 or 6 membered heteroaryl ring.
  • Ar in Formula III can be an optionally substituted phenyl ring , an optionally substituted thienyl ring, an optionally substituted furyl ring, an optionally substituted pyridyl ring, or an optionally Substituted pyrimidinyl ring.
  • Ar 20 in Formula III can also be an optionally substituted bicyclic aryl or bicyclic heteroaryl ring, each of which is optionally substituted.
  • L 20 -W 20 can be attached to either bicyclic ring.
  • Ar in Formula III may be an optionally substituted phenyl ring , wherein two adjacent substituents together with the carbons to which they are attached form an optionally substituted cycloalkyl, heterocyclyl , aryl or heteroaryl ring.
  • Ar 20 in Formula III can be a benzo-fused bicyclic aryl or heteroaryl ring.
  • Ar 20 in Formula III can have the following structure:
  • -L 20 -W 20 may be attached at any one of the two rings, wherein either or both rings may be optionally substituted.
  • a compound of Formula III may have Formula III-1, III-2, or III-3:
  • n 0, 1, 2 or 3;
  • R 30 and R 31 is independently, at each occurrence, halogen, -L 20' -W 20' , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl , optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, any Optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; wherein -L 20' -W 20' is independently selected at each occurrence; wherein L 20' is independently empty at each occurrence, optionally substituted C 1-6 alkylene, optionally substituted C 1-6 heteroalkylene, optionally substituted C 2-6 alkenylene, Optionally substituted C 2-6 alkynylene, optionally substituted C 3-6 cycloalkylene, optionally substituted arylene, optionally substituted hetero
  • Ring B is a 4-7 membered cycloalkyl ring, a 4-7 membered heterocycle, a phenyl ring, a 5 or 6 membered heteroaryl ring, each of which is optionally substituted by 1-3 independently selected R ;
  • X 20 and X 21 are each independently empty, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a -;
  • R 100a is a lone pair (when applicable), hydrogen, COR 2c , -SO 2 R 5c , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6-membered heteroaryl, or optionally substituted 4-7-membered heterocyclyl; Or R 100a and one of R 30 or R 31 together with the atoms to which they are bound form an optionally substituted heterocyclic or heteroaryl ring, such as an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 4- 7-membered heterocyclyl;
  • R 101a and R 102a when present, are each independently hydrogen, -OH, halogen; optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkyne group, optionally substituted C 3-6 cycloalkyl group, optionally substituted C 1-6 alkoxy group, optionally substituted C 3-6 cycloalkoxy group, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4-7-membered heterocyclyl, or R 101a and R 102a together with the atoms they are bound to form an optionally substituted 3-7 a membered cycloalkyl or heterocyclyl ring; or one of R 101a and R 102a together with the R 30 or R 31 group forms an optionally substituted cycloalkyl or heterocyclyl ring; and
  • R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1 -6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy, optionally substituted phenyl; optionally substituted 5 or 6 membered heteroaryl; Or an optionally substituted 4-7 membered heterocyclyl;
  • R 30 or two adjacent R 31 , or R 30 or R 31 and X 20 or X 21 together with their bonded atoms form an optionally substituted cycloalkyl, heterocyclyl, aryl base or heteroaryl ring.
  • X 20 or X 21 forms a double bond with one of the ring carbons, it cannot be CR 101a R 102a where both R 101a and R 102a are present, because the valence of the carbon will exceed 4. In such cases, it is understood that one of R 101a and R 102a is absent, and X 20 or X 21 is CR 101a or CR 102a as defined herein.
  • X 20 or X 21 forms a double bond with one of the ring carbons, it can be NR 100a , where R 100a is usually a lone pair.
  • each instance of the structural unit -L 20' -W 20' and -L 20 -W 20 is independently selected and may be the same or different.
  • compounds of Formula III can have any of the following structures:
  • R 30 , m, R 31 , n, R 100a , L 20 and W 20 are defined herein, see for example formula III and sub-formulas herein, such as formulas III-1 to III-3, wherein for tricyclic structures, piperidine The pyridine or morpholine rings may be optionally substituted.
  • L 20 in formula III (eg, any sub-formula, such as formulas III-1 to III-3) is typically empty, ie, the W 20 group is directly attached to Ar 20 .
  • L 20 in Formula III can also be C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, or C 1-4 heteroalkylene.
  • a W 20 group may be attached to Ar 20 through a methylene or vinyl group.
  • W in formula III can be -OH, -COOH, -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 , -NH 2 , -SO 2 NH 2 , -SO 2 NH (C 1-4 alkyl); -SO 2 NH(C 1-4 alkanoyl), -OC(O)NH(C 1-4 alkyl)-, -O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 alkyl), wherein each C 1-4 alkyl is independently optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, - Substituted by 1-3 substituents of OH, -NH2 and fluorine.
  • the W 20 group in Formula III (eg, any subformula, such as Formulas III-1 to III-3) is -OH, -NH 2 , -SO 2 NH 2 , -SO 2 NH ( Acetyl), -C(O)-(OC 8 alkyl), -COOH or -OC(O)-CH 3 .
  • L 20′ -W 20′ may be selected as substituents for Ar 20 in some embodiments.
  • L 20' in Formula III (including any sub-formulas described herein, such as Formulas III-1 to III-3) may independently be empty at each occurrence, i.e., when applicable, W 20
  • the ' group is directly attached to Ar 20 , or is a C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, or C 1-4 heteroalkylene.
  • the W 20' group may be attached to Ar 20 through a methylene or vinyl group, when applicable.
  • W in Formula III may independently at each occurrence be -OH, -COOH, -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 , -NH 2 , -SO 2 NH 2 , -SO 2 NH (C 1-4 alkyl); -SO 2 NH(C 1-4 alkanoyl), -OC(O)NH(C 1-4 alkyl)-, -O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 alkyl), wherein each C 1-4 alkyl is independently optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, - Substituted by 1-3 substituents of OH, -NH2 and fluorine.
  • each instance of W 20' in Formula III may be -OH, -NH 2 , -SO 2 NH 2 , -SO 2 NH(acetyl), -COOH, -C(O)(OC 8 alkyl) or -OC(O)-CH 3 .
  • each of R 30 and R 31 may independently at each occurrence be F; Cl; -OH; -COOH; -OC(O)NH 2 ; -OC(O)NH( C 1-4 alkyl)-; -O-(CO)-(C 1-4 alkyl); optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH C 1-4 alkyl substituted with 1-3 substituents of , -NH 2 and fluorine; optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH, -NH C 2-6 alkenyl substituted with 1-3 substituents of 2 and fluorine; optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and fluorine C 2-6 alkynyl substituted with 1-3 substitu
  • each of R and R can independently at each occurrence be -OH, C 2-6 alkenyl, -O-(C 1-4 alkyl), -COOH, or -C(O)(OC 1-10 alkyl).
  • each occurrence of R 30 and R 31 can be -OH or -OMe.
  • one or more instances of R 30 and/or one or more instances of R 31 can be independently selected L 20' -W 20' as described herein.
  • n 1, 2 or 3.
  • the present disclosure also provides the following compounds: or a pharmaceutically acceptable salt or ester thereof.
  • the present disclosure also provides the following compounds: or a pharmaceutically acceptable salt or ester thereof, wherein q is 1, 2, 3, 4 or 5, and Glu is a glucose residue. In some specific embodiments, the present disclosure also provides
  • the compounds herein may also be alkaloids with antibacterial activity.
  • certain indole alkaloids such as vinca alkaloids, hydroglycyrrhizine, vindolin, vinblastine, vincristine, etc. have been shown to be effective in killing microorganisms such as Bacillus megaterium.
  • the compounds herein are characterized by Formula IV-1 or IV-2, which are hydroglycyrrhizine or pventaline and derivatives:
  • R 40 is hydrogen; -COR 2 ; -COOR 1a ; -SO 2 R 5a ; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
  • R 4 1 is -OR 1 ; -OCOOR 1a ; -OCONR 3b R 4b ; -OCOR 2a ; or -OSO 2 R 5a ; n is 0 or 1;
  • R 42 , R 43 and R 44 are each independently hydrogen, -OR 1 , OCOR 2a ; or -O5O 2 R 5a ;
  • L 30 is empty or methylene
  • W 30 is -OR 1 ; -COR 3 ; -COOR 1a ; -OCOOR 1a ; -NR 3 R 4 ; -CONR 3a R 4a ; -OCONR 3b R 4b ; -OSO 2 NR 3d R 4d ; -OCOR 2a ; or -O5O 2 R 5a
  • R and R are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted A heteroaryl or optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently hydrogen, -COR 2b , -SO 2 R 5b , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4-7 membered heterocyclyl, or R 3 and R 4 together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclyl;
  • R 2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , optionally substituted C 1-6 alkyl, optionally substituted C 2- 6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkoxy Base, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; and
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl, optionally C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4-7-membered heterocyclyl; or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d or R 3e and R 4e together with the atoms to which they are bound form an optionally substituted 4-7 membered heterocyclic group.
  • the compound of Formula IV-1 or IV-2 has a formula according to one of Formulas IV-3 to IV-6:
  • R 45 is hydrogen or methyl
  • R 40 of any one of Formulas IV-1 to IV-6 can be hydrogen, C 1-4 alkyl, or C 1-4 alkanoyl.
  • L 30 in Formulas IV-1 to IV-6 is usually empty. However, in some embodiments, L 30 in Formulas IV-1 to IV-6 may also be CH 2 .
  • W 30 in Formulas IV-1 to IV-6 is generally a carboxylic acid derivative, amine derivative or alcohol derivative useful in the compositions and methods herein.
  • the naturally occurring indole alkaloid hydroglycyrrhizine contains a CO 2 Me group as W 30 , while L 30 is empty.
  • the CO2Me group can be converted to the corresponding acid, amide, etc. via conventional transformations, or can be reduced or converted to the amine by rearrangement such as the Curtius rearrangement.
  • W 30 in Formulas IV-1 to IV-6 can be -OH, -NH 2 , -OSO 2 NH 2 , -COOH, -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl)-, -O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 alkyl), wherein each C 1-4 alkyl is independently optionally independently selected from C 1-4 alkyl, C 1-4 alkoxy, - Substituted by 1-3 substituents of OH, -NH2 and fluorine.
  • W 30 in Formulas IV-1 to IV-6 may be -OH, -NH 2 , -OSO 2 NH 2 , -C(O)-(OC 8 alkyl), -COOH, or - OC(O) NH2 .
  • compounds can have the following structures:
  • the compounds herein may also be glycosides having antibacterial activity, or pharmaceutically acceptable salts or esters thereof.
  • certain glycosides such as ginsenosides and gallic acid glycosides have been shown to be effective against microorganisms such as Bacillus megaterium.
  • Other useful glycosides include any of those glycosides known in the art to have antibacterial activity, which may, for example, include glycosides characterized in that their corresponding aglycon is a phenolic compound, a flavonoid, a coumarin, a benzoic acid, or a sterol .
  • the glycoside is a glucoside, but other glycosides can also be used.
  • glycosides can be characterized as amphipathic, which can disrupt biofilms and impart antimicrobial activity to the glycosides.
  • glycosides may also be characterized as saponins, which include, for example, various plant-derived glycosides that may act as "surfactants" and may aid in killing bacteria.
  • glycosides herein can be characterized by Formula V:
  • each R 50 is independently hydrogen, -L 50 -D, an oxygen protecting group, or a sugar residue;
  • L 50 is empty or -C(O)-
  • D is optionally substituted aryl (eg, C 6-10 aryl), optionally substituted heteroaryl (eg, 5 to 14 membered heteroaryl), optionally substituted comprising two or more independent A fused ring selected from aryl, heteroaryl, cycloalkyl and heterocyclyl (e.g., 8-14 membered, e.g., benzofused cycloalkyl/heterocyclic, pyridofused cycloalkyl/ heterocyclyl) or a steroid residue of formula VA:
  • R independently at each occurrence is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -OH optionally substituted with an oxygen protecting group, oxo, halogen, any Optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted amino, optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted or two R groups together with the atoms to which they are bound form an optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl ring;
  • n is an integer from 1 to 8.
  • each R 50 is hydrogen.
  • one to four R 50 may be independently selected -L 50 -D.
  • R 50 may be independently selected -L 50 -D.
  • two or more -L 50 -D units are attached to the pyranose unit in formula V, they are preferably identical.
  • one or more (eg, 1 or 2) R 50 may be a sugar residue linked to the remainder of Formula V via a glycosidic bond.
  • the sugar residue is a glucose residue or a rhamnose residue.
  • L50 in formula V can be empty or a carbonyl group i.e. -C(O)-, depending on whether the linking group is from the phenolic -OH or COOH group of benzoic acid or the heteroaryl counterpart.
  • a variety of residues can be used as D, typically residues from phenolic compounds, coumarins, flavonoids or sterols, which in some embodiments can have antibacterial activity without a glycoside unit.
  • D can be an optionally substituted ring selected from:
  • R 100a is lone pair (when applicable), hydrogen, nitrogen protecting group, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, Optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl or optionally substituted 4-7-membered heterocyclyl; or R 100a with phenyl or The pyridyl ring forms an optionally substituted heterocyclic or heteroaryl ring;
  • Each ring system of D is optionally substituted with 1-5 (eg, 1, 2 or 3) substituents, each substituent independently selected from -OH; -COOH; -C(O)(OC 1- 10 alkyl); -C(O)(OC 2-10 alkenyl); -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl)-; -O-(CO)- (C 1-4 alkyl); -NH 2 ; -SO 2 NH 2 ; -SO 2 NH(C 1-4 alkyl); -SO 2 NH(C 1-4 alkanoyl); halogen; optionally substituted C 1-6 alkyl; optionally substituted C 2-6 alkenyl; optionally substituted C 2-6 alkynyl; optionally substituted C 3-6 cycloalkyl; optionally substituted C 1-6 Alkoxy; Optionally substituted C cycloalkoxy ; Optionally substituted amino; Optionally substituted phenyl; Optionally
  • each ring system of D shown above can be optionally substituted with 1-5 substituents, each substituent independently selected from F; Cl; -OH; -COOH; -C (O)(OC 1-10 alkyl); -C(O)(OC 2-10 alkenyl); -OC(O)NH 2 ; -OC(O)NH(C 1-4 alkyl)-; -O-(CO)-(C 1-4 alkyl); -NH 2 ; -SO 2 NH 2 ; -SO 2 NH(C 1-4 alkyl); -SO 2 NH(C 1-4 alkanoyl ); C 1-4 alkyl optionally substituted by 1-3 substituents independently selected from C 1-4 alkyl; C 1-4 alkoxy, -OH, -NH 2 and fluorine; any C 2-6 alkenyl optionally substituted by 1-3 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, -OH, -NH 2 and fluorine; any C
  • D can be selected from:
  • each phenolic OH group is optionally linked to a sugar such as glucose via a glycosidic bond.
  • D is derived from a sterol.
  • D is
  • R is optionally substituted alkyl or optionally substituted alkenyl
  • each remaining -OH group in D is optionally linked to a sugar via a glycosidic bond.
  • R 52 may be
  • the glycoside can have formula V-1 or V-2:
  • the glycoside may be a compound selected from:
  • the compounds herein may be any one or more compounds selected from the group consisting of benzoic acid, benzyl alcohol, coumarins, catechols, polyphenols, chalcones (including licorice Chalcones), etc., stilbenes such as resveratrol, isoresveratrol, etc., phenolic acids such as p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechuic acid, gallic acid, vanillic acid , syringic acid, cinnamic acid, coumaric acid, caffeic acid, ferulic acid, chlorogenic acid, sinapic acid, etc., flavonoids such as catechin, naringenin, quercetin, rutin, chrysin etc., tannins such as ellagic acid, and pharmaceutically acceptable salts or esters thereof and glycosides thereof.
  • the microorganism inhibitor or killing agent is compound 1-8, which has the following chemical structure:
  • the microbial inhibitor or sterilant of the present invention is a natural plant or an extract thereof, preferably, the natural plant is selected from the group consisting of licorice, white peony root, forsythia, citrus aurantium, rehmannia glutinosa, tangerine peel, notoginseng , turtle shell, rhodiola rosea, raw land, coix seed, white peony root, forsythia, cassia seed and licorice, or a combination of two or more, or the above natural plant extracts or a combination thereof.
  • the natural plant is selected from the group consisting of licorice, white peony root, forsythia, citrus aurantium, rehmannia glutinosa, tangerine peel, notoginseng , turtle shell, rhodiola rosea, raw land, coix seed, white peony root, forsythia, cassia seed and licorice, or a combination of two or
  • the microbial inhibitor or killer is a composition comprising turtle shell, rhodiola rosea, rehmannia root, coix seed, white peony root, forsythia, cassia seed and licorice, preferably, the According to weight fractions, the composition includes 5-15 parts of turtle shell, 10-30 parts of rhodiola, 5-15 parts of raw land, 5-15 parts of barley, 8-20 parts of white peony root, 5-15 parts of forsythia 5-15 parts, cassia seed 5-15 parts and licorice 5-15 parts, more preferably, described composition comprises 10 parts of turtle shell, 20 parts of rhodiola rosea, 10 parts of raw land, 10 parts of barley, 12 parts of white peony root, forsythia 10 parts, cassia seed 10 parts and licorice 9 parts.
  • said administration to the patient's eye includes aqueous humor in the anterior chamber of the patient's eye, zonular ligament, ciliary body, ciliary body and ciliary muscle, vitreous humor in the posterior chamber, retina, choroid , optic nerve, lens or iris.
  • the administration to the patient's gastrointestinal tract includes administration to the patient's stomach, jejunum, ileum, cecum, colon or rectum.
  • Another aspect of the present invention provides the application of microbial inhibitors or killing agents in the preparation of medicaments for treating retinal degeneration.
  • the retinal degeneration is progressive retinal degeneration; more preferably, the retinal degeneration is hereditary retinal degeneration; more preferably, hereditary retinal degeneration includes congenital amaurosis (LCA), retinitis pigmentosa (RP), Premature Rod-Cone Dystrophy, Rod-Rod Dystrophy, Congenital Stationary Night Blindness and Color Blindness, and Stargardt Disease.
  • LCA congenital amaurosis
  • RP retinitis pigmentosa
  • Premature Rod-Cone Dystrophy Rod-Rod Dystrophy
  • Congenital Stationary Night Blindness and Color Blindness and Stargardt Disease.
  • the microorganism is one or a combination of two or more of bacteria, archaea, protists, fungi or viruses.
  • the microorganisms are bacteria selected from the group consisting of: Anearostipes, Bifidobacterium, Megamonas, Nitrosomonas, Oscillibacter, Tatum (Tatumella), Thiobacillus sp., Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Platts Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella Klebsiella, Porphyromonas, Azospira, Aquimarina, Achromobacter, Acidithiobacillus, Burke Burkholderia, Marinobacter, Treponema, Actinosporangium, Vibrio, Ruminococcus, Methanobacillus One or more
  • the bacterium is selected from: Anearostipeshadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp.Is79A3, Oscillibactervalericigenes, Tatumella sp.TA1, Megamonasfuniformis, Thiobacillus denitrificans, Akkermansiamucinphila.
  • the microbial inhibitors or killing agents include compounds, polypeptides, polynucleotides, natural plants or natural plant extracts.
  • the microorganism inhibitor or killing agent is an antibiotic
  • the antibiotic is a ⁇ -lactam antibiotic; an aminoglycoside antibiotic; a tetracycline antibiotic; a chloramphenicol antibiotic; Antibiotics; glycopeptide antibiotics; quinolone antibiotics; nitroimidazole antibiotics; rifamycin antibiotics; echinocandin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; One or two or more of other antibiotics.
  • antibiotics may include one or more of the following: ⁇ -lactam antibiotics, including penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacancilin, carbenicillin, Xacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pimacillin, pimacillin, ticarcillin, cephalosporins such as cefacetonitrile, Cefadroxil, cephalexin, cefalaxine, cefuroxime, cefotaxime, cephalothin, cefapirin, ceftriaxone, cefazolin, cefoxizone, cefazolin, cefradine, cefoxadin, ceftezole , Cefaclor, Cefamandole, Cefmetazole, Cefdinir, Cefotet
  • penicillins e
  • the antibiotic may be selected from the group consisting of amikacin, amoxicillin, ampicillin, arsenamin, azithromycin, azlocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefixime Lo, cefadroxil, cephalexin, cephalothin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil , ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, Colistin, cycloserine, dalfopristin, dapsone, dap
  • the microorganism inhibitor or killing agent is formula I (for example, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5), formula II (for example, Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula II-5, Formula II-6, Formula II-7, Formula II-8, Formula II-9, Formula II-10) , formula III (for example, formula III-1, formula III-2, formula III-3), formula IV-1 or IV-2 (for example, formula IV-3, formula IV-4, formula IV-5, formula IV -6), a compound of glycoside (for example, formula V), or a pharmaceutically acceptable salt or ester thereof, wherein the aglycon of the glycoside is a phenolic compound, a flavonoid, a coumarin, a benzoic acid or a sterol, wherein The formulas I, II, III, IV-1, IV-2, V and their subformulas are as defined above.
  • the microorganism inhibitor or killing agent is compound 1-8, which has the following chemical structure:
  • the microbial inhibitor or sterilant of the present invention is a natural plant or an extract thereof, preferably, the natural plant is selected from the group consisting of licorice, white peony root, forsythia, citrus aurantium, rehmannia glutinosa, tangerine peel, notoginseng , turtle shell, rhodiola rosea, raw land, coix seed, white peony root, forsythia, cassia seed and licorice, or a combination of two or more, or the above natural plant extracts or a combination thereof.
  • the natural plant is selected from the group consisting of licorice, white peony root, forsythia, citrus aurantium, rehmannia glutinosa, tangerine peel, notoginseng , turtle shell, rhodiola rosea, raw land, coix seed, white peony root, forsythia, cassia seed and licorice, or a combination of two or
  • the microbial inhibitor or killer is a composition comprising turtle shell, rhodiola rosea, rehmannia root, coix seed, white peony root, forsythia, cassia seed and licorice, preferably, the According to weight fractions, the composition includes 5-15 parts of turtle shell, 10-30 parts of rhodiola, 5-15 parts of raw land, 5-15 parts of barley, 8-20 parts of white peony root, 5-15 parts of forsythia 5-15 parts, cassia seed 5-15 parts and licorice 5-15 parts, more preferably, described composition comprises 10 parts of turtle shell, 20 parts of rhodiola rosea, 10 parts of raw land, 10 parts of barley, 12 parts of white peony root, forsythia 10 parts, cassia seed 10 parts and licorice 9 parts.
  • the drug is a preparation for ophthalmic administration or a preparation for gastrointestinal administration.
  • the ophthalmic preparations are eye drops, ophthalmic ointments, ophthalmic gels, ophthalmic films, eye washes, and intraocular injections.
  • the preparations for gastrointestinal administration are tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules formulations, capsules (including soft capsules, microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled release formulations (eg, instant release formulations, sustained release formulations, sustained release microcapsules), aerosols Doses, films (eg, orally disintegrating films, oromucosa-adhesive films).
  • the above-mentioned pharmaceutically acceptable excipients may include sweeteners (such as sucrose, xylitol, fructooligosaccharides, cyclamate, stevioside, aspartame, etc.), flavoring agents (such as spices, essences, etc.) ), mucilage agent (specifically, sodium alginate, gum arabic, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), clarifying agent (specifically, chitosan, gelatin, etc.), preservative (specifically Such as benzoic acid and its salts, sorbic acid and its salts, paraben series, etc.), disintegrants (such as low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, cross-linked carboxy Sodium methylcellulose, starch, etc.), binder (specifically, such as hydroxypropyl cellulose, hypromellose, povidone, copovidone, pregelatinized starch, etc
  • the present invention also provides a method for establishing an eye disease model, the method comprising infecting the eye disease model with microorganisms.
  • the infection includes direct contact with microorganisms or indirect contact with microorganisms.
  • the ocular disease model in which the eye is infected with microorganisms is obtained by raising the non-human animal in an SPF environment.
  • said microorganisms are from or identical to the intestinal bacteria of the same individual.
  • the eye disease includes retinal degeneration; more preferably, the retinal degeneration is progressive retinal degeneration.
  • the retinal degeneration is Inherited Retinal Degeneration (IRD).
  • IFD Inherited Retinal Degeneration
  • the eye diseases comprise LCA, RP, arRP, EORD, EORP, PPRPE, rettelangiectasia and/or choroideremia like fundus.
  • said eye disease comprises ocular inflammation, such as uveitis, glaucoma, and age-related macular degeneration (AMD), vitreitis, choroiditis, retinitis, retinal vasculitis, optic neuritis, and grapevine Meningitis, Behcet's disease, Vogt-Koyanagi-Harada syndrome, uveitis, retinopathy, sympathetic ophthalmia, cataract, conjunctivitis, glaucoma, etc.
  • ocular inflammation such as uveitis, glaucoma, and age-related macular degeneration (AMD)
  • vitreitis choroiditis
  • retinitis retinal vasculitis
  • optic neuritis and grapevine Meningitis
  • Behcet's disease Vogt-Koyanagi-Harada syndrome
  • uveitis retinopathy
  • sympathetic ophthalmia cataract
  • conjunctivitis glaucom
  • said model is a non-human animal, preferably monkey, dog, chimpanzee, rat, mouse.
  • the model carrier is a cell, tissue or organ, and the cell, tissue or organ is derived from a human or a non-human animal.
  • the cells are primary cells or cell lines.
  • said tissue is eye tissue
  • said organ is eye organ
  • said tissue or organ is a regenerative tissue or organ.
  • the said model has a pathogenic mutation of a gene.
  • the gene with pathogenic mutation is a gene related to maintaining the retinal barrier structure, and the retinal barrier is the outer blood-retinal barrier and/or the inner blood-retinal barrier.
  • the gene with the pathogenic eye gene mutation is selected from the following one or a combination of two or more genes: ABCA4 , ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS1, BBS2, BBS5, BEST1 , C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, CDH23, CDH23, CDHR1, CEMIP2, CEP104, CEP250, CEP290, CEP290, CEP41, CEP78, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8 , CLRN1, CLRN1, CNGA1, CNGA
  • the ocular disease-related genes in which pathogenic mutations have occurred in the model or model carrier include the CRB1 gene.
  • the mutation of the CRB1 gene of the model or model carrier includes one or more of the following mutations: c.107C>G, c.111delT, c.135C>G, c.257_258dupTG, c.258C >T, c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c .915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C >A, c.1298A>G, c.
  • the mutation of the CRB1 gene of the model or model carrier includes one or more of the following mutations: c.4006-1G>T, c.3686G>C, (p.Cys1229Ser), c. 2842+1delinsAA, c.4060G>A, (p.Ala1354Thr), c.3991C>T, (p.Arg1331Cys), c.3014A>T, (p.Asp1005Val), c.4005+1G>A, c.
  • 2680_2684del (p.Asn894fs), c.1733T>A, (p.Val578Glu), c.455G>A, (p.Cys152Tyr), c.3462_3463del, (p.Cys1154_Glu1155delinsTer), c.3037C>T, (p .Gln1013Ter), c.2673C>A, (p.Cys891Ter), c.2230C>T, (p.Arg744Ter), c.3676G>T, (p.Gly1226Ter), c.2842+5G>A, c.
  • the mutation of the CRB1 gene of the model or model carrier is Rd8 mutation.
  • the mutation is a homozygous mutation or a heterozygous mutation.
  • the above-mentioned gene mutations are congenitally present in the model or model carrier or the mutations are acquired acquired due to gene recombination operations.
  • the humanized CRB1 gene or human CRB1 gene exists in the model or model vector, and the endogenous CRB1 gene is deleted or not expressed.
  • said non-human animal has a defect in the colonic epithelial barrier and/or associated inflammation of the colonic wall.
  • the Occludin protein in the model body is significantly absent, and in a specific embodiment, the Occludin protein is significantly absent in the model body and the expression of Claudin1 is not obvious.
  • the microorganism is one or a combination of two or more of bacteria, archaea, protozoa, fungus or virus, preferably, the microorganism is a bacterium, and the bacterium is selected from: Anearostipes, Bifidobacterium (Bifidobacterium), Megamonas, Nitrosomonas, Oscillibacter, Tatumella, Thiobacillus sp., Clostridium, Acinetobacter Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, Azospirillum ( Azospira), Aquimarina, Achromobacter, Acithiobacillus, Burkholderia, Marinobacter, Treponema ), Actinosporangium, Vibrio, Ruminococc
  • the bacteria are selected from: Anearostipeshadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp.Is79A3, Oscillibactervalericigenes, Tatumella sp.TA1, Megamonasfuniformis, Thiobacillus denitrificans, Clostridium tetani, Clostridium perfringens, Clostridium botulinum, calcium acetate Acinetobacter, Acinetobacter rufia, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter johnsoni, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Filamentobacter succinogenes, Enterobacter Filamentous bacteria, Porphyromonas nonsaccharolyticus, Porphyromonas pulpum, Porphyromonas gingivalis, Campy
  • the infection method comprises direct contact or indirect contact between the microorganism and the site to be infected by the model carrier, the indirect contact means that there is a blood-retinal barrier between the microorganism and the site to be infected, preferably , for the outer blood-retinal barrier or the inner blood-retinal barrier.
  • the infection method comprises infecting the eye with intestinal bacteria through peripheral blood.
  • the intestinal epithelial barrier was significantly damaged in non-human animal models, allowing intestinal bacteria to enter the peripheral blood.
  • the retinal barrier was also significantly damaged, allowing intestinal bacteria entering the peripheral blood to infect the retina;
  • the non-human animal model has a mutation in the CRB1 gene; in a specific embodiment In the mode, the mutation of the CRB1 gene is Rd8 mutation.
  • the present invention provides a method for preparing an ocular inflammation model, wherein the method model is a non-human animal infection microorganism.
  • the ocular inflammation is caused by intestinal flora or the same flora as intestinal flora.
  • Said non-human animal is the animal as mentioned above.
  • microorganisms are as described above.
  • the present invention provides a method for preparing a retinal degenerative disease model, the method comprising infecting a non-human animal suffering from retinal degeneration with microorganisms.
  • the ocular inflammatory retinal degenerative disease is the aforementioned retinal disease.
  • Said non-human animal is the animal as mentioned above.
  • microorganisms are as described above.
  • the present invention provides a model carrier with ocular inflammation caused by microbial infection.
  • said microorganisms are from or identical to the intestinal bacteria of the same individual.
  • the eye disease includes retinal degeneration; more preferably, the retinal degeneration is progressive retinal degeneration.
  • the retinal degeneration is Inherited Retinal Degeneration (IRD).
  • IFD Inherited Retinal Degeneration
  • the retinal degeneration is a disease of the model animal itself or the retinal degeneration of the model animal is caused by genetic manipulation.
  • the eye diseases comprise LCA, RP, arRP, EORD, EORP, PPRPE, rettelangiectasia and/or choroideremia like fundus.
  • said eye disease comprises ocular inflammation, such as uveitis, glaucoma, and age-related macular degeneration (AMD), vitreitis, choroiditis, retinitis, retinal vasculitis, optic neuritis, and grapevine Meningitis, Behcet's disease, Vogt-Koyanagi-Harada syndrome, uveitis, retinopathy, sympathetic ophthalmia, cataract, conjunctivitis, glaucoma, etc.
  • ocular inflammation such as uveitis, glaucoma, and age-related macular degeneration (AMD)
  • vitreitis choroiditis
  • retinitis retinal vasculitis
  • optic neuritis and grapevine Meningitis
  • Behcet's disease Vogt-Koyanagi-Harada syndrome
  • uveitis retinopathy
  • sympathetic ophthalmia cataract
  • conjunctivitis glaucom
  • said model is a non-human animal, preferably monkey, dog, chimpanzee, rat, mouse.
  • the model carrier is a cell, tissue or organ, and the cell, tissue or organ is derived from a human or a non-human animal.
  • the cells are primary cells or cell lines.
  • said tissue is eye tissue
  • said organ is eye organ
  • said tissue or organ is a regenerative tissue or organ.
  • the said model has a pathogenic mutation of a gene.
  • the gene with pathogenic mutation is a gene related to maintaining the retinal barrier structure, and the retinal barrier is the outer blood-retinal barrier and/or the inner blood-retinal barrier.
  • one or more of the following genes are mutated in the model carrier: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B , ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS1, BBS2, BBS5, BEST1, C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, CDH23, CDH23, CDHR1, CEMIP2, CEP104, CEP250, CEP290, CEP290 , CEP41, CEP78, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CLRN1, CNGA1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL11A2, COL18A1, COL
  • the eye disease-related genes with pathogenic mutations in the model carrier include the CRB1 gene.
  • the mutation of the CRB1 gene of the model carrier includes one or more of the following mutations: c.107C>G, c.111delT, c.135C>G, c.257_258dupTG, c.258C>T , c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T >A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C>A , c.1298A>G, c.13
  • the mutation of the CRB1 gene of the model or model carrier includes one or more of the following mutations: c.4006-1G>T, c.3686G>C, (p.Cys1229Ser), c. 2842+1delinsAA, c.4060G>A, (p.Ala1354Thr), c.3991C>T, (p.Arg1331Cys), c.3014A>T, (p.Asp1005Val), c.4005+1G>A, c.
  • 2680_2684del (p.Asn894fs), c.1733T>A, (p.Val578Glu), c.455G>A, (p.Cys152Tyr), c.3462_3463del, (p.Cys1154_Glu1155delinsTer), c.3037C>T, (p .Gln1013Ter), c.2673C>A, (p.Cys891Ter), c.2230C>T, (p.Arg744Ter), c.3676G>T, (p.Gly1226Ter), c.2842+5G>A, c.
  • the mutation of the CRB1 gene of the model carrier is Rd8 mutation.
  • the mutation is a homozygous mutation or a heterozygous mutation.
  • the above-mentioned gene mutations are congenitally present in the model vector or the mutations are acquired acquired due to gene recombination operations.
  • the humanized CRB1 gene or human CRB1 gene exists in the model vector, and the endogenous CRB1 gene is deleted or not expressed.
  • said non-human animal has a defect in the colonic epithelial barrier and/or associated inflammation of the colonic wall.
  • the Occludin protein in the model body is significantly absent, and in a specific embodiment, the Occludin protein is significantly absent in the model body and the expression of Claudin1 is not obvious.
  • the microorganism is one or a combination of two or more of bacteria, archaea, protozoa, fungus or virus, preferably, the microorganism is a bacterium, and the bacterium is selected from: Anearostipes, Bifidobacterium (Bifidobacterium), Megamonas, Nitrosomonas, Oscillibacter, Tatumella, Thiobacillus sp., Clostridium, Acinetobacter Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, Azospirillum ( Azospira), Aquimarina, Achromobacter, Acithiobacillus, Burkholderia, Marinobacter, Treponema ), Actinosporangium, Vibrio, Ruminococc
  • the bacteria are selected from: Anearostipeshadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp.Is79A3, Oscillibactervalericigenes, Tatumella sp.TA1, Megamonasfuniformis, Thiobacillus denitrificans, Clostridium tetani, Clostridium perfringens, Clostridium botulinum, calcium acetate Acinetobacter, Acinetobacter rufia, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter johnsoni, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Filamentobacter succinogenes, Enterobacter Filamentous bacteria, Porphyromonas nonsaccharolyticus, Porphyromonas pulpum, Porphyromonas gingivalis, Campy
  • the infection method comprises direct contact or indirect contact between the microorganism and the site to be infected by the model carrier, the indirect contact means that there is a blood-retinal barrier between the microorganism and the site to be infected, preferably , for the outer blood-retinal barrier or the inner blood-retinal barrier.
  • the infection method comprises infecting the eye with intestinal bacteria through peripheral blood.
  • the intestinal epithelial barrier was significantly damaged in non-human animal models, allowing intestinal bacteria to enter the peripheral blood.
  • the retinal barrier was also significantly damaged, allowing intestinal bacteria entering the peripheral blood to infect the retina;
  • the non-human animal model has a mutation in the CRB1 gene; in a specific embodiment In the mode, the mutation of the CRB1 gene is Rd8 mutation.
  • the inflammatory model carrier is obtained from the disease model prepared by the method described above, or obtained from three-dimensional ocular cells, tissues or organs from non-human animals as described above with microorganism infection
  • the present invention provides an application of the above-mentioned method in evaluating the curative effect of targeted therapy for ocular diseases, and the ocular diseases include the above-mentioned ocular diseases.
  • the aforementioned model or model carrier is subjected to targeted therapy for the aforementioned gene mutation, and the model or model carrier that has not undergone targeted therapy is divided into two groups: Groups were established eye disease models according to the method described above, if in comparison, the group after targeted therapy can not be successfully modeled, indicating that targeted therapy has achieved beneficial effects.
  • the targeted therapy targets one of the following genes or a combination of two or more genes: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B , APC, ARFGEF1, ARL13B, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS1, BBS2, BBS5, BEST1, C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, CDH23, CDH23, CDHR1, CEMIP2, CEP104 , CEP250, CEP290, CEP290, CEP41, CEP78, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CLRN1, CNGA1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL11A2, COL
  • the targeted therapy targets one or more of the following mutations of the CRB1 gene: c.257_258dupTG, c.258C>T, c.428_432delGATTC, c.430T>G, c.
  • the targeted therapeutic drug comprises modified cells, modified proteins, RNA targeting the aforementioned gene or targeting the aforementioned mutation site, and/or DNA targeting a gene as previously described or targeting a mutation site as previously described.
  • the present invention provides an application of the disease model prepared by the aforementioned method in research related to eye diseases.
  • the eye diseases include the aforementioned eye diseases.
  • the research described includes the interaction between diseases associated with inherited retinal degeneration and gut microbiota, among others.
  • the disease model is infected with an intestinal bacterium, and when the disease-causing mutation it carries is treated with cells, the curative effect of administration and non-administration is observed, and the drug is A small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the disease model is infected with an intestinal bacterium, and when the pathogenic mutation it carries is treated with RNA, the curative effect of administration and non-administration is observed, and the drug is A small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the disease model is infected with more than two kinds of intestinal bacteria, and when the pathogenic mutations carried by them are treated with cells, the curative effect of administration and non-administration is observed, and the The drug is a small molecule drug, preferably a broad spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the disease model is infected with two kinds of intestinal bacteria, and when the pathogenic mutations carried by them are treated with RNA, the curative effect of administration and non-administration is observed, and the drug is A small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the pathogenic mutation occurs with the aforementioned gene, or, the pathogenic mutation is a mutation of the aforementioned CRB gene.
  • the present invention provides an application of the disease model carrier prepared by the above-mentioned method in research related to eye diseases.
  • the eye diseases include the aforementioned eye diseases.
  • the studies described include the synergistic effect of gut microbiota in diseases associated with hereditary retinal degeneration, among others.
  • the disease model carrier is infected with an intestinal bacterium, and when the disease-causing mutation it carries is treated by cells, the curative effect of administration and non-administration is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the disease model carrier is infected with an intestinal bacterium, and when the pathogenic mutation carried by it is treated with RNA, the curative effect of administration and non-administration is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the disease model carrier is infected with more than two kinds of intestinal bacteria, and when the pathogenic mutations carried by them are treated by cells, the curative effect of administration and non-administration is observed, and the The drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the disease model carrier is infected with two kinds of intestinal bacteria, and when the pathogenic mutation it carries is treated with RNA, the curative effect of administration and non-administration is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic directed against the infected bacteria.
  • the pathogenic mutation occurs with the aforementioned gene, or, the pathogenic mutation is a mutation of the aforementioned CRB gene.
  • the present invention provides an application of the aforementioned disease model or disease model carrier in the screening of drugs related to eye diseases.
  • the medicines include one or a combination of small molecule medicines, chemical medicines, macromolecular medicines, biological medicines or natural medicines (such as traditional Chinese medicine or Chinese medicine extracts), cellular medicines, RNA medicines, and DNA medicines.
  • the eye diseases include the aforementioned eye diseases.
  • the small molecule compound is an antibiotic
  • the antibiotic is a broad-spectrum antibiotic drug generally known to those skilled in the art.
  • the small molecular compound is a non-broad-spectrum antibiotic targeted to specific bacteria.
  • the cells include modified immune cells, such as one or a combination of two or more groups of T cells, B cells or stem cells.
  • modified immune cells such as one or a combination of two or more groups of T cells, B cells or stem cells.
  • the RNA comprises mRNA, siRNA, sgRNA, miRNA, ASO and/or replicon RNA.
  • the disease model or disease model carrier is subjected to targeted therapy, and at the same time, the disease model or disease model carrier that has undergone targeted therapy and the disease model or disease model carrier that has not undergone targeted therapy are administered With or without administration of drugs as previously described, the progression of inflammation in several groups was observed, and the drug efficacy of targeted therapy was evaluated.
  • the disease model or disease model carrier is subjected to targeted therapy, and at the same time, the disease model or disease model carrier that has undergone targeted therapy and the disease model or disease model carrier that has not undergone targeted therapy are administered With or without drug administration as previously described, the progression of inflammation in several groups was observed to evaluate the efficacy of small molecule drugs.
  • Figure 1 Genotype and phenotype of Crb1 rd8/rd8 (rd8)-SPF mice.
  • Figure 1A is the genotype gel electrophoresis of Crb1 rd8/rd8 (rd8) and Crb1 wt/wt (C57BL/J, referred to as wt) mice
  • Figure 1B is the representative of Rd8-SPF and WT-SPF mice In the fundus image, typical white spots appear in the subretinal nasal quadrant of Rd8-SPF mice.
  • Figure 1C shows the H&E staining of the pathological changes in both eyes of Rd8-SPF mice at E18.
  • Figure 2 Potential mechanism of retinal abnormalities and retinopathy in Rd8-SPF mice.
  • Figure 2A shows the pathological changes of the eyes of Rd8-SPF and WT-SPF mice at E18, P12 (before opening), P15 (after opening) and 8 weeks (8W) by H&E staining.
  • Rd8 mice showed typical retinal Abnormalities, including progressive retinal dysplasia (ruffles and false rosettes) and degeneration, whereas WT mice exhibited normal retinal architecture;
  • S1amf1 (signaling lymphocyte activation molecular family member 1) and Ncf4 (neutrophil cytoplasmic factor) are the two genes with the highest multiplication factor in Rd8-SPF mouse retinopathy;
  • Figure 2D is the IPA functional analysis of DEGs;
  • Figure 2E Immunofluorescent staining showed that there were abundant IBA1+ microglia (red) in the retinopathy area of Rd8 mice.
  • Figure 3 Comparison of gene expression profiles in the upper and lower retinal regions of Rd8-SPF mice by RNA-seq analysis.
  • Figure 3A is a diagram of the upper (no lesion) and lower (with lesion) regions of Rd8-SPF mice;
  • Figure 3B shows that RNA-seq analysis found that there is at least 2 times expression in the upper and lower retinal regions of Rd8-SPF mice Difference (P ⁇ 0.05);
  • Figure 3C shows the expression patterns of 179DEGs in the upper and lower retinal regions of Rd8- and WT-SPF mice.
  • Figure 4 Identification of bacteria within retinopathy of Rd8-SPF mice.
  • Figure 4A principal coordinates analysis (PCoA), showing that the bacterial composition in retinal tissues of Rd8 mice is significantly different from that of WT mice;
  • Figure 4C is the detection of retinal bacteria 16srDNA and vanco-bodipy in Rd8- and WT-SPF mice (4 weeks old) by fluorescence in situ hybridization;
  • Figure 4D is the observation of Rd8 by transmission electron microscope (TEM) The distribution of bacteria in the mouse retinopathy, the positive control is the coliform group;
  • TEM transmission electron microscope
  • Figure 5 Disruption of retinal adherens junctions in Rd8-SPF mice.
  • Figure 5A is the immunofluorescence staining of Rd8- and WT-SPF mouse retina CRB1 (red), BM is Bruch's membrane, CC is chorionic capillary, BL is basement membrane;
  • Figure 5B is Rd8- and WT-SPF small TEM observation of adherent junctions in the external membrane of the mouse retina, the red arrows are adherens junctions, AJ refers to adherens junctions, OLM refers to the external membrane, ONL refers to the outer nuclear layer, IS refers to the inner segment;
  • Figure 5C is the transmission electron microscope observation of Rd8-SPF Mouse retinal pigment epithelium (RPE) basal layer adhesion dissolution, chorionic capillary basal layer distortion, collagen layer disorder, CC is chorionic capillary, CH is choroid, BL is basement membrane;
  • Figure 5D shows Rd8
  • Fig. 6A Adhesive junction disruption (AJ) and outer nuclear layer (ONL) of Rd8-SPF mice outer membrane (OLM) shown for transmission electron microscopy (TEM).
  • AJ Adhesive junction disruption
  • ONL outer nuclear layer
  • TEM transmission electron microscopy
  • Fig. 6B Brunch membrane thickness of Rd8-SPF mice and WT-SPF mice shown by transmission electron microscope (TEM).
  • Figure 7 Defective colonic epithelial barrier and its associated inflammation in Rd8-SPF mice.
  • Figure 7B-D is the CRB1 protein of colonic enterocytes of Rd8- and WT-SPF mice (B) , Immunofluorescent staining of phalloidin (C) and occludin (D)
  • Figure 7E is the statistical analysis of the relative intensity of occludin in Rd8- and WT-SPF mice
  • Figure 7F is the westernblot detection of Rd8- and WT-SPF
  • Figure 7G is the statistical analysis of the relative intensity of Claudin1 in Rd8- and WT-SPF mice
  • Figure 7H is the transmission electron microscope observation of the adherent junction and Tight junctions
  • Figure 7I-L is the
  • Figure 8 Microbial species composition of the flora in different parts of the gastrointestinal tract of Rd8-SPF mice.
  • PCoA principal coordinate analysis
  • 8G is PCoA distinguishing the lower digestive tract (cecum, Microbial composition (H-J) of the colon and rectum) comparing the relative abundance of Akkermansia mucilage in the cecum (H), colon (I), and rectum (J) of Rd8 and WT mice. Data are expressed as mean ⁇ SEM*P ⁇ 0.05.
  • Figure 9 Tight junctions and adherens junctions of Rd8 mouse cecum.
  • Figure 9A is the immunofluorescence staining of Rd8- and WT-SPF mouse cecum enterocyte CRB1 protein (green);
  • Figure 9B is the immunofluorescence staining of Rd8- and WT-SPF mouse cecum enterocyte occlusivein (red);
  • Figure 9C is the statistical analysis of the relative intensity of occludin in Rd8- and WT-SPF mice *P ⁇ 0.05;
  • Figure 9D is the westernblot detection of the expression of Claudin1 in the cecum of Rd8- and WT-SPF mice;
  • Figure 9E is the expression of Rd8- and WT-SPF Statistical analysis of the relative intensity of mouse Claudin1, NS stands for not important;
  • Figure 9F shows transmission electron microscopy showing normal tight junctions and adherens junctions at the cecal epithelial barrier, MVs are microvesicles, and MCs are mitochondria
  • Figure 10 is the transmission electron microscope observation of the adherens junction (AJ) between the colonic epithelium and the tight junction (TJ) of Rd8- and WT-SPF mice, MV is the microvesicle, and MC is the mitochondria;
  • Figure 10B is the flow cytometry The frequency of fluorescence+ bacteria/cell in the peripheral blood of Rd8 and WT mice was detected.
  • Figure 11 Disruption of intestinal epithelial barrier function in Rd8-SPF mice.
  • Figure 11A shows the intestinal FICT-dextran permeability assay shows that the fluorescence intensity of Rd8 mice serum is significantly higher than that of WT mice***P ⁇ 0.001
  • Figure 11B shows the comparison of fecal microbiota transplantation method using vanco-bodipy Percentage of fluorescence+bacteria/cell in the peripheral blood of Rd8 and WT mice *P ⁇ 0.05
  • Figure 11C-D shows that both under the fluorescence microscope (C) and immunofluorescence staining (D) can be detected in the retinopathy of Rd8 mice vanco-bodipy+bacteria
  • Figure 11F-G compares the colon length, serum bacterial 16srrna (F) and bacterial LPS (G) levels of Rd8 and WT mice after DSS treatment for 13 days ****P ⁇ 0.0001
  • Figure 12 Retinal phenotypes of Rd8GF and Rd8GF SPF mice.
  • Figure 12A is the representative fundus images of Rd8-SPF and Rd8GF mice at 4 weeks, 8 weeks, 12 weeks and 16 weeks;
  • Figure 12B is the retinal histology of E18, P12, P15, and 8W eyes of Rd8-GF mice Observation;
  • Figure 12C is the fluorescent in situ hybridization staining of Rd8-GF mouse retinal bacteria 16srDNA and vanco-bodipy;
  • Figure 12D is the immunofluorescent staining of IBA1 (red) in Rd8-SPF, Rd8GF and WT-SPF mouse retina;
  • FIG. 12E is the percentage of IBA1+ microglial cells in ONL of Rd8-SPF, Rd8GF and WT-SPF mice ***P ⁇ 0.001; NS means not important;
  • Figure 12F is Rd8-SPF, Rd8-GF and WT-SPF mice Immunofluorescent staining of retinal ZO-1 (red) and Phalloidin (green) proteins;
  • Figure 12G is H&E staining for detection of retinopathy at P15 and 8W in Rd8-GF mice (Rd8-GF-SPF mice) raised in postnatal SPF environment .
  • FIG. 13 Octyl gallate (compound 6) in the treatment of Crb1 rd8/rd8 mouse fundus degenerative retinopathy experiment by intragastric administration for 2 weeks and 4 weeks after the changes in the number of light-colored spots in the fundus
  • C57BL/6N mice Crb1 rd8/Rd8 , named Rd8 mice
  • C57BL/6J mice Crb1 wt/wt , named wt mice carrying the Rd8 mutation
  • SPF pathogen-free
  • GF Germ-free RD8 mice were generated from embryos of female RD8 mice at the Animal Facility of the First affiliated Hospital of Sun Yat-sen University. GF mice were kept sterile, and facility staff performed weekly microbiological and parasite testing of fecal samples to ensure the sterility of the GF unit.
  • mice were sacrificed by cervical dislocation, eyeballs were enucleated, and fixed with 4% paraformaldehyde (PFA) in phosphate buffered saline (PBS) at 4°C for 24 hours.
  • PFA paraformaldehyde
  • PBS phosphate buffered saline
  • Samples were washed 3 times with PBS, dehydrated in a series of alcohols and 2 times in xylene, then embedded in paraffin and serially sectioned at 10 ⁇ m with a microtome (RM 223; Leica, Wetzlar, Hesse-Darmstadt, Germany ). Sections were stained with hematoxylin and eosin (H&E). H&E images were acquired by Imager.Z2 (Zeiss).
  • Tissue sections were blocked with 10% donkey serum/PBST (0.1% tritonx-100/PBS) for 30 minutes and then incubated with primary antibodies overnight at 4°C. After washing with PBST, sections were incubated with fluorochrome-conjugated secondary antibodies and mounted with Fluoromount-G (Southern Biotech, Birmingham, AL, USA). Phalloidin (A12379; Thermo-Fisher) staining was performed using the same immunohistochemical method, except that the secondary antibody was omitted.
  • a Zeiss confocal microscope Zeiss LSM880; Zeiss, Oberkochen, Germany
  • Imager.Z2 equipped with an ApoTome was used.
  • the primary antibodies used in this study were: anti-Crb1 (PA5-66373, ThermoFisher; 1:50), anti-Iba1 (ab178846, Abcam; 1:500), anti-ZO-1 (61-7300, ThermoFisher; 1:500 ), anti-Occludin (OC-3F10, Invitrogen; 1:200), AlexaFluor 488 phalloidin (A12379, ThermoFisher; 1:500).
  • mice were anesthetized with dilated pupils. Regularly apply hypromellose eye drops to keep the cornea moist.
  • Mouse fundus photographs were obtained using a Micron IV mouse fundus camera (Phoenix Research Laboratories, Inc., Pleasanton, CA, USA).
  • Raw reads were first quality control assessed by FastQC (v0.11.8) and cutadapt (v1.15). Clean reads were aligned to the mouse genome (mm10) using HISAT2 (v2.1.0).
  • the gene expression data were imported into the DESeq2 package of R software (v3.6.1) for differential expression analysis. Differentially expressed genes (DEGs) were imported into intelligent pathway analysis (IPA) for functional enrichment analysis.
  • DEGs Differentially expressed genes
  • Retinal samples were collected and DNA was extracted using the MasterPure TM Intact DNA and RNA Purification Kit (epicentre). The contents of the stomach, jejunum, ileum, cecum, colon and rectum were collected and DNA was extracted using the QIAampPowerFecal DNA kit (QIAGEN). After concentration measurement, DNA was subjected to sequencing library preparation using VAHTS TM MGI Universal DNA Library Prep Kit (Vazyme, China) according to the standard protocol provided by the manufacturer. Metagenome sequencing was performed with MGISEQ-2000RS. Raw reads were quality filtered by Trimmomatic (v0.36) and PRINSEQ (v0.20.4).
  • KneadData (v0.6.1) (https://bitbucket.org/biobakery/kneaddata).
  • Non-mouse-depleted reads were mapped to a pre-built MiniKraken database using Kraken 2 (v2.0.9). Classification results were screened with a confidence level of 0.20.
  • a negative blank control was processed with the samples. All species present in the negative blank control group were removed.
  • In vivo permeability assays were performed using the FITC-dextran method to evaluate barrier function. Food and water were removed overnight, and 8-week-old mice were orally administered 50 mg of FITC-labeled dextran (FD-70; Sigma-Aldrich) per 100 g (body weight). Serum was collected 5 hours after administration, and the fluorescence intensity (excitation, 492nm; emission, 525nm) of each sample was measured.
  • mice WT and Rd8 mice were fasted overnight and given 1 x 109E by gavage.
  • E. coli designed to consistently express RFP.
  • the mice were euthanized and 400 ⁇ L of peripheral blood was gently pipetted into a tube containing 4 mL of ACK lysis buffer (Gibco, USA) and incubated at RT for 3–5 min. After centrifugation at 300 x g for 5 minutes, cells were fixed and permeabilized (Cytofix/perm solution, BD Biosciences, USA) and then analyzed by flow cytometry (MACSQuantAnalyzer 10, MiltenyiBiotec, Germany).
  • Colons and eyes were collected immediately after euthanasia and fixed in phosphate-buffered glutaraldehyde-paraformaldehyde solution for 1 h at room temperature. Colons were cut into 2 mm pieces. The anterior segment was resected, and the posterior segment was cut into 2mm ⁇ 2mm blocks. The dissected tissues were placed in fresh fixative for 12 hours, fixed with 1% osmium tetroxide, dehydrated and embedded in epon-resin. Regions of interest were pre-screened on micrometer thick sections stained with toluidine blue under a light microscope. Ultrasound images were then collected at 80 nm and counterstained with uranyl acetate and lead citrate. Ultrasonic sections were observed with a transmission electron microscope.
  • oligonucleotide probe was used in this study: EUB338, 5'-GCTGCCTCCGTAG-GAGT-3' (Amann et al., 1990). The 5' end of the probe bears a primary amino group to which tetramethylrhodamine isothiocyanate is covalently bonded.
  • Dye-oligonucleotide conjugates (100 ⁇ ) were stored at -20°C.
  • Prefixed retinal sections were rinsed 3 times with DEPC-treated PBS. After treatment with 0.2% Triton X-100/DEPC-treated PBS, sections were hybridized with probe (500 nM) overnight at 37°C and mounted with Fluoromount-G.
  • Plasma LPS concentration was measured with enzyme-linked immunosorbent assay kit (SEB526Ge; Cloud-Clone Corp., USA).
  • Fresh stool samples were collected in 50 ml conical tubes with sterile 1xPBS and spun down until homogeneous. The contents were filtered with a 0.22 ⁇ m filter (Millipore) to remove fecal residues and centrifuged to obtain gut microbiota before incubation with vanco-bodipy for 30 min at RT. Gut bacteria labeled with vanco-bodipy were gavaged at 1x108 cfu/mouse in PBS. After gavage for 24 hours, the mouse retinal slices were taken for observation.
  • DSS 2.5% DSS
  • FIG. 1A The characteristics of the retinal microenvironment of Crb1rd8/rd8 (rd8) and Crb1wt/wt (C57BL/J, named wt) mice were observed (Fig. 1A). Phenotyped in Rd8 mice raised in a specific pathogen-free (Rd8-SPF) environment, they exhibited all the typical retinal findings, including leukoplakia in the inferior nasal quadrant of the eye on fundoscopy (Fig. 1B), and progressive retinal Dysplasia (ruffles and false rosettes) and retinal histological degeneration (H&E staining) ( Figure 2A). The results showed that 7 out of 32 Rd8 mice developed mild retinal dysplasia (E18) before birth (Fig.
  • mice revealed that seven bacterial species were significantly enriched in the subretinal region, including Taenia hadrus, Pseudomonas Streptococcus Bifidobacterium pseudocatenulatum, Megamonas funiformis, Nitrosomonas Is79A3, Valerian Oscillibacter, Tatumella sp.TA1, and Thiobacillus denitrificans (Figure 4B).
  • Example 5 demonstrates that the major defect in the Rd8-SPF mouse retina is the outer blood-retinal barrier
  • Immunofluorescence staining data confirmed reduced or absent expression of CRB1 protein in the outer retinal membrane of Rd8 (Fig. 5A). The data confirmed that weak expression of CRB1 protein could be found on Bruch's membrane (Fig. 5A). Using transmission electron microscopy, it was found that in the retinopathy site of Rd8-SPF mice, the adherens junctions on the external membrane were disrupted, which was related to the outward migration of the outer nuclear layer (Fig. 5B and Fig. 6A).
  • CRB1 protein in cecum enterocytes of wild-type mice was identified by immunofluorescence staining, while its expression was significantly attenuated in Rd8 mice (Fig. 9A).
  • Fig. 9B-C a significant loss of Occludin
  • Fig. 9D-E Claudin1
  • CRB1 protein was found to be significantly expressed on the apical and basal surfaces of colonic enterocytes (Fig. 7B). Loss of CRB1 protein was associated with significantly reduced expression of Phalloidin (Fig. 7C) and Occludin (Fig. 7D and 4E), but not Claudin1 (Fig. 7F and 4G) protein.
  • Fig. 7C Phalloidin
  • Fig. 7D and 4E Occludin
  • Fig. 7F and 4G Claudin1
  • Example 8 Examining whether intestinal epithelial barrier defects lead to altered intestinal permeability and microbiota like peripheral blood flow and retinal tissue migration in Rd8 mice
  • Intestinal FICT-dextran permeability assays were performed on WT and Rd8 mice. As shown in FIG. 11A , compared with the fluorescence intensity in the blood of WT mice, the fluorescence in the peripheral blood of Rd8 mice increased significantly 5 hours after administration of FICT dextran. Furthermore, using Vancompy-labeled fecal microbiota transplantation assays, a significant increase in fluorescence+ bacteria/cell was found in the peripheral blood of Rd8 mice compared with WT mice at 24 h after fecal transplantation (Fig. 10B and Fig. 11B). Importantly, the presence of Vancomopy+ bacteria was detectable in Rd8 mouse retinopathy (Fig.
  • Rd8 mice were re-isolated under sterile (GF) conditions and tested for changes in their retinal degeneration phenotype.
  • GF sterile
  • FIG. 12A retinopathy (white spots) found in Rd8-SPF mice was hardly observed in germ-free Rd8(Rd8GF) mice.
  • Retinal histology of Rd8-GF mice showed normally developing retinal tissue (Fig. 12B) without the typical lesions found in Rd8-SPF mice (Fig. 2A and Fig.
  • Example 11 Pharmacodynamic evaluation of octyl gallate (compound 6) for intragastric administration of Crb1 rd8/rd8 mouse fundus degenerative retinopathy
  • test product When preparing the test product, measure 4 mL of castor oil that has been autoclaved, weigh 1.2 g of compound 6 powder, add 1 to 2 mL of castor oil, fully grind, and use 36 mL of ultrapure water to grind the drug and the remaining castor oil All were transferred to a 50mL tube, shaken to mix, and left to stand overnight to prepare a compound 6 suspension with a concentration of 30mg/mL. Label the prepared liquid and store it at room temperature, and use it up within one month.
  • the animals were stratified according to body weight and randomly divided into model control group and compound 6 group. See the table below for detailed design:
  • Administration route and method intragastric administration, 10.0mL/kg body weight
  • Dosing frequency and duration 1 time every other day for 4 weeks
  • the dose of Compound 6 in mice was 0.3 g/kg body weight, which was calculated based on previous clinical medication.
  • One-month-old Crb1 rd8/rd8 mice were randomly divided into model control group and compound 6 treatment group. Animals were intragastrically administered vehicle or Compound 6, and the dose of Compound 6 was 0.3 g/kg, once every other day, for 4 consecutive weeks. The number of light-colored spots in the fundus of the mice after gavage for 2 weeks and 4 weeks were recorded for analysis and comparison.
  • mice in the model control group all had light-colored spots on the fundus at the beginning of the medication, 2 weeks and 4 weeks, indicating that the model animals had fundus degenerative retinopathy.
  • the change in the number of light-colored spots after administration of compound 6 for 2 weeks was 1.31 ⁇ 3.18, which was not statistically different from the change in the number of spots in the model control group (2.88 ⁇ 3.41).
  • the change in the number of light-colored spots in the fundus of C57BL/6N mice was -3.63 ⁇ 4.06, which was statistically different from the change in the number of spots in the model control group of 2.24 ⁇ 4.01 (Figure 13). See the table below for detailed results:
  • Compound 6 can effectively inhibit fundus degenerative retinopathy in Crb1 rd8/rd8 mice at a dose of 0.3 g/kg.

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Abstract

一种视网膜变性的治疗方法，所述的方法包括向患者的眼部或胃肠道施用微生物抑制剂或杀灭剂，具体的，通过建立眼部疾病模型或眼部疾病模型载体，尤其是视网膜变性模型或模型载体，验证了微生物抑制剂或杀灭剂可作为药物治疗视网膜变性疾病。

Description

视网膜变性的治疗方法 技术领域
本发明属于生物医药领域，具体涉及一种视网膜变性的治疗方法以及微生物抑制剂或杀灭剂在制备治疗视网膜变性的药物中的应用。
背景技术
遗传性视网膜变性(IRD)是一组以光感受器细胞进行性丢失为特征的遗传性疾病，包括先天性黑蒙(LCA)、色素性视网膜炎(RP)、早发性视杆-视锥细胞营养不良、视杆-视杆营养不良、先天性静止性夜盲和色盲，和Stargardt病(Broadgate等人，2017年)。它是工业化国家工作人口视力丧失的最常见原因，估计发病率为1∶2000(Kutluer等人，2020年)。由于遗传和临床的异质性，IRDs的治疗需要高度个性化的治疗策略。虽然神经保护、基因治疗和细胞替代治疗是治疗不同阶段IRD的拟议方法，但到目前为止，只有一种纠正RPE65基因突变的基因治疗(Luxturna)被FDA批准用于治疗LCA(Botto等人，2021；Ikelle等人，2020年；Kutluer等人，2020年)。因此，迫切需要一种挽救CRB1相关视力丧失的治疗方法。
发明人在先的研究PCT/CN2018/112022(其内容整体以引用方式并入)中发现了微生物当以活的状态施用时可以在猕猴体内激活补体系统并诱导玻璃膜疣样病变。此外，诸如通过玻璃体内施用抗生素万古霉素来杀灭此类微生物或抑制其生长可以与对照相比导致猕猴视网膜组织中玻璃膜疣样病变的大小减小，杀灭此类微生物诸如巨大芽孢杆菌或抑制其生长的药剂可用于治疗年龄相关性黄斑变性。
发明人的在先研究PCT/CN2018/118929、PCT/CN2019/070572和PCT/CN2019/117444(其内容整体以引用方式并入)中报道了可用于杀灭微生物或抑制其生长的化合物/组合物，以及使用所述化合物/组合物来治疗微生物感染以及治疗或预防与此类感染相关的疾病或病症诸如AMD的方法。
基于在先的研究，发明人进一步发现了微生物抑制剂或杀灭剂可作为药物治疗视网膜变性。
发明内容
本发明首先通过建立眼部疾病模型或眼部疾病模型载体，尤其是视网膜变性模型或模型载体，验证了微生物抑制剂或杀灭剂可作为药物治疗视网膜变性。
本发明的目的是通过以下技术方案实现的：
本发明首先提供了一种视网膜变性的治疗方法，所述的方法包括向患者的眼部或胃肠道施用微生物抑制剂或杀灭剂。
优选的，所述的视网膜变性为进行性视网膜变性；更优选的，所述的视网膜变性为遗传性视网膜变性；更优选的，遗传性视网膜变性包括先天性黑蒙(LCA)、色素性视网膜炎(RP)、早发性视杆-视锥细胞营养不良、视杆-视杆营养不良、先天性静止性夜盲和色盲和Stargardt病。
优选的，所述微生物为细菌、古细菌、原生生物、真菌或病毒中的一种或两种以上的组合。所述微生物为细菌，所述细菌选自：Anearostipes、双歧杆菌(Bifidobacterium)、巨单胞菌(Megamonas)、亚硝基单胞菌(Nitrosomonas)，颤螺旋菌(Oscillibacter)、塔特姆菌(Tatumella)、硫杆菌(Thiobacillussp.)、梭菌属(Clostridium)、不动杆菌属(Acinetobacter)、链球菌属(Streptococcus)、曼氏杆菌属(Mannheimia)、纤维杆菌属(Fibrobacter)、普氏菌属(Prevotella)、弯曲杆菌属(Campylobacter)、放线菌属(Actinomyces)、薄层菌属(Hymenobacter)、埃希氏杆菌属(Escherichia)、泰氏菌属(Tissierella)、克雷白氏杆菌属(Klebsiella)、卟啉单胞菌属(Porphyromonas)、固氮螺菌属(Azospira)、海水菌属(Aquimarina)、无色菌属(Achromobacter)、嗜酸硫杆菌属(Acidithiobacillus)、伯克霍尔德菌属(Burkholderia)、海杆菌属(Marinobacter)、密螺旋体属(Treponema)、孢裹放线菌属(Actinosporangium)、弧菌属(Vibrio)、瘤胃球菌属(Ruminococcus)、甲烷短杆菌(Methanobrevibacter)、志贺氏杆菌(Shigella)、弗兰克氏菌属(Frankia)、链霉菌属厌氧原体属(Anaeroplasma)、粪球菌属(Coprococcus)中的一种或两种以上。更优选的，所述细菌选自：Anearostipeshadrus、Bifidobacterium pseudocatenulatum、Nitrosomonas sp.Is79A3、Oscillibactervalericigenes、Tatumella sp.TA1、Megamonasfuniformis、Thiobacillus denitrificans、Akkermansiamucinphila。
优选的，所述的微生物抑制剂或杀灭剂包含化合物、多肽、多核苷酸、天然植物或天然植物提取物。
更优选的，所述的微生物抑制剂或杀灭剂为抗生素，例如所述的抗生素为β-内酰胺类抗生素；氨基糖苷类抗生素；四环素类抗生素；氯霉素类抗生素；大环内脂类抗生素；糖肽类抗生素；喹诺酮类抗生素；硝基咪唑类抗生素；利福霉素类抗生素；棘白菌素类抗生素；多烯类抗生素；嘧啶类抗生素；烯丙胺类抗生素；氮唑类抗生素；其它抗生素中的一种或者两种以上。
例如，在一些实施方案中，抗生素可以包括以下一种或多种：β-内酰胺类抗生素，包括青霉素类(例如青霉素V)、阿莫西林、氨苄西林、巴坎西林、羧苄西林、氯唑西林、双氯西林、氟氯西林、美洛西林、萘夫西林、苯唑西林、青霉素G、哌拉西林、匹氨西林、匹美西林、替卡西林，头孢菌素类如头孢乙腈、头孢羟氨苄、头孢氨苄、头孢甘氨酸、头孢洛宁、头孢噻啶、头孢噻吩、头孢匹林、头孢曲嗪、头孢氮氟、头孢西酮、头孢唑啉、头孢拉定、头孢沙定、头孢替唑、头孢克洛、头孢孟多、头孢美唑、头孢尼西、头孢替坦、头孢西丁、头孢丙烯、头孢呋辛、头孢唑喃、头孢卡品、头孢达肟、头孢地尼、头孢托仑、头孢他美、头孢克肟、头孢甲肟、头孢地嗪、头孢噻肟、头孢咪唑、头孢泊肟、头孢特仑、头孢布烯、头孢噻呋、头孢噻林、头孢唑肟、头孢曲松、头孢哌酮、头孢他啶、头孢克啶、头孢吡肟、头孢瑞南、头孢噻利、头孢唑兰、头孢匹罗、头孢喹肟、头孢吡普、头孢洛林、头孢氯嗪、头孢洛仑、头孢派罗、头孢卡奈、头孢屈洛、头孢吡酮、头孢三唑、头孢维曲、头孢马替林(cefmatilen)、头孢氯铵 (cefmepidium)、头孢维星、头孢噁唑、头孢罗替、头孢舒米、头孢呋汀、头孢噻氧，噻烯霉素类，单内酰环类，β-内酰胺酶抑制剂，甲氧西林类；氨基糖苷类抗生素，包括链霉素、庆大霉素、卡那霉素(例如，卡那霉素A)、妥布霉素、阿米卡星、新霉素(例如，新霉素B、新霉素C、新霉素E)、核糖霉素、小诺霉素、阿奇霉素、地贝卡星、西索米星、奈替米星、巴龙霉素、短霉素等；四环素类抗生素，包括四环素、氧四环素、金霉素和强力霉素等；氯霉素类抗生素，包括氯霉素、甲砜霉素等；大环内酯类抗生素，包括红霉素、白霉素、无味红霉素、乙酰螺旋霉素、麦迪霉素、交沙霉素、阿奇霉素、克拉霉素、地红霉素、罗红霉素、泰利霉素等；糖肽类抗生素，包括万古霉素、去甲万古霉素、替考拉宁等；喹诺酮类抗生素，包括诺氟沙星、氧氟沙星、环丙沙星、培氟沙星、加替沙星、依诺沙星、洛美沙星、萘啶酮酸、左氧氟沙星、莫西沙星、贝西沙星；硝基咪唑类抗生素，包括甲硝唑、替硝唑、奥硝唑等；利福霉素类抗生素，包括利福平；棘白菌素类抗生素；多烯类抗生素；嘧啶类抗生素；烯丙胺类抗生素；氮唑类抗生素；其他抗生素：磷霉素、卷曲霉素、环丝氨酸、林可霉素、克林霉素、丝裂霉素、放线菌素D、博莱霉素、阿霉素、异烟肼、吡嗪酰胺、环孢霉素、多粘菌素B组合诸如多粘菌素B/甲氧苄啶、多粘菌素B/杆菌肽、多粘菌素B/新霉素/短杆菌肽等。
在一些实施方案中，抗生素可以选自阿米卡星、阿莫西林、氨苄西林、胂凡纳明、阿奇霉素、阿洛西林、氨曲南、杆菌肽、卷曲霉素、羧苄青霉素、头孢克洛、头孢羟氨苄、头孢氨苄、头孢噻吩、头孢孟多、头孢唑啉、头孢地尼、头孢托仑、头孢克肟、头孢哌酮、头孢噻肟、头孢西丁、头孢泊肟、头孢丙烯、头孢他啶、头孢布烯、头孢唑肟、头孢曲松、头孢呋辛、氯霉素、西司他丁、克拉霉素、克拉维酸、克林霉素、氯法齐明、氯唑西林、粘菌素、环丝氨酸、达福普汀、氨苯砜、达托霉素、双氯西林、地红霉素、多利培南、强力环素、红霉素、乙胺丁醇、乙硫异烟胺、氟氯西林、磷霉素、呋喃唑酮、夫西地酸、庆大霉素、亚胺培南、异烟肼、卡那霉素、林可霉素、利奈唑胺、氯拉卡比、磺胺米隆、美罗培南、甲氧西林、甲硝唑、美洛西林、米诺环素、莫匹罗星、萘夫西林、新霉素、奈替米星、呋喃妥因、苯唑西林、氧四环素、巴龙霉素、青霉素G、青霉素V、哌拉西林、平板霉素、多粘菌素B、吡嗪酰胺、奎奴普丁、雷帕霉素、利福布汀、利福平(Rifampicin)、利福霉素(Rifampin)、利福喷丁、利福昔明、罗红霉素、磺胺嘧啶银、壮观霉素、链霉素、舒巴坦、磺胺醋酰、磺胺嘧啶、磺胺甲二唑、磺胺甲噁唑、磺胺二甲异噁唑、柳氮磺吡啶、磺胺异噁唑、他唑巴坦、替考拉宁、替拉万星(Telavancin)、替利霉素、替莫西林、四环素、甲砜霉素、替卡西林、替加环素、替硝唑、妥布霉素、甲氧苄啶、醋竹桃霉素、万古霉素、依诺沙星、洛美沙星、萘啶酮酸、环丙沙星、左氧氟沙星、加替沙星、莫西沙星、氧氟沙星、诺氟沙星、头孢替坦、头孢尼西、头孢拉定、头孢匹林、头孢噻吩、头孢美唑、头孢噻肟、拉氧头孢、头孢吡肟、头孢洛林酯、头孢吡普、达巴万星、地美环素、美他环素、厄他培南、非达霉素、格尔德霉素、除莠霉素、泼斯唑来 (Posizolid)、雷得唑来(Radezolid)、特地佐利(Torezolid)、奥利万星(Oritavancin)、螺旋霉素、磺胺二甲嘧啶、磺酰氨基柯衣定(Sulfonamidochrysoidine)、吉米沙星、那氟沙星、曲伐沙星、格雷沙星、司帕沙星、替马沙星、泰斯巴汀(Teixobactin)、美拉希汀(Malacidins)以及它们的组合。
优选的，所述的微生物抑制剂或杀灭剂为式I(例如，式I-1、式I-2、式I-3、式I-4、式I-5)、式II(例如，式II-1、式II-2、式II-3、式II-4、式II-5、式II-6、式II-7、式II-8、式II-9、式II-10)、式III(例如，式III-1、式III-2、式III-3)、式IV-1或IV-2(例如，式IV-3、式IV-4、式IV-5、式IV-6)的化合物，糖苷(例如，式V)，或其药学上可接受的盐或酯，其中所述糖苷的苷元是酚类化合物、类黄酮、香豆素、苯甲酸或甾醇，其中所述式I、II、III、IV-1、IV-2、V及其子式如下所定义。
在一些实施方案中，本发明的化合物可以通过具有式I或其药学上可接受的盐或酯来表征：
Figure PCTCN2022114540-appb-000001
为了避免疑问，在式I中，环状结构Cy 1与另一环状结构Cy 2通过两个连接基L和L ’连接，这两个环状结构可以是相同或不同的，这两个连接基在Cy 1与Cy 2之间形成另外的环结构。应当理解，Cy 1和Cy 2均分别是独立于L和L ’的环结构。
在式I中，Cy 1和Cy 2各自独立地是任选取代的环烷基环(例如，C3-7环烷基环)、任选取代的杂环诸如任选取代的4-7元杂环(例如，具有独立地选自N、O和S的一个或两个环杂原子)、任选取代的芳基环(例如，C 6-10芳基环(例如，苯基))或任选取代的杂芳基环诸如任选取代的5-10元杂芳基环(例如，5或6元杂芳基环，其具有独立地选自N、O和S的一个或两个环杂原子)；
L和L ’各自独立地是空或连接基(例如，本文所述)；如本文所用，术语“连接基”不限于任何特定类型的连接基团。例如，在一些实施方案中，连接基还可以与其附接的一个部分形成环结构，例如，L和Cy 1可以独立于Cy 2形成环结构；
L 2是空、任选取代的C 1-6亚烷基、任选取代的C 1-6杂亚烷基、任选取代的C 2-6亚烯基、任选取代的C 2-6亚炔基、任选取代的C 3-6亚环烷基、任选取代的亚芳基、任选取代的杂亚芳基或任选取代的4-7元杂亚环基；
W是-OR 1；-COR 2；-COOR 1a；-OCOOR 1a；-NR 3R 4；-CONR 3aR 4a；-OCONR 3bR 4b；-SO 2NR 3cR 4c； -OSO 2NR 3dR 4d；-SR 5；-SO 2R 5a；-OCOR 2a；-OSO 2R 5a或
Figure PCTCN2022114540-appb-000002
其中：
R 1和R 1a各自独立地是氢、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环基；
R 3和R 4各自独立地是氢、-COR 2b、-SO 2R 5b、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基，或者R 3和R 4与它们所结合的原子一起形成任选取代的4-7元杂环基；
R 2、R 2a、R 2b、R 5、R 5a和R 5b各自独立地是氢、-OH、-NR 3eR 4e、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；以及
R 3a、R 3b、R 3c、R 3d、R 3e、R 4a、R 4b、R 4c、R 4d和R 4e各自独立地是氢、任选取代的C 1-6烷基、任选取的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或R 3a和R 4a、R 3b和R 4b、R 3c和R 4c、R 3d和R 4d或者R 3e和R 4e与它们所结合的原子一起形成任选取代的4-7元杂环基。
式I中的Cy 1和Cy 2可以是芳族或非芳族环系，并且在一些情况下可以包含杂原子。在优选的实施方案中，式I中的Cy 1和Cy 2中的至少一者是芳基或杂芳基环，诸如任选取代的C 6-10芳基环、或任选取代的5-10元杂芳基环。例如，在一些实施方案中，Cy 1和Cy 2使得式I的核心结构即不显示任选的取代基的
Figure PCTCN2022114540-appb-000003
的结构可以是以下任一者：
Figure PCTCN2022114540-appb-000004
Figure PCTCN2022114540-appb-000005
其中L 2-W可以附接到左侧环或右侧环，其中L和L ’可以是本文所述的任一种，并且本文描述了用于环的合适取代基。
在一些实施方案中，式I中的Cy 1和Cy 2均可以是芳基或杂芳基环。例如，在一些实施方案中，式I的化合物可以具有式I-1：
Figure PCTCN2022114540-appb-000006
在一些实施方案中，式I-1中的Ar1和Ay 2各自独立地是任选取代的C 6-10芳基环、或任选取代的5-10元杂芳基环。在一些实施方案中，式I-1中的Ar 1和Ar 2各自独立地是任选取代的苯基环或者5或6元杂芳基环。例如，在一些实施方案中，式I-1中的Ar 1和Ar 2各自独立地是任选取代的苯基环、任选取代的噻吩基环、任选取代的呋喃基环、任选取代的吡啶基环或任选取代的嘧啶基环。
式I-1通常具有多环核心结构。例如，在一些实施方案中，Ar 1和Ar 2使得式I-1的核心结构即不显示任选的取代基的
Figure PCTCN2022114540-appb-000007
可以是以下任一者：
Figure PCTCN2022114540-appb-000008
Figure PCTCN2022114540-appb-000009
其中L 2-W可以附接到左侧环或右侧环，其中L和L ’在本文定义，并且本文描述了用于环的合适取代基。
在一些实施方案中，式I的化合物可以具有式I-2：
Figure PCTCN2022114540-appb-000010
其中：
m是0、1、2或3，
R 10在每次出现时独立地是卤素、L 2’-W ’、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或者两个相邻的R 10、或一个R 10和L或L ’与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环；
其中-L 2’-W ’在每次出现时独立地选择；以及
L 2’在每次出现时独立地是空、任选取代的C 1-6亚烷基、任选取代的C 1-6杂亚烷基、任选取代的C 2-6亚烯基、任选取代的C 2-6亚炔基、任选取代的C 3-6亚环烷基、任选取代的亚芳基、任选取代的杂亚芳基或任选取代的4-7元杂亚环基；并且W ’在每次出现时独立地是-OR 1；-COR 2；-COOR 1a；-OCOOR 1a；-NR 3R 4；-CONR 3aR 4a；-OCONR 3bR 4b；-SO 2NR 3cR 4c；-OSO 2NR 3dR 4d；-SR 5；-SO 2R 5a；-OCOR 2a；-OSO 2R 5a或
Figure PCTCN2022114540-appb-000011
其中R 1、R 1a、R 2、R 2a、R 2b、R 3、R 4、R 3a、 R 3b、R 3c、R 3d、R 3e、R 4a、R 4b、R 4c、R 4d、R 4e、R 5、R 5a和R 5b在本文定义，参见例如式I。
应当注意的是，结构单元-L 2’-W ’和-L 2-W的每个实例独立地选择并且可以是相同或不同的。
在一些实施方案中，式I-2中的Cy 1是任选取代的苯基环、任选取代的噻吩基环、任选取代的呋喃基环、任选取代的吡啶基环或任选取代的嘧啶基环。在一些实施方案中，式I-2中的Cy 1是任选取代的C 3-6环烷基环或任选取代的4-7杂环，该杂环具有独立地选自N、O和S的1或2个环杂原子。
在一些实施方案中，Cy 1使得式I-2的核心结构可以是以下任一种：
Figure PCTCN2022114540-appb-000012
Figure PCTCN2022114540-appb-000013
其中-L 2-W附接到右侧苯基环，L和L ’在本文定义，并且本文描述了用于环的合适取代基。
在更优选的实施方案中，式I中的Cy 1和Cy 2均是苯基环。例如，在一些实施方案中，式I-2的化合物可以具有式I-3：
Figure PCTCN2022114540-appb-000014
其中：L、L ’、L 2、W、R 10和m在本文定义，参见例如式I-2，
n是0、1、2或3，
R 11在每次出现时独立地是卤素、-L 2’-W ’、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或者两个相邻的R 11、或一个R 11和L或L ’与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环；其中L 2’和W ’在本文定义，参见例如针对式I-2所定义，并且-L 2’-W ’在每次出现时独立地选择。
式I(例如，式I-1至I-3中的任一者)中的L和L ’可以独立地是空或连接基。在一些实施方案中，式I中的L和L ’各自独立地是空、-C(O)-、任选取代的C 1-4亚烷基、任选取代的C 2-4亚烯基、-O-、-S-、-NR 100-、-S(O)-、-SO 2-、-X 1-G 1-、-X 2-G 2-X 2a-或-CR 101R 102-，
其中：
X 1、X 2和X 2a独立地是任选取代的C 1-4亚烷基、任选取代的C 2-4亚烯基、-O-、-C(O)-、-S-、 -NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；
G 1和G 2独立地是任选取代的C 1-4亚烷基、任选取代的C 2-4亚烯基、-C(O)-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；
优选地，在一些实施方案中，-X 1-G 1-或-X 2-G 2-X 2a-不含O-N、S-S、S-N(SO 2-N除外)或-C(O)-S键；
R 100和R 100a各自独立地是孤对(当适用时)、氢、COR 2c、-SO 2R 5c、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基；或者R 100或R 100a与R 10或R 11基团形成任选取代的杂环或杂芳基环；
R 101、R 101a、R 102和R 102a当存在时各自独立地是氢、-OH、卤素、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷氧基、任选取代的氨基基团、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基，或者R 101和R 102、或R 101a和R 102a与它们所结合的原子一起形成任选取代的3-7元环烷基或杂环基环；或者R 101和R 102之一、或R 101a和R 102a之一与R 10或R 11基团一起形成任选取代的环烷基或杂环基环；以及
R 2c和R 5c各自独立地是氢、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基。
当连接基L或L ’与环碳之一形成双键时，它不能是R 101和R 102均存在的CR 101R 102，因为碳的化合价将超过4。在此类情况下，应当理解的是，R 101和R 102之一不存在，并且L或L ’是如本文所定义的CR 101或CR 102。当L或L ’与环碳之一形成双键时，它可以是NR 100，其中R 100通常是孤对。类似地，应当理解本公开中的其他类似情形。
在一些实施方案中，式I中的L和L ’各自独立地是空、-O-、-C(O)-、-S-、-NR 100-、-S(O)-、-SO 2-或-CR 101R 102-。在一些实施方案中，式I的化合物具有根据I-4至I-5中的任一者的式：
Figure PCTCN2022114540-appb-000015
其中：
X 3、X 4和X 5各自独立地是空、-O-、-C(O)-、-S-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；以及
R 10、R 11、R 100a、R 101a、R 102a、W、L 2、m和n在本文定义。
在一些实施方案中，化合物具有式I-4，其中X 3和X 4各自独立地是-O-、-C(O)-、-S-、-NR 100a-或-SO 2-。在一些实施方案中，化合物具有式I-5，其中X 5是-O-、-C(O)-、-S-、-NR 100a-或-SO 2-。在一些实施方案中，R 100a是氢或任选取代的C 1-4烷基。
式I(例如，本文所述的任何子式，诸如式I-1至I-5)中的L 2通常是空，即，W基团直接附接到Cy 2。在一些实施方案中，式I中的L 2也可以是C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基或C 1-4杂亚烷基。例如，W基团可以通过亚甲基或乙烯基基团附接到Cy 2。
多种W基团适合于式I(例如，本文所述的任何子式，诸如式I-1至I-5)的化合物。在优选的实施方案中，W基团在每次出现时独立地是-OH、-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)、-SO 2NH(C 1-4烷酰基)、-COOH、
Figure PCTCN2022114540-appb-000016
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2、-OC(O)NH(C 1-4烷基)-、-O-(CO)-(C 1-4烷基)、-O-(C 1-4烷基)，其中每个C 1-4烷基独立地任选被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代。在一些实施方案中，式I中的W是-OH、-NH 2、-SO 2NH 2、-SO 2NH(乙酰基)、-COOH、
Figure PCTCN2022114540-appb-000017
或-O-C(O)-CH 3。
如本文所述，L 2’-W ’可以在一些实施方案中被选择为用于Cy 1或Cy 2诸如用于Ar 1或Ar 2的取代基。当适用时，式I(包括本文所述的任何子式，诸如式I-1至I-5)中的L 2’在每次出现时可以独立地是空，即，W ’基团直接附接到Cy 1或Cy 2，诸如对于Ar 1或Ar 2而言(当适用时)，或是C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基或C 1-4杂亚烷基。例如，W ’基团可以通过亚甲基或乙烯基基团附接到Cy 1或Cy 2，诸如对于Ar 1或Ar 2而言。当适用时，式I(包括本文所述的任何子式，诸如式I-1至I-5)中的W ’在每次出现时可以独立地是-OH、-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)、-SO 2NH(C 1-4烷酰基)、-COOH、
Figure PCTCN2022114540-appb-000018
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2、-OC(O)NH(C 1-4烷基)-、-O-(CO)-(C 1-4烷基)、-O-(C 1-4烷基)，其中每个C 1-4烷基独立地任选被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代。在一些实施方案中，当适用时，式I中的W ’的每个实例可以是-OH、-NH 2、-SO 2NH 2、-SO 2NH(乙酰基)、-COOH、
Figure PCTCN2022114540-appb-000019
或-O-C(O)-CH 3。
多种基团可以适用于任何适用的式I(例如，本文所述的任何子式，诸如当适用时，式I-2至I-5)中的R 10和R 11。在一些实施方案中，R 10和R 11中的每一者在每次出现时可以独立地是 F；C1；-OH；-NH 2；-SO 2NH 2；-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)；-COOH；
Figure PCTCN2022114540-appb-000020
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6烯基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6炔基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷氧基；或任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷氧基。在一些实施方案中，R 10和R 11中的每一者在每次出现时可以独立地是-OH；-NH 2；-SO 2NH 2；-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)；-COOH；
Figure PCTCN2022114540-appb-000021
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；C 1-4烷基；或C 1-4烷氧基。在一些实施方案中，R 10的一个或多个实例和/或R 11的一个或多个实例可以是独立地选择的如本文所述的L 2’-W ’。
通常，m在适用时是0、1或2；优选地，是1。
通常，n在适用时是0、1、2或3；优选地，是1或2。
在一些实施方案中，本文的化合物可以通过具有式II或其药学上可接受的盐或酯来表征：
Figure PCTCN2022114540-appb-000022
其中：
Cy 10和Cy 11各自独立地是任选取代的环烷基环(例如，C 3-7环烷基环)、任选取代的杂环(例如，4-7元杂环)、任选取代的芳基环(例如，C 6-10芳基环)、任选取代的杂芳基环(例如，5-10元杂芳基环)、或任选取代的包含环烷基环或杂环和芳基或杂芳基环的环结构，其中该环结构可以是稠环或以其他方式连接；
L 10是空或连接基；
L 11是空、任选取代的C 1-6亚烷基、任选取代的C 1-6杂亚烷基、任选取代的C 2-6亚烯基、任选取代的C 2-6亚炔基、任选取代的C 3-6亚环烷基、任选取代的亚芳基、任选取代的杂亚芳基或任选取代的4-7元杂亚环基，
W 10是-OR 1；-COOR 1a；-OCOOR 1a；-COR 2；-NR 3R 4；-CONR 3aR 4a；-OCONR 3bR 4b；-SO 2NR 3cR 4c； -OSO 2NR 3dR 4d；-SR 5；-SO 2R 5a；-OCOR 2a；-OSO 2R 5a；或
Figure PCTCN2022114540-appb-000023
其中：
R 1和R 1a各自独立地是氢、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环基；
R 3和R 4各自独立地是氢、-COR 2b、-SO 2R 5b、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基，或者R 3和R 4与它们所结合的原子一起形成任选取代的4-7元杂环基；
R 2、R 2a、R 2b、R 5、R 5a和R 5b各自独立地是氢、-OH、-NR 3eR 4e、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；以及
R 3a、R 3b、R 3c、R 3d、R 3e、R 4a、R 4b、R 4c、R 4d和R 4e各自独立地是氢、任选取代的C 1-6烷基、任选取的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或R 3a和R 4a、R 3b和R 4b、R 3c和R 4c、R 3d和R 4d或者R 3e和R 4e与它们所结合的原子一起形成任选取代的4-7元杂环基。
在一些实施方案中，在式II中，Cy 10和Cy 11中的至少一者是任选取代的C 6-10芳基环或任选取代的5-10元杂芳基环。在一些实施方案中，Cy 11是任选取代的C 6-10芳基环或任选取代的5-10元杂芳基环。当Cy 11是双环或多环芳基或杂芳基环时，L 10-Cy 10和L 11-W 10可以独立地通过任何环连接到Cy 11。在一些实施方案中，Cy 11可以具有包含芳基或杂芳基环以及环烷基或杂环结构的稠环结构。在此类实施方案中，Cy 11可以通过芳基或杂芳基环以及环烷基或杂环结构中的任一者连接到L 10-Cy 10和L 11-W 10；或者替代性地，L 10-Cy 10和L 11-W 10之一通过芳基或杂芳基环连接到Cy 11，而L 10-Cy 10和L 11-W 10中的另一者通过环烷基或杂环结构连接到Cy 11。
在一些实施方案中，式II的化合物具有至少一个苯基环，其可以具有作为Cy 10-L 10-Cy 11的以下核心结构：
Figure PCTCN2022114540-appb-000024
其中Cy 10可以是上图中的左侧环或右侧环，即，图不限于特定的方向，其中L 11-W 10可以连接到左侧环或右侧环中的任一者，两个环均可以任选地被取代。
在一些实施方案中，式II的化合物可以具有作为Cy 10-L 10-Cy 11的以下核心结构：
Figure PCTCN2022114540-appb-000025
其中Cy 10可以是上图中的左侧环或右侧环，即，图不限于特定的方向，其中L 11-W 10可以连接到左侧环或右侧环中的任一者，两个环均可以任选地被取代。
在一些实施方案中，式II中的Cy 10和Cy 11均为芳基或杂芳基环。在一些实施方案中，式II的化合物具有式II-1：
Figure PCTCN2022114540-appb-000026
其中Ar 10和Ar 11各自独立地是任选取代的C 6-10芳基环或任选取代的5-10元杂芳基环。在一些实施方案中，式II-1中的Ar 10和Ar 11各自独立地是任选取代的苯基环或任选取代的5或6元杂芳基环。在一些实施方案中，式II-1中的Ar 10和Ar 11各自独立地是任选取代的苯基环、任选取代的噻吩基环、任选取代的呋喃基环、任选取代的吡啶基环或任选取代的嘧啶基环。在一些实施方案中，式II-1中的Ar 10和Ar 11之一是双环芳基或双环杂芳基环，其中每一者任选 地被取代，例如，在一些实施方案中，Ar 11可以是任选取代的双环芳基或双环杂芳基环。
在一些实施方案中，式II中的Cy 11是苯基环。在一些实施方案中，式II的化合物具有式II-2：
Figure PCTCN2022114540-appb-000027
其中Ar 10、L 10、L 11和W 10在本文定义，参见例如式II-1，
m是0、1、2或3，
R 20在每次出现时独立地是卤素、-L 11’-W 10’、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或者两个相邻的R 20、或一个R 20和L 10或L 11与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环；
其中-L 11’-W 10’在每次出现时独立地选择；
其中L 11’在每次出现时独立地是空、任选取代的C 1-6亚烷基、任选取代的C 1-6杂亚烷基、任选取代的C 2-6亚烯基、任选取代的C 2-6亚炔基、任选取代的C 3-6亚环烷基、任选取代的亚芳基、任选取代的杂亚芳基或任选取代的4-7元杂亚环基；并且W 10’在每次出现时独立地是-OR 1；-COR 2；-COOR 1a；-OCOOR 1a；-NR 3R 4；-CONR 3aR 4a；-OCONR 3bR 4b；-SO 2NR 3cR 4c；-OSO 2NR 3dR 4d；-SR 5；-SO 2R 5a；-OCOR 2a；-OSO 2R 5a或
Figure PCTCN2022114540-appb-000028
其中R 1、R 1a、R 2、R 2a、R 2b、R 3、R 4、R 3a、R 3b、R 3c、R 3d、R 3e、R 4a、R 4b、R 4c、R 4d、R 4e、R 5、R 5a和R 5b在本文定义，参见例如式II。应当注意的是，结构单元-L 11’-W 10’和-L 11-W 10的每个实例独立地选择并且可以是相同或不同的。
在一些实施方案中，式II中的Cy 11是苯并稠环。在一些实施方案中，式II的化合物具有式II-3：
Figure PCTCN2022114540-appb-000029
其中Ar 10、L 10、L 11和W 10在本文定义，参见例如式II-1，
m是0、1、2或3，
R 20在每次出现时独立地是卤素、-L 11’-W 10’、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或者两个相邻的R 20、或一个R 20和L 10或L 11与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环；
其中L 11’和W 10’在本文定义，参见例如式II-2，并且-L 11’-W 10’在每次出现时独立地选择；以及
环B是4-7元环烷基环、4-7元杂环、苯基环、5或6元杂芳基环，其中每一者任选地被取代。
在一些实施方案中，式II中的Cy 11是苯并稠合双环芳基或杂芳基环。例如，在一些实施方案中，式II中的Cy 11可以具有以下核心结构：
Figure PCTCN2022114540-appb-000030
其中L 10-Cy 10和L 11-W 10可以独立地通过两个环中的任一个连接到Cy 11，其中苯基环可以任选地被1-3个本文所定义的R 20基团取代。例如，就苯并噻吩环而言，在一些实施方案中，L 10-Cy 10可以附接到噻吩环，而L 11-W 10可以附接到苯基环，反之亦然，以及在一些情况下，L 10-Cy 10和L 11-W 10均可以附接到同一环，诸如苯基环。
在一些实施方案中，式II的化合物可以具有以下任何结构：
Figure PCTCN2022114540-appb-000031
其中：Cy 10、L 10、R 20、m、R 21、n、R 100a、L 11和W 10在本文定义，参见例如本文的式II和子式，诸如式II-3。在一些实施方案中，Cy 10是如针对式II-3所定义的Ar 10。
在一些实施方案中，式II-3的化合物可以具有式II-4：
Figure PCTCN2022114540-appb-000032
其中：Ar 10、L 10、R 20、m、L 11和W 10在本文定义，参见例如式II-3，
n是0或1，
R 21在每次出现时独立地是卤素、氧代、-L 11’-W 10’、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；其中L 11’和W 10’在本文定义，参见例如式II-2，并且-L 11’-W 10’在每次出现时独立地选择；
当化合价允许时，X 10和X 11各自独立地是空、-O-、-C(O)-、-S-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；
其中R 100a是孤对(当适用时)、氢、COR 2c、-SO 2R 5c、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基；或者R 100a与R 20或R 21基团形成任选取代的杂环或杂芳基环；
R 101a和R 102a当存在时各自独立地是氢、-OH、卤素；任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的C 1-6烷氧基、任选取代 的C 3-6环烷氧基、任选取代的氨基基团、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基；或者R 101a和R 102a与它们所结合的原子一起形成任选取代的3-7元环烷基或杂环基环；或者R 101a和R 102a之一与R 20或R 21基团一起形成任选取代的环烷基或杂环基环；以及
R 2c和R 5c各自独立地是氢、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；
或者R 20或R 21和L 10、X 10或X 11与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环。
当X 10或X 11与环碳之一形成双键时，它不能是R 101a和R 102a均存在的CR 101aR 102a，因为碳的化合价将超过4。在此类情况下，应当理解的是，R 101a和R 102a之一不存在，并且X 10或X 11是如本文所定义的CR 101a或CR 102a。当X 10或X 11与环碳之一形成双键时，它可以是NR 100a，其中R 100a通常是孤对。
在一些实施方案中，式II的化合物具有式II-5：
Figure PCTCN2022114540-appb-000033
其中：Ar 10、L 10、R 20、m、R 21、n、L 11和W 10在本文定义，参见例如式II-4。
式II(例如，本文所述的任何子式，诸如式II-1至II-4)中的Cy 10和Cy 11可以直接地或经由多种基团连接。例如，在一些实施方案中，式II(例如，式II-1至II-5)中的L 10是空、-C(O)-、任选取代的C 1-4亚烷基、任选取代的C 2-4亚烯基、任选取代的C 3-6亚环烷基、任选取代的4-7元杂亚环基、任选取代的亚苯基、任选取代的5或6元杂亚芳基、-O-、-S-、-NR 100-、-S(O)-、-SO 2-、-X 1-G 1-、-X 2-G 2-X 2a-、-X 12-G 10-、-X 13-G 11-X 13a-或-CR 101R 102-，
其中：
X 1、X 2和X 2a独立地是任选取代的C 1-4亚烷基、任选取代的C 2-4亚烯基、任选取代的C 3-6亚环烷基、任选取代的4-7元杂亚环基、任选取代的亚苯基、任选取代的5或6元杂亚芳基、-O-、-C(O)-、-S-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；
G 1和G 2独立地是任选取代的C 1-4亚烷基、任选取代的C 2-4亚烯基、任选取代的C 3-6亚环烷基、任选取代的4-7元杂亚环基、任选取代的亚苯基、任选取代的5或6元杂亚芳基、-C(O)-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；
优选地，在一些实施方案中，-X 1-G 1-或-X 2-G 2-X 2a-不含O-N、S-S、S-N(SO 2-N键除外)或-C(O)-S键；
X 12、X 13和X 13a独立地是任选取代的C 1-4亚烷基、任选取代的C 2-4亚烯基、任选取代的C 3-6亚环烷基、任选取代的4-7元杂亚环基、任选取代的亚苯基、任选取代的5或6元杂亚芳基、-O-、-C(O)-、-S-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；
以及G 10和G 11独立地是-X 1-G 1-或-X 2-G 2-X 2a-；
在一些实施方案中，优选地，-X 12-G 10-或-X 13-G 11-X 13a-不含O-O、O-N、S-S、S-N(SO 2-N键除外)、或-C(O)-S键或三个(或更多个)连续杂原子，其中O-SO 2-O、O-SO 2-N和N-SO 2-N除外；
R 100和R 100a各自独立地是孤对(当适用时)、氢、COR 2c、-SO 2R 5c、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基；
R 101、R 101a、R 102和R 102a各自独立地是氢、-OH、卤素；任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷氧基、任选取代的氨基基团、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基；或者R 101和R 102、或R 101a和R 102a与它们所结合的原子一起形成任选取代的3-7元环烷基或杂环基环。
在一些实施方案中，式II中的L 10可以是空，并且Cy 10直接与Cy 11连接。在一些实施方案中，式II中的L 10可以是空、-O-、-C(O)-、-S-、-NR 100-、-S(O)-、-SO 2-或-CR 101R 102-。在一些实施方案中，式II中的L 10可以是-X 1-G 1-或-X 2-G 2-X 2a-，其中：X 1、X 2和X 2a独立地是-O-、-C(O)-、-S-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；并且G 1和G 2独立地是-C(O)-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-。
在一些实施方案中，式II中的L 10可以是-X 12-G 10-。在一些实施方案中，X 12是任选取代的C 2-4亚烯基，优选地
Figure PCTCN2022114540-appb-000034
并且G 10是-X 1-G 1-或-X 2-G 2-X 2a-；其中：X 1、X 2和X 2a独立地是-O-、-C(O)-、-S-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；并且G 1和G 2独立地是-C(O)-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-。
在一些优选的实施方案中，式II中的L 10可以是
Figure PCTCN2022114540-appb-000035
Figure PCTCN2022114540-appb-000036
在一些实施方案中，式II的化合物可以具有以下核心结构：
Figure PCTCN2022114540-appb-000037
其中L 11-W 10可以直接附接到任一个环，优选地附接到两个苯基环中的一个或附接到唯一的苯基环，其中每个环可以任选地被一个或多个合适的本文所述的取代基取代，例如，每个取代基可以独立地选自F；Cl；-OH；-NH 2；-SO 2NH 2；-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)；-COOH；
Figure PCTCN2022114540-appb-000038
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取 代基取代的C 1-4烷基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6烯基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6炔基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷氧基；或任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷氧基；任选取代的C 3-6环烷基；任选取代的4-10元杂环基；任选取代的5-10元杂芳基；或任选取代的C 6-10芳基。例如，在一些实施方案中，L 11-W 10是NH 2或NH(C 1-4烷酰基)，其连接到两个苯基环中的一个或连接到唯一的苯基环，而另一个环任选地被1或2个选自甲基和甲氧基的取代基取代。
在一些特定的实施方案中，式II的化合物具有根据式II-6或II-7的式：
Figure PCTCN2022114540-appb-000039
其中：L 11、W 10、R 20和m在本文定义，参见例如式II-3，
p是0、1、2、3或4，
R 22在每次出现时独立地是卤素、-L 11’-W 10’、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或者两个相邻的R 22与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环；
其中L 11’和W 10’在本文定义，参见例如式II-2，并且-L 11’-W 10’在每次出现时独立地选择。
式II(例如，任何子式，诸如式II-1至II-7)中的L 11通常是空，即，当适用时，W 10基团直接附接到Cy 11。在一些实施方案中，式II中的L 11也可以是C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基或C 1-4杂亚烷基。例如，W 10基团可以通过亚甲基或乙烯基基团附接到Cy 11。
多种W 10基团适用于式II(例如，式II-1至II-7)的化合物。在优选的实施方案中，W 10基团在每次出现时独立地是-OH、-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)、-COOH、
Figure PCTCN2022114540-appb-000040
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2、-OC(O)NH(C 1-4烷基)-、-O-(CO)-(C 1-4烷基)、-O-(C 1-4烷基)，其中每个C 1-4烷基独立地任选被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代。在一些实施方案中，式II中的W 10基 团是-OH、-OMe、-NH 2、-SO 2NH 2、-SO 2NH(乙酰基)、-COOH、
Figure PCTCN2022114540-appb-000041
或-O-C(O)-CH 3。
如本文所述，L 11’-W 10’可以在一些实施方案中被选择为用于Cy 10或Cy 11诸如用于Ar 10或Ar 11的取代基。当适用时，式II(包括本文所述的任何子式，诸如式II-1至I-7)中的L 11’在每次出现时可以独立地是空，即，W 10’基团直接附接到Cy 10或Cy 11，诸如对于Ar 10或Ar 11而言(当适用时)，或是C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基或C 1-4杂亚烷基。例如，W 10’基团可以通过亚甲基或乙烯基基团附接到Cy 10或Cy 11，诸如对于Ar 10或Ar 11而言(当适用时)。当适用时，式II(包括本文所述的任何子式，诸如式II-1至II-7)中的W 10’在每次出现时可以独立地是-OH、-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)、-SO 2NH(C 1-4烷酰基)、-COOH、
Figure PCTCN2022114540-appb-000042
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2、-OC(O)NH(C 1-4烷基)-、-O-(CO)-(C 1-4烷基)、-O-(C 1-4烷基)，其中每个C 1-4烷基独立地任选被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代。在一些实施方案中，当适用时，式II中的W 10’的每个实例可以是-OH、-OMe、-NH 2、-SO 2NH 2、-SO 2NH(乙酰基)、-COOH或-O-C(O)-CH 3。
多种基团可以适用于任何适用的式II(例如，当适用时，式II-1至II-7)中的R 20、R 21和R 22。在一些实施方案中，R 20、R 21和R 22中的每一者在每次出现时可以独立地是F；C1；-OH；-NH 2；-SO 2NH 2；-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)；-COOH；
Figure PCTCN2022114540-appb-000043
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6烯基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6炔基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷氧基；或任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷氧基。在一些实施方案中，R 20、R 21和R 22中的每一者在每次出现时可以独立地是F；Cl；-OH；-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)、-SO 2NH(C 1-4烷酰基)、-COOH；
Figure PCTCN2022114540-appb-000044
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；-O-(C 1-6烷基)；-O-(C 2-6烯基)；任选地被独立地选 自C 1-4烷基、C 1-6烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-6烷基；或任选地被独立地选自C 1-4烷基、C 1-6烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6烯基。在一些实施方案中，R 20、R 21和R 22中的每一者在每次出现时可以独立地是-OH、C 1-4烷基、C 2-6烯基或-O-(C 1-4烷基)。在一些实施方案中，R 20、R 21和R 22中的每一者在每次出现时可以独立地是-OH、-OMe或
Figure PCTCN2022114540-appb-000045
在一些实施方案中，R 20的一个或多个实例、R 21的一个或多个实例和/或R 22的一个或多个实例可以是独立地选择的如本文所述的L 11’-W 10’。
通常，m和p在适用时是0、1、2或3；优选地，是1或2。
通常，n在适用时是0、1或2；优选地，是0或1。
在一些实施方案中，式II的化合物可以具有根据式II-8至II-10中的任一者的式：
Figure PCTCN2022114540-appb-000046
其中R 20、R 22、m和p在本文定义。在一些实施方案中，m是1或2，p是1、2或3。在一些实施方案中，R 20和R 22中的每一者在每次出现时独立地是F；Cl；-OH；-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)、-SO 2NH(C 1-4烷酰基)、-COOH；
Figure PCTCN2022114540-appb-000047
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；-O-(C 1-6烷基)；-O-(C 2-6烯基)；任选地被独立地选自C 1-4烷基、C 1-6烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-6烷基；或任选地被独立地选自C 1-4烷基、C 1-6烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6烯基。
在一些实施方案中，在任何适用的式II中的结构单元
Figure PCTCN2022114540-appb-000048
可以选自
Figure PCTCN2022114540-appb-000049
在一些具体实施方案中，式II的化合物可以是：
Figure PCTCN2022114540-appb-000050
或其药学上可接受的盐或酯。
在一些实施方案中，本文的化合物可以通过具有式III或其药学上可接受的盐或酯来表征：
Figure PCTCN2022114540-appb-000051
其中Ar 20是任选取代的芳基环(例如，C 6-10芳基环)或任选取代的杂芳基环(例如，5-10元杂芳基环)；
L 20是空、任选取代的C 1-6亚烷基、任选取代的C 1-6杂亚烷基、任选取代的C 2-6亚烯基、任选取代的C 2-6亚炔基、任选取代的C 3-6亚环烷基、任选取代的亚芳基、任选取代的杂亚芳基 或任选取代的4-7元杂亚环基，
W 20是-OR 1；-COR 2；-COOR 1a；-OCOOR 1a；-NR 3R 4；-CONR 3aR 4a；-OCONR 3bR 4b；-SO 2NR 3cR 4c；-OSO 2NR 3dR 4d；-SR 5；-SO 2R 5a；-OCOR 2a；-OSO 2R 5a；或
Figure PCTCN2022114540-appb-000052
其中：
R 1和R 1a各自独立地是氢、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环基；
R 3和R 4各自独立地是氢、-COR 2b、-SO 2R 5b、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基，或者R 3和R 4与它们所结合的原子一起形成任选取代的4-7元杂环基；
R 2、R 2a、R wb、R 5、R 5a和R 5b各自独立地是氢、-OH、-NR 3eR 4e、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；以及
R 3a、R 3b、R 3c、R 3d、R 3e、R 4a、R 4b、R 4c、R 4d和R 4e各自独立地是氢、任选取代的C 1-6烷基、任选取的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或R 3a和R 4a、R 3b和R 4b、R 3c和R 4c、R 3d和R 4d或者R 3e和R 4e与它们所结合的原子一起形成任选取代的4-7元杂环基。
在一些实施方案中，式III中的Ar 20是任选取代的苯基环或任选取代的5或6元杂芳基环。例如，在一些实施方案中，式III中的Ar 20可以是任选取代的苯基环、任选取代的噻吩基环、任选取代的呋喃基环、任选取代的吡啶基环或任选取代的嘧啶基环。在一些实施方案中，式III中的Ar 20也可以是任选取代的双环芳基或双环杂芳基环，其中每一者任选地被取代。在此类实施方案中，L 20-W 20可以附接到任一个双环。
在一些实施方案中，式III中的Ar 20可以是任选取代的苯基环，其中两个相邻的取代基与它们所附接的碳一起形成任选取代的环烷基、杂环基、芳基或杂芳基环。
例如，在一些实施方案中，式III中的Ar 20可以是苯并稠合双环芳基或杂芳基环。例如，在一些实施方案中，式III中的Ar 20可以具有以下结构：
Figure PCTCN2022114540-appb-000053
其中-L 20-W 20可以附接在两个环中的任一个环处，其中任一个或两个环可以任选地被取代。
在一些实施方案中，式III的化合物可以具有式III-1、III-2或III-3：
Figure PCTCN2022114540-appb-000054
其中L 20和W 20在本文定义，
m是0、1、2或3；n是0、1、2或3；
R 30和R 31中的每一者在每次出现时独立地是卤素、-L 20’-W 20’、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；其中-L 20’-W 20’在每次出现时独立地选择；其中L 20’在每次出现时独立地是空、任选取代的C 1-6亚烷基、任选取代的C 1-6杂亚烷基、任选取代的C 2-6亚烯基、任选取代的C 2-6亚炔基、任选取代的C 3-6亚环烷基、任选取代的亚芳基、任选取代的杂亚芳基或任选取代的4-7元杂亚环基；并且W 20’在每次出现时独立地是-OR 1；-COR 2；-COOR 1a；-OCOOR 1a；-NR 3R 4；-CONR 3aR 4a；-OCONR 3bR 4b；-SO 2NR 3cR 4c；-OSO 2NR 3dR 4d；-SR 5；-SO 2R 5a；-OCOR 2a；-OSO 2R 5a或
Figure PCTCN2022114540-appb-000055
其中R 1、R 1a、R 2、R 2a、R 2b、R 3、R 4、R 3a、R 3b、R 3c、R 3d、R 3e、R 4a、R 4b、R 4c、R 4d、R 4e、R 5、R 5a和R 5b在本文定义，参见例如式III，
环B是4-7元环烷基环、4-7元杂环、苯基环、5或6元杂芳基环，其中每一者任选地被 1-3个独立选择的R 31取代；
当化合价允许时，X 20和X 21各自独立地是空、-O-、-C(O)-、-S-、-NR 100a-、-S(O)-、-SO 2-或-CR 101aR 102a-；
其中R 100a是孤对(当适用时)、氢、COR 2c、-SO 2R 5c、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基；或者R 100a和R 30或R 31之一与它们所结合的原子一起形成任选取代的杂环或杂芳基环，例如任选取代的5或6元杂芳基或任选取代的4-7元杂环基；
R 101a和R 102a当存在时各自独立地是氢、-OH、卤素；任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷氧基、任选取代的氨基基团、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基，或者R 101a和R 102a与它们所结合的原子一起形成任选取代的3-7元环烷基或杂环基环；或者R 101a和R 102a之一与R 30或R 31基团一起形成任选取代的环烷基或杂环基环；以及
R 2c和R 5c各自独立地是氢、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；
或者两个相邻的R 30或两个相邻的R 31、或者R 30或R 31和X 20或X 21与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环。
当X 20或X 21与环碳之一形成双键时，它不能是R 101a和R 102a均存在的CR 101aR 102a，因为碳的化合价将超过4。在此类情况下，应当理解的是，R 101a和R 102a之一不存在，并且X 20或X 21是如本文所定义的CR 101a或CR 102a。当X 20或X 21与环碳之一形成双键时，它可以是NR 100a，其中R 100a通常是孤对。
应当注意的是，结构单元-L 20’-W 20’和-L 20-W 20的每个实例独立地选择并且可以是相同或不同的。
在一些实施方案中，式III的化合物可以具有以下任何结构：
Figure PCTCN2022114540-appb-000056
其中：R 30、m、R 31、n、R 100a、L 20和W 20在本文定义，参见例如本文的式III和子式，诸如式III-1至III-3，其中对于三环结构，哌啶环或吗啉环可以任选地被取代。
式III(例如，任何子式，诸如式III-1至III-3)中的L 20通常是空，即，W 20基团直接附接到Ar 20。在一些实施方案中，式III中的L 20也可以是C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基或C 1-4杂亚烷基。例如，W 20基团可以通过亚甲基或乙烯基基团附接到Ar 20。
多种W 20基团适用于式III(例如，任何子式，诸如式III-1至III-3)的化合物。在优选的实施方案中，式III中的W 20可以是-OH、-COOH、
Figure PCTCN2022114540-appb-000057
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10 烯基)、-OC(O)NH 2、-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)、-OC(O)NH(C 1-4烷基)-、-O-(CO)-(C 1-4烷基)、-O-(C 1-4烷基)，其中每个C 1-4烷基独立地任选被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代。在一些实施方案中，式III(例如，任何子式，诸如式III-1至III-3)中的W 20基团是-OH、-NH 2、-SO 2NH 2、-SO 2NH(乙酰基)、
Figure PCTCN2022114540-appb-000058
-C(O)-(O-C 8烷基)、-COOH或-O-C(O)-CH 3。
如本文所述，L 20’-W 20’可以在一些实施方案中被选择为用于Ar 20的取代基。当适用时，式III(包括本文所述的任何子式，诸如式III-1至III-3)中的L 20’在每次出现时可以独立地是空，即，当适用时，W 20’基团直接附接到Ar 20，或是C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基或C 1-4杂亚烷基。例如，当适用时，W 20’基团可以通过亚甲基或乙烯基基团附接到Ar 20。当适用时，式III(包括本文所述的任何子式，诸如式III-1至III-3)中的W 20’在每次出现时可以独立地是-OH、-COOH、
Figure PCTCN2022114540-appb-000059
-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2、-NH 2、-SO 2NH 2、-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)、-OC(O)NH(C 1-4烷基)-、-O-(CO)-(C 1-4烷基)、-O-(C 1-4烷基)，其中每个C 1-4烷基独立地任选被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代。在一些实施方案中，当适用时，式III中的W 20’的每个实例可以是-OH、-NH 2、-SO 2NH 2、-SO 2NH(乙酰基)、
Figure PCTCN2022114540-appb-000060
-COOH、-C(O)(O-C 8烷基)或-O-C(O)-CH 3。
多种基团可以适用于任何适用的式III(例如，任何子式，诸如式III-1至III-3)中的R 30和R 31。在一些实施方案中，R 30和R 31中的每一者在每次出现时可以独立地是F；Cl；-OH；-COOH；-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6烯基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6炔基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷氧基；或任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷氧基。在一些实施方案中，R 30和R 31中的每一者在每次出现时可以独立地是-OH、C 2-6烯基、-O-(C 1-4烷基)、-COOH或-C(O)(O-C 1-10烷基)。在一些实施方案中，R 30和R 31中的每一者在每次出现时可以是-OH或-OMe。在一些实施方案中，R 30的一个或多个实例和/或R 31的一个或多个实例可以是独立地选择的如本文所述的L 20’-W 20’。
通常，m是0、1、2或3；优选地，是2或3。通常，n是1、2或3。
在一些实施方案中，本公开还提供了以下化合物：
Figure PCTCN2022114540-appb-000061
或其药学上可接受的盐或酯。
在一些实施方案中，本公开还提供了以下化合物：
Figure PCTCN2022114540-appb-000062
或其药学上可接受的盐或酯，其中q是1、2、3、4或5，并且Glu是葡萄糖残基。在一些具体实施方案中，本公开还提供了
Figure PCTCN2022114540-appb-000063
其药学上可接受的盐或酯。
在一些实施方案中，本文的化合物也可以是具有抗菌活性的生物碱。如本文所示，某些吲哚生物碱诸如长春花生物碱、水甘草碱、文多灵、长春花碱、长春新碱等显示能有效杀灭诸如巨大芽孢杆菌的微生物。在一些实施方案中，本文的化合物由式IV-1或IV-2来表征，其为水甘草碱或文多灵和衍生物：
Figure PCTCN2022114540-appb-000064
其中：
R 40是氢；-COR 2；-COOR 1a；-SO 2R 5a；任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环基；
R 41是-OR 1；-OCOOR 1a；-OCONR 3bR 4b；-OCOR 2a；或-OSO 2R 5a；n是0或1；
R 42、R 43和R 44各自独立地是氢、-OR 1、OCOR 2a；或-O5O 2R 5a；
L 30是空或亚甲基，
W 30是-OR 1；-COR 3；-COOR 1a；-OCOOR 1a；-NR 3R 4；-CONR 3aR 4a；-OCONR 3bR 4b；-OSO 2NR 3dR 4d；-OCOR 2a；或-O5O 2R 5a
其中：
R 1和R 1a各自独立地是氢、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环基；
R 3和R 4各自独立地是氢、-COR 2b、-SO 2R 5b、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基、或任选取代的4-7元杂环基，或者R 3和R 4与它们所结合的原子一起形成任选取代的4-7元杂环基；
R 2、R 2a、R 2b、R 5、R 5a和R 5b各自独立地是氢、-OH、-NR 3eR 4e、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；以及
R 3a、R 3b、R 3c、R 3d、R 3e、R 4a、R 4b、R 4c、R 4d和R 4e各自独立地是氢、任选取代的C 1-6烷基、任选取的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 1-6烷氧基、任选取代的C 3-6环烷基、任选取代的C 3-6环烷氧基、任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基；或R 3a和R 4a、R 3b和R 4b、R 3c和R 4c、R 3d和R 4d或者R 3e和R 4e与它们所结合的原子一起形成任选取代的4-7元杂环基。
在一些实施方案中，式IV-1或IV-2的化合物具有根据式IV-3至IV-6之一的式：
Figure PCTCN2022114540-appb-000065
其中R 45是氢或甲基。
在一些实施方案中，式IV-1至IV-6中任一个的R 40可以是氢、C 1-4烷基或C 1-4烷酰基。
式IV-1至IV-6中的L 30通常是空。然而，在一些实施方案中，式IV-1至IV-6中的L 30也可以是CH 2。
式IV-1至IV-6中的W 30通常是可用于本文的组合物和方法的羧酸衍生物、胺衍生物或醇衍生物。天然存在的吲哚生物碱水甘草碱包含CO 2Me基团作为W 30，而L 30为空。CO 2Me基团可以经由常规转化而转化成对应的酸、酰胺等，或者可以通过重排诸如柯提斯(Curtius)重排而还原或转化成胺。在一些实施方案中，式IV-1至IV-6中的W 30可以是-OH、-NH 2、-OSO 2NH 2、-COOH、-C(O)(O-C 1-10烷基)、-C(O)(O-C 2-10烯基)、-OC(O)NH 2、-OC(O)NH(C 1-4烷基)-、-O-(CO)-(C 1-4烷基)、-O-(C 1-4烷基)，其中每个C 1-4烷基独立地任选被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代。在一些实施方案中，式IV-1至IV-6中的W 30可以是-OH、-NH 2、-OSO 2NH 2、-C(O)-(O-C 8烷基)、-COOH或-OC(O)NH 2。
在一些具体实施方案中，化合物可以具有以下结构：
Figure PCTCN2022114540-appb-000066
在一些实施方案中，本文的化合物也可以是具有抗菌活性的糖苷，或其药学上可接受的盐或酯。如本文所示，某些糖苷诸如人参皂苷和没食子酸糖苷显示出能有效杀灭诸如巨大芽孢杆 菌的微生物。其他有用的糖苷包括本领域已知具有抗菌活性的那些糖苷中的任一种，其可以例如包括特征在于其相应的苷元为酚类化合物、类黄酮、香豆素、苯甲酸或甾醇的糖苷。通常，糖苷是葡糖苷，但是也可以使用其他糖苷。在一些实施方案中，糖苷可以表征为两亲性的，这可以破坏生物膜并赋予糖苷的抗微生物活性。在一些实施方案中，糖苷也可以表征为皂苷，其例如包括可以充当“表面活性剂”并且可以有助于杀灭细菌的多种植物来源的糖苷。
在一些实施方案中，本文的糖苷可以通过式V表征：
Figure PCTCN2022114540-appb-000067
其中每个R 50独立地是氢、-L 50-D、氧保护基或糖残基；
L 50是空或-C(O)-；
D是任选取代的芳基(例如，C 6-10芳基)、任选取代的杂芳基(例如，5至14元杂芳基)、任选取代的包含两个或更多个独立地选自芳基、杂芳基、环烷基和杂环基的稠环(例如，8-14元，例如，苯并稠合环烷基/杂环基、吡啶并稠合环烷基/杂环基)或具有式V-A的类固醇残基：
Figure PCTCN2022114540-appb-000068
其中当化合价允许时，
Figure PCTCN2022114540-appb-000069
可以经由类固醇骨架或任何R 51基团连接到式V-A，
其中R 51在每次出现时独立地是任选取代的烷基、任选取代的烯基、任选取代的炔基、任选地被氧保护基取代的-OH、氧代、卤素、任选取代的环烷基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的氨基基团、任选取代的苯基、任选取代的杂芳基或任选取代的杂环基，或者两个R 51基团与它们所结合的原子一起形成任选取代的环烷基、杂环基、芳基或杂芳基环；
m是1-8的整数；以及
其中-L 50-D在每次出现时独立地选择。
在一些实施方案中，每个R 50是氢。
在一些实施方案中，一个至四个R 50可以是独立地选择的-L 50-D。当两个或更多个-L 50-D单元连接到式V中的吡喃糖单元时，它们优选地是相同的。在一些实施方案中，一个或多个 (例如，1个或2个)R 50可以是经由糖苷键连接到式V的其余部分的糖残基。在一些实施方案中，糖残基是葡萄糖残基或鼠李糖残基。
式V中的L 50可以是空或羰基基团即-C(O)-，这取决于连接基团是来自苯甲酸的酚-OH或COOH基团还是杂芳基对应物。
多种残基可以用作D，其通常是来自酚类化合物、香豆素、类黄酮或甾醇的残基，在一些实施方案中可以在没有糖苷单元的情况下具有抗菌活性。
在一些实施方案中，D可以是选自以下的任选取代的环：
Figure PCTCN2022114540-appb-000070
其中
R 100a是孤对(当适用时)、氢、氮保护基、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-6环烷基、任选取代的苯基、任选取代的5或6元杂芳基或任选取代的4-7元杂环基；或R 100a与苯基或吡啶基环形成任选取代的杂环或杂芳基环；
其中
Figure PCTCN2022114540-appb-000071
可以经由任何可用的位置连接到D，并且
D的每个环系任选地被1-5(例如，1、2或3)个取代基取代，每个取代基独立地选自-OH；-COOH；-C(O)(O-C 1-10烷基)；-C(O)(O-C 2-10烯基)；-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；-NH 2；-SO 2NH 2；-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)；卤素；任选取代的C 1-6烷基；任选取代的C 2-6烯基；任选取代的C 2-6炔基；任选取代的C 3-6环烷基；任选取代的C 1-6烷氧基；任选取代的C 3-6环烷氧基；任选取代的氨基基团；任选取代的苯基；任选取代的5或6元杂芳基；或任选取代的4-7元杂环基。
在一些实施方案中，如上所示的D的每个环系可以任选地被1-5个取代基取代，每个取代 基各自独立地选自F；Cl；-OH；-COOH；-C(O)(O-C 1-10烷基)；-C(O)(O-C 2-10烯基)；-OC(O)NH 2；-OC(O)NH(C 1-4烷基)-；-O-(CO)-(C 1-4烷基)；-NH 2；-SO 2NH 2；-SO 2NH(C 1-4烷基)；-SO 2NH(C 1-4烷酰基)；任选地被独立地选自C 1-4烷基的l-3个取代基取代的C 1-4烷基；C 1-4烷氧基、-OH、-NH 2和氟；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6烯基；任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 2-6炔基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷基；任选地被独立地选自C 1-4烷基和氟的1-3个取代基取代的C 3-6环烷氧基；或任选地被独立地选自C 1-4烷基、C 1-4烷氧基、-OH、-NH 2和氟的1-3个取代基取代的C 1-4烷氧基。
在一些实施方案中，D可以选自：
Figure PCTCN2022114540-appb-000072
其中每个酚OH基团任选地经由糖苷键与糖(诸如葡萄糖)连接。
在一些实施方案中，D衍生自甾醇。例如，在一些实施方案中，D是
Figure PCTCN2022114540-appb-000073
其中R 52是任选取代的烷基或任选取代的烯基，
其中D中的每个其余的-OH基团任选地经由糖苷键与糖连接。
优选地，R 52可以是
Figure PCTCN2022114540-appb-000074
在上文所述的任何实施方案中，糖苷可以具有式V-1或V-2：
Figure PCTCN2022114540-appb-000075
在一些实施方案中，糖苷可以是选自以下的化合物：
Figure PCTCN2022114540-appb-000076
在一些实施方案中，本文的化合物可以是选自以下的任一种或多种化合物：苯甲酸，苯甲醇，香豆素类，儿茶酚类，多酚类，查耳酮类(包括甘草查耳酮类)等，茋类诸如白藜芦醇、异白藜芦醇等，酚酸类诸如对羟基苯甲酸、2，4-二羟基苯甲酸、原儿茶酸、没食子酸、香草酸、丁香酸、肉桂酸、香豆酸类、咖啡酸类、阿魏酸类、绿原酸、芥子酸类等，类黄酮诸如儿茶素、柚皮素、槲皮素、芦丁、白杨素等，单宁类诸如鞣花酸，以及其药学上可接受的盐或酯及其糖苷。
在本发明的实施方式中，所述的微生物抑制剂或杀灭剂为化合物1-8，具有以下化学结构：
Figure PCTCN2022114540-appb-000077
优选的，本发明所述的微生物抑制剂或杀灭剂为天然植物或其提取物，优选的，所述的天然植物选自甘草、白芍、连翘、枳壳、地黄、陈皮、三七、鳖甲、红景天、生地、薏仁、白芍、连翘、决明子和甘草中的一种或两种以上的组合，或上述天然植物提取物或其组合。
在本发明的一个具体实施方式中，所述的微生物抑制剂或杀灭剂为包含鳖甲、红景天、生地、薏仁、白芍、连翘、决明子和甘草的组合物，优选的，所述的组合物中按照重量分数计，包括鳖甲5-15份、红景天10-30份、生地5-15份、薏仁5-15份、白芍8-20份、连翘5-15份、决明子5-15份和甘草5-15份，更优选的，所述的组合物包括鳖甲10份、红景天20份、生地10份、薏仁10份、白芍12份、连翘10份、决明子10份和甘草9份。
优选的，所述的向患者的眼部施用包括向患者眼部的前房中的房水、悬韧带、睫状体、睫状体和睫状肌、后房中的玻璃体液、视网膜、脉络膜、视神经、晶状体或虹膜中施用。
优选的，所述的向患者的胃肠道施用包括向患者的胃、空肠、回肠、盲肠、结肠或直肠中施用。
本发明还一个方案提供了微生物抑制剂或杀灭剂在制备治疗视网膜变性的药物中的应用。
优选的，所述的视网膜变性为进行性视网膜变性；更优选的，所述的视网膜变性为遗传性视网膜变性；更优选的，遗传性视网膜变性包括先天性黑蒙(LCA)、色素性视网膜炎(RP)、早发性视杆-视锥细胞营养不良、视杆-视杆营养不良、先天性静止性夜盲和色盲和Stargardt病。
优选的，所述微生物为细菌、古细菌、原生生物、真菌或病毒中的一种或两种以上的组合。所述微生物为细菌，所述细菌选自：Anearostipes、双歧杆菌(Bifidobacterium)、巨单胞菌(Megamonas)、亚硝基单胞菌(Nitrosomonas)，颤螺旋菌(Oscillibacter)、塔特姆菌(Tatumella)、硫杆菌(Thiobacillussp.)、梭菌属(Clostridium)、不动杆菌属(Acinetobacter)、链球菌属(Streptococcus)、曼氏杆菌属(Mannheimia)、纤维杆菌属(Fibrobacter)、普氏菌属(Prevotella)、弯曲杆菌属(Campylobacter)、放线菌属(Actinomyces)、薄层菌属(Hymenobacter)、埃希氏杆菌属(Escherichia)、泰氏菌属(Tissierella)、克雷白氏杆菌属(Klebsiella)、卟啉单胞菌属(Porphyromonas)、固氮螺菌属(Azospira)、海水菌属(Aquimarina)、无色菌属(Achromobacter)、嗜酸硫杆菌属(Acidithiobacillus)、伯克霍尔德菌属(Burkholderia)、海杆菌属(Marinobacter)、密螺旋体属(Treponema)、孢裹放线菌属(Actinosporangium)、弧菌属(Vibrio)、瘤胃球菌属(Ruminococcus)、甲烷短杆菌(Methanobrevibacter)、志贺氏杆菌(Shigella)、弗兰克氏菌属(Frankia)、链霉菌属厌氧原体属(Anaeroplasma)、粪球菌属(Coprococcus)中的一种或两种以上。更优选的，所述细菌选自：Anearostipeshadrus、Bifidobacterium pseudocatenulatum、Nitrosomonas sp.Is79A3、Oscillibactervalericigenes、Tatumella sp.TA1、Megamonasfuniformis、Thiobacillus denitrificans、Akkermansiamucinphila。
优选的，所述的微生物抑制剂或杀灭剂包含化合物、多肽、多核苷酸、天然植物或天然植物提取物。
更优选的，所述的微生物抑制剂或杀灭剂为抗生素，例如所述的抗生素为β-内酰胺类抗生素；氨基糖苷类抗生素；四环素类抗生素；氯霉素类抗生素；大环内脂类抗生素；糖肽类抗生素；喹诺酮类抗生素；硝基咪唑类抗生素；利福霉素类抗生素；棘白菌素类抗生素；多烯类抗生素；嘧啶类抗生素；烯丙胺类抗生素；氮唑类抗生素；其它抗生素中的一种或者两种以上。
例如，在一些实施方案中，抗生素可以包括以下一种或多种：β-内酰胺类抗生素，包括青霉素类(例如青霉素V)、阿莫西林、氨苄西林、巴坎西林、羧苄西林、氯唑西林、双氯西林、氟氯西林、美洛西林、萘夫西林、苯唑西林、青霉素G、哌拉西林、匹氨西林、匹美西林、替卡西林，头孢菌素类如头孢乙腈、头孢羟氨苄、头孢氨苄、头孢甘氨酸、头孢洛宁、头孢噻啶、头孢噻吩、头孢匹林、头孢曲嗪、头孢氮氟、头孢西酮、头孢唑啉、头孢拉定、头孢沙定、头孢替唑、头孢克洛、头孢孟多、头孢美唑、头孢尼西、头孢替坦、头孢西丁、头孢丙烯、头孢呋辛、头孢唑喃、头孢卡品、头孢达肟、头孢地尼、头孢托仑、头孢他美、头孢克肟、头孢甲肟、头孢地嗪、头孢噻肟、头孢咪唑、头孢泊肟、头孢特仑、头孢布烯、头孢噻呋、头孢噻 林、头孢唑肟、头孢曲松、头孢哌酮、头孢他啶、头孢克啶、头孢吡肟、头孢瑞南、头孢噻利、头孢唑兰、头孢匹罗、头孢喹肟、头孢吡普、头孢洛林、头孢氯嗪、头孢洛仑、头孢派罗、头孢卡奈、头孢屈洛、头孢吡酮、头孢三唑、头孢维曲、头孢马替林(cefmatilen)、头孢氯铵(cefmepidium)、头孢维星、头孢噁唑、头孢罗替、头孢舒米、头孢呋汀、头孢噻氧，噻烯霉素类，单内酰环类，β-内酰胺酶抑制剂，甲氧西林类；氨基糖苷类抗生素，包括链霉素、庆大霉素、卡那霉素(例如，卡那霉素A)、妥布霉素、阿米卡星、新霉素(例如，新霉素B、新霉素C、新霉素E)、核糖霉素、小诺霉素、阿奇霉素、地贝卡星、西索米星、奈替米星、巴龙霉素、短霉素等；四环素类抗生素，包括四环素、氧四环素、金霉素和强力霉素等；氯霉素类抗生素，包括氯霉素、甲砜霉素等；大环内酯类抗生素，包括红霉素、白霉素、无味红霉素、乙酰螺旋霉素、麦迪霉素、交沙霉素、阿奇霉素、克拉霉素、地红霉素、罗红霉素、泰利霉素等；糖肽类抗生素，包括万古霉素、去甲万古霉素、替考拉宁等；喹诺酮类抗生素，包括诺氟沙星、氧氟沙星、环丙沙星、培氟沙星、加替沙星、依诺沙星、洛美沙星、萘啶酮酸、左氧氟沙星、莫西沙星、贝西沙星；硝基咪唑类抗生素，包括甲硝唑、替硝唑、奥硝唑等；利福霉素类抗生素，包括利福平；棘白菌素类抗生素；多烯类抗生素；嘧啶类抗生素；烯丙胺类抗生素；氮唑类抗生素；其他抗生素：磷霉素、卷曲霉素、环丝氨酸、林可霉素、克林霉素、丝裂霉素、放线菌素D、博莱霉素、阿霉素、异烟肼、吡嗪酰胺、环孢霉素、多粘菌素B组合诸如多粘菌素B/甲氧苄啶、多粘菌素B/杆菌肽、多粘菌素B/新霉素/短杆菌肽等。
在一些实施方案中，抗生素可以选自阿米卡星、阿莫西林、氨苄西林、胂凡纳明、阿奇霉素、阿洛西林、氨曲南、杆菌肽、卷曲霉素、羧苄青霉素、头孢克洛、头孢羟氨苄、头孢氨苄、头孢噻吩、头孢孟多、头孢唑啉、头孢地尼、头孢托仑、头孢克肟、头孢哌酮、头孢噻肟、头孢西丁、头孢泊肟、头孢丙烯、头孢他啶、头孢布烯、头孢唑肟、头孢曲松、头孢呋辛、氯霉素、西司他丁、克拉霉素、克拉维酸、克林霉素、氯法齐明、氯唑西林、粘菌素、环丝氨酸、达福普汀、氨苯砜、达托霉素、双氯西林、地红霉素、多利培南、强力环素、红霉素、乙胺丁醇、乙硫异烟胺、氟氯西林、磷霉素、呋喃唑酮、夫西地酸、庆大霉素、亚胺培南、异烟肼、卡那霉素、林可霉素、利奈唑胺、氯拉卡比、磺胺米隆、美罗培南、甲氧西林、甲硝唑、美洛西林、米诺环素、莫匹罗星、萘夫西林、新霉素、奈替米星、呋喃妥因、苯唑西林、氧四环素、巴龙霉素、青霉素G、青霉素V、哌拉西林、平板霉素、多粘菌素B、吡嗪酰胺、奎奴普丁、雷帕霉素、利福布汀、利福平(Rifampicin)、利福霉素(Rifampin)、利福喷丁、利福昔明、罗红霉素、磺胺嘧啶银、壮观霉素、链霉素、舒巴坦、磺胺醋酰、磺胺嘧啶、磺胺甲二唑、磺胺甲噁唑、磺胺二甲异噁唑、柳氮磺吡啶、磺胺异噁唑、他唑巴坦、替考拉宁、替拉万星(Telavancin)、替利霉素、替莫西林、四环素、甲砜霉素、替卡西林、替加环素、替硝唑、妥布霉素、甲氧苄啶、醋竹桃霉素、万古霉素、依诺沙星、洛美沙星、萘啶酮酸、环丙沙星、 左氧氟沙星、加替沙星、莫西沙星、氧氟沙星、诺氟沙星、头孢替坦、头孢尼西、头孢拉定、头孢匹林、头孢噻吩、头孢美唑、头孢噻肟、拉氧头孢、头孢吡肟、头孢洛林酯、头孢吡普、达巴万星、地美环素、美他环素、厄他培南、非达霉素、格尔德霉素、除莠霉素、泼斯唑来(Posizolid)、雷得唑来(Radezolid)、特地佐利(Torezolid)、奥利万星(Oritavancin)、螺旋霉素、磺胺二甲嘧啶、磺酰氨基柯衣定(Sulfonamidochrysoidine)、吉米沙星、那氟沙星、曲伐沙星、格雷沙星、司帕沙星、替马沙星、泰斯巴汀(Teixobactin)、美拉希汀(Malacidins)以及它们的组合。
优选的，所述的微生物抑制剂或杀灭剂为式I(例如，式I-1、式I-2、式I-3、式I-4、式I-5)、式II(例如，式II-1、式II-2、式II-3、式II-4、式II-5、式II-6、式II-7、式II-8、式II-9、式II-10)、式III(例如，式III-1、式III-2、式III-3)、式IV-1或IV-2(例如，式IV-3、式IV-4、式IV-5、式IV-6)的化合物，糖苷(例如，式V)，或其药学上可接受的盐或酯，其中所述糖苷的苷元是酚类化合物、类黄酮、香豆素、苯甲酸或甾醇，其中所述式I、II、III、IV-1、IV-2、V及其子式如前述所定义。
在本发明的具体实施方式中，所述的微生物抑制剂或杀灭剂为化合物1-8，具有以下化学结构：
Figure PCTCN2022114540-appb-000078
优选的，本发明所述的微生物抑制剂或杀灭剂为天然植物或其提取物，优选的，所述的天然植物选自甘草、白芍、连翘、枳壳、地黄、陈皮、三七、鳖甲、红景天、生地、薏仁、白芍、连翘、决明子和甘草中的一种或两种以上的组合，或上述天然植物提取物或其组合。
在本发明的一个具体实施方式中，所述的微生物抑制剂或杀灭剂为包含鳖甲、红景天、生地、薏仁、白芍、连翘、决明子和甘草的组合物，优选的，所述的组合物中按照重量分数计，包括鳖甲5-15份、红景天10-30份、生地5-15份、薏仁5-15份、白芍8-20份、连翘5-15份、决明子5-15份和甘草5-15份，更优选的，所述的组合物包括鳖甲10份、红景天20份、生地10份、薏仁10份、白芍12份、连翘10份、决明子10份和甘草9份。
优选的，所述药物为眼部给药制剂或胃肠道给药制剂。更优选的，所述的眼部给药制剂为滴眼剂、眼膏剂、眼用凝胶剂、眼用膜剂、洗眼剂、眼内注射剂。更优选的，所述的胃肠道给药制剂为片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片、口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊、微胶囊)、锭剂、糖浆剂、溶液剂、乳剂、混悬剂、控制释放制剂(例如，瞬时释放制剂、缓释制剂、缓释微囊)、气雾剂、膜剂(例如，口服崩解膜剂、口腔粘膜-粘附膜剂)。
具体地，上述药学上可接受的辅料可以包括甜味剂(具体如，蔗糖、木糖醇、低聚果糖、甜蜜素、甜菊糖、阿斯巴甜等)、芳香剂(如香料、香精等)、胶浆剂(具体如，海藻酸钠、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠等)、澄清剂(具体如，壳聚糖、明胶等)、防腐剂(具体如，苯甲酸及其盐、山梨酸及其盐、尼泊金类系列等)、崩解剂(具体如，低取代羟丙基纤维素、交聚维酮、羧基乙酸淀粉钠、交联羧甲基纤维素钠、淀粉等)、粘结剂(具体如，羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮、预胶凝淀粉等)、润滑剂(具体如，硬脂酸、硬脂酸镁、富马酰硬脂酸钠等)、润湿剂(具体如，聚氧乙烯山梨糖醇酐脂肪酸酯、泊洛沙姆、聚氧乙烯蓖麻油衍生物等)、悬浮剂(具体如，羟丙甲纤维素、羟丙基纤维素、聚维酮、共聚维酮、羧甲基纤维素钠、甲基纤维素等)、稳定剂(具体如，柠檬酸、富马酸、琥珀酸等)、填充剂(具体如，淀粉、蔗糖、乳糖、微晶纤维素等)、粘合剂(具体如，纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮等)等中的一种或多种。本发明还提供一种建立眼部疾病模型的方法，所述方法包括让眼部疾病模型感染微生物。
优选的，所述的感染包括直接与微生物接触或者间接与微生物接触。在一个具体实施方式中，是通过将非人动物饲养于SPF环境中获得眼部感染了微生物的眼部疾病模型。
优选的，所述的微生物来自同一个体的肠道细菌或者与该个体的肠道细菌相同。
优选的，所述的眼部疾病包含视网膜变性；更优选的，所述的视网膜变性为进行性视网膜变性。
优选的，所述的视网膜变性为遗传性视网膜变性(IRD)。
优选的，所述的眼部疾病包含LCA、RP、arRP、EORD、EORP、PPRPE、rettelangiectasia和/或choroideremia like fundus。
优选的，所述的眼部疾病包含眼部炎症，例如葡萄膜炎、青光眼、和年龄相关的黄斑变性(AMD)、玻璃体炎，脉络膜炎、视网膜炎，视网膜血管炎，视神经炎，还有葡萄膜炎、白塞病、伏格特-小柳-原田综合征、葡萄膜炎、视网膜病变、交感性眼炎、白内障、结膜炎、青光眼等。
优选的，所述的模型是非人动物，优选猴、犬、黑猩猩、大鼠、小鼠。
优选的，所述的模型载体是细胞、组织或器官，所述的细胞、组织或器官来源于人或非人动物。
优选的，所述的细胞为原代细胞或细胞系。
优选的，所述的组织为眼部组织，所述的器官为眼部器官。
优选的，所述的组织或器官为再生组织或器官。
优选的，所述的模型存在基因的致病突变。
优选的，所述的发生了致病突变的基因为与维持视网膜屏障结构有关的基因，所述的视网膜屏障为外血-视网膜屏障和/或内血-视网膜屏障。
优选的，所述的模型或模型载体中存在致病的眼部疾病相关基因的突变，所述的发生了致病的眼部基因突变的基因选自以下一个或两个以上基因的组合：ABCA4、ABCC6、ABCC9、ACBD5、ACO2、ACO2、ACTG1、ADGRV1、AHI1、AIPL1、ALMS1、AMY2B、APC、ARFGEF1、ARL13B、ARL13B、ARL6、ARMC9、ATOH7、B9D1、BAG3、BBS1、BBS1、BBS2、BBS5、BEST1、C2CD3、CA4、CABP4、CACNA1F、CBS、CC2D2A、CDH23、CDH23、CDHR1、CEMIP2、CEP104、CEP250、CEP290、CEP290、CEP41、CEP78、CERKL、CFAP410、CFAP418、CHM、CLCC1、CLCN7、CLN3、CLN5、CLN8、CLRN1、CLRN1、CNGA1、CNGA1、CNGA3、CNGB1、CNGB3、CNNM4、COL11A1、COL11A2、COL18A1、COL2A1、COL4A1、COL9A1、COL9A2、CP、CP、CPLANE1、CRB1、ERCC4、CSPP1、CTNNA1、CYP4V2、DHDDS、DYNC2H1、DYNC2I1、DYNC2I2、ENPP1、ERCC4、EVC2、EYS、EYS、F5、FAM161A、FBN1、FKRP、FKTN、FLG、FLVCR1、FOXE3、FUZ、GLB 1、GMPPB、GNAT1、GRK1、GRM6、GUCA1A、GUCA1B、GUCY2D、HADHA、HGSNAT、HPS3、HPS5、IDH3B、IFT122、IFT140、IFT140、IFT43、IFT52、IFT74、IFT80、IFT80、IFT81、IFT88、IKBKG、IMPDH1、IMPG2、INPP5E、INTU、IQCB1、IQCE、IREB2、KCNJ13、KCNQ1、KCNV2、KIAA0586、KIAA0753、KIF7、KIZ、KIZ-AS1、KLHL7、KRIT1、LBR、LCA5、LOC101927157、 LOC111365204、LRP2、LRP5、MAK、MAPKAPK3、MATK、MCOLN1、MERTK、MKS1、MPDZ、MT-ATP6、MT-CO3、MT-TE、MT-TL1、MTHFR、MUTYH、MYO7A、MYO7A、NMNAT1、NPHP1、NR2E3、OCA2、OTX2、PANK2、PAX6、PCARE、PCDH15、PDE6A、PDE6B、PDE6B、PDE6D、PEX1、PEX1、PEX12、PEX26、PEX6、PHF3、PITPNM3、PKD2、PLA2G5、POC5、POMT1、PRCD、PRDM13、PROM1、PRPF3、PRPF31、PRPF8、PRPH2、RAD51C、RBP3、RBP4、RD3、RDH12、RDH5、RGR、RGR、RHO、RIMS1、RLBP1、ROM1、RP1、RP1L1、RP2、RPE65、RPE65、RPGR、RPGRIP1、RPGRIP1L、RS1、SACS、SAG、SCAPER、SDCCAG8、SIX6、SLC19A1、SLC22A5、SLC26A4、SLC2A9、SLTM、SNRNP200、SPAG17、SPATA7、SPG11、TFAP2A、TGFB2、TGFBR2、TMEM107、TMEM237、TMEM67、TOGARAM1、TOPORS、TPP1、TRAF3IP1、TREX1、TRIM59-IFT80、TSPAN12、TTC21B、TTC21B、TTC8、TULP1、USH1C、USH2A、USH2A、USH2A、USH2A、USH2A-AS1、VAC14、VCAN、VCAN、VCAN-AS1、VHL、VPS13B、WDR19、WDR19、WDR35、WDR73、YARS1、ZFYVE26、ZFYVE26、ZNF408。
在一个具体实施方式中，所述的模型或模型载体发生了致病突变的眼部疾病相关的基因中包含CRB1基因。
优选的，所述的模型或模型载体的CRB1基因的突变包含如下的一种或两种以上的突变：c.107C＞G、c.111delT、c.135C＞G、c.257_258dupTG、c.258C＞T、c.428_432delGATTC、c.430T＞G、c.470G＞C、c.481dupG、c.482C＞T、c.584G＞T、c.613_619del、c.717_718insG、c.750T＞G、c.915T＞A、c.929G＞A、c.936T＞G、c.998G＞A、c.1084C＞T、c.1125C＞G、c.1148G＞A、c.1208C＞G、c.1269C＞A、c.1298A＞G、c.1313G＞A、c.1438T＞C、c.1438T＞G、c.1576C＞T、c.1604T＞C、c.1690G＞T、c.1733T＞A、c.1750G＞T、c.1760G＞A、c.1834T＞C、c.1963delC、c.2025G＞T、c.2042G＞A、c.2128G＞C、c.2129C＞T、c.2185_2186insAlu、c.2219C＞T、c.2222T＞C、c.2234C＞T、c.2245_2247del 3bp(TCA)、c.2258T＞C、c.2290C＞T、c.2365_2367del AAT.inframe deletion、c.2401A＞T、c.2438_2439ins＞100A、c.2441_2442del、c.2465G＞A、c.2479G＞T、c.2506C＞A、c.2509G＞C、c.2536G＞A、c.2548_2551delGGCT、c.2548G＞A、c.2555T＞C、c.2611_2613insT、c.2671T＞G、c.2676delG、c.2681A＞G、c.2688T＞A、c.2816G＞A、c.2843G＞A、c.2853dupT、c.2884_2886delTTA、c.2957A＞T、c.2966T＞C、c.2983G＞T、c.3002A＞T、c.3008T＞C、c.3035T＞C、c.3037C＞T、c.3074G＞A、c.3074G＞T、c.3122T＞C、c.3212T＞C、c.3296C＞A、c.3299T＞C、c.3299T＞G、c.3307G＞A/C、c.3320T＞C、c.3320T＞G、c.3331G＞T、c.3343_3352del、c.3347delT、c.3343_3352del、c.3347delT、c.3427delT、c.3482A＞G、c.3493T＞C、c.3655T＞G、c.3541T＞C、c.3542dupG、c.3593A＞G、c.3613G＞A、c.3653G＞T、c.3659_3660delinsA、c.3664C＞T、c.3668G＞C、c.3676G＞T、c.3713_3716dup、c.3879G＞A、c.3914C＞T、c.3949A＞C、c.3961T＞A、c.3988delG、c.3988G＞T、c.3995G＞T、c.3996C＞A、c.3997G＞T、c.4094C＞A、c.4121_4130del、c.4142C＞T、c.4148G＞A、c.2128+2T＞G、c.2842+5G＞A、c.3878+1G＞T、c.4005+1G＞A、c.4005+2T＞G、c.4006-2A＞G、c.4006-1G＞T、c.619G＞A、c.614T＞C、c.1472A＞T、c.1903T＞C、c.2809G＞A、 c.3103C＞T、c.4082G＞A、c.4060G＞A、c.866C＞T、c.1463T＞C、c.2033C＞G、c.2306_230/GC＞AG、c.2306G＞A、c.2714G＞A、c.2875G＞A、c.3992G＞A。
进一步优选的，所述的模型或模型载体的CRB1基因的突变包含如下的一种或两种以上的突变：c.4006-1G＞T、c.3686G＞C、(p.Cys1229Ser)、c.2842+1delinsAA、c.4060G＞A、(p.Ala1354Thr)、c.3991C＞T、(p.Arg1331Cys)、c.3014A＞T、(p.Asp1005Val)、c.4005+1G＞A、c.2680_2684del、(p.Asn894fs)、c.1733T＞A、(p.Val578Glu)、c.455G＞A、(p.Cys152Tyr)、c.3462_3463del、(p.Cys1154_Glu1155delinsTer)、c.3037C＞T、(p.Gln1013Ter)、c.2673C＞A、(p.Cys891Ter)、c.2230C＞T、(p.Arg744Ter)、c.3676G＞T、(p.Gly1226Ter)、c.2842+5G＞A、c.2842T＞C、(p.Cys948Arg)、c.3988del、(p.Glu1330fs)、c.2506C＞A、(p.Pro836Thr)、c.2291G＞A、(p.Arg764His)、c.1576C＞T、(p.Arg526Ter)、c.613_619del、(p.Ile205fs)、c.3320T＞C、(p.Leu1107Pro)、c.2688T＞A、(p.Cys896Ter)、c.2555T＞C、(p.Ile852Thr)、c.2222T＞C、(p.Met741Thr)、c.1148G＞A、(p.Cys383Tyr)、c.2843G＞A、(p.Cys948Tyr)、c.4121_4130del、(p.Ala1374fs)、c.3307G＞A、(p.Gly1103Arg)、c.484G＞A、(p.Val162Met)、c.2401A＞T、(p.Lys801Ter)、c.2234C＞T、(p.Thr745Met)、c.2290C＞T、(p.Arg764Cys)、c.3122T＞C、(p.Met1041Thr)。
优选的，所述的模型或模型载体的CRB1基因的突变为Rd8突变。
优选的，所述的突变为纯和突变或杂合突变。
优选的，所述的模型或模型载体体内先天存在如前所述的基因的突变或者所述的突变是由于基因重组操作而后天携带的。
优选的，所述的模型或模型载体体内存在人源化CRB1基因或人CRB1基因，其内源CRB1基因缺失或不表达。
优选的，所述的非人动物具有结肠上皮屏障缺陷和/或相关的结肠壁炎症。
在一个具体实施例中，所述的模型体内Occludin蛋白的显著缺失，在一个具体实施例中，所述的模型体内Occludin蛋白显著缺失和Claudin1表达不明显。
所述微生物为细菌、古细菌、原生生物、真菌或病毒中的一种或两种以上的组合，优选的，所述微生物为细菌，所述细菌选自：Anearostipes、双歧杆菌(Bifidobacterium)、巨单胞菌(Megamonas)、亚硝基单胞菌(Nitrosomonas)，颤螺旋菌(Oscillibacter)、塔特姆菌(Tatumella)、硫杆菌(Thiobacillussp.)、梭菌属(Clostridium)、不动杆菌属(Acinetobacter)、链球菌属(Streptococcus)、曼氏杆菌属(Mannheimia)、纤维杆菌属(Fibrobacter)、普氏菌属(Prevotella)、弯曲杆菌属(Campylobacter)、放线菌属(Actinomyces)、薄层菌属(Hymenobacter)、埃希氏杆菌属(Escherichia)、泰氏菌属(Tissierella)、克雷白氏杆菌属(Klebsiella)、卟啉单胞菌属(Porphyromonas)、固氮螺菌属(Azospira)、海水菌属(Aquimarina)、无色菌属(Achromobacter)、嗜酸硫杆菌属(Acidithiobacillus)、伯克霍尔德菌属(Burkholderia)、海杆菌属(Marinobacter)、密螺旋体属(Treponema)、孢裹放线菌属(Actinosporangium)、 弧菌属(Vibrio)、瘤胃球菌属(Ruminococcus)、甲烷短杆菌(Methanobrevibacter)、志贺氏杆菌(Shigella)、弗兰克氏菌属(Frankia)、链霉菌属厌氧原体属(Anaeroplasma)、粪球菌属(Coprococcus)中的一种或两种以上。
具体的，所述细菌选自：Anearostipeshadrus、Bifidobacterium pseudocatenulatum、Nitrosomonas sp.Is79A3、Oscillibactervalericigenes、Tatumella sp.TA1、Megamonasfuniformis、Thiobacillus denitrificans、破伤风梭菌、产气荚膜梭菌、肉毒梭菌、醋酸钙不动杆菌、鲁菲不动杆菌、鲍曼不动杆菌、溶血不动杆菌、琼氏不动杆菌、约翰逊不动杆菌、化脓性链球菌、溶血性链球菌、产琥珀酸丝状杆菌、肠道丝状杆菌、非解糖卟啉单胞菌、牙髓卟啉单胞菌、牙龈卟啉单胞菌、空肠弯曲菌、结肠弯曲菌、海鸟弯曲菌、乌普萨拉弯曲菌、简明弯曲菌、胎儿弯曲菌、衣氏放线菌、奈氏放线菌、溶齿放线菌、粘稠放线菌、纽氏放线菌、大肠埃希菌、蟑螂埃希菌、弗格森埃希菌、赫尔曼埃希菌、伤口埃希菌、极尖泰氏菌、肺炎克雷伯氏菌、臭鼻克雷伯氏菌、巴西固氮螺菌、无色杆菌、脱氮硫杆菌、氧化亚铁硫杆菌、氧化硫硫杆菌、那不勒斯硫杆菌、伯克霍尔德菌、海洋分枝杆菌、苍白密螺旋体、猪痢疾密螺旋体、梅氏弧菌、白色瘤胃球菌、生黄瘤胃球菌、瘤胃甲烷短杆菌、痢疾志贺菌、福氏志贺菌、鲍氏志贺菌、宋内志贺菌、弗兰克氏菌、规则粪球菌、白色链霉菌、门多萨假单胞菌，栖息微球菌，脂环素反硝化菌，氧化木糖无色杆菌，鞘脂单胞杆菌，脓肿分枝杆菌，金黄节杆菌，普氏菌，草木樨中华根瘤菌，酸性酵母，表皮葡萄球菌，铜绿假单胞菌，金黄色葡萄球菌，溶血性葡萄球菌，恶臭假单胞菌，嗜麦芽寡养单胞菌，蜡状芽孢杆菌，巨大芽孢杆菌，罗氏乳酸杆菌，阴道嗜血杆菌，蜜蜂屎肠球菌，正哈氏嗜纤维菌，地衣芽孢杆菌，白叶枯菌，鲍曼不动杆菌，醋酸钙不动杆菌，睾丸酮丛毛单胞菌，堪萨斯分枝杆菌，斯润金芽孢杆菌，柯氏柠檬酸杆菌，发酵成对杆菌，粘质沙雷氏菌，维氏鞘氨醇单胞菌，肺炎克雷伯菌，荧光假单胞菌，皮氏罗尔斯顿菌，卷曲乳杆菌，伯克霍尔德菌，德氏乳杆菌，Meiothermussilvanus(D)，大肠杆菌，藤黄微球菌，枯草芽孢杆菌，粘金色棒状杆菌，大芬戈尔德菌中的一种或两种以上。
优选的，所述的感染方法包含是让微生物与模型载体待感染的部位直接接触或间接接触，所述的间接接触是指所述的微生物和待感染的部位之间存在血视网膜屏障，优选的，为外血-视网膜屏障或内血-视网膜屏障。
在一个具体实施方式中，所述的感染方法包含通过外周血使肠道细菌感染眼部。具体的，非人动物模型的肠上皮屏障收到显著损伤，致使肠道细菌进入外周血。在一个模型体内，视网膜屏障也收到了显著受损，使得进入外周血的肠道细菌感染视网膜；在一个具体实施方式中，所述的非人动物模型发生了CRB1基因的突变；在一个具体实施方式中，所述的CRB1基因的突变是Rd8突变。
进一步，本发明提供一种制备眼部炎症模型的方法，所述的方法模型为非人动物感染微生 物。
优选的，所述的眼部炎症是由肠道菌群或与肠道菌群相同的菌群引起的。
所述的非人动物为如前所述的动物。
所述的微生物为如前所述的微生物。
进一步，本发明提供一种制备视网膜变性疾病模型的方法，所述的方法包括使患有视网膜变性的非人动物感染微生物。
优选的，所述的眼部炎症视网膜变性疾病为如前所述的视网膜疾病。
所述的非人动物为如前所述的动物。
所述的微生物为如前所述的微生物。
进一步，本发明提供一种有眼部炎症的模型载体，所述的眼部炎症是由微生物感染引起的。
优选的，所述的微生物来自同一个体的肠道细菌或者与该个体的肠道细菌相同。
优选的，所述的眼部疾病包含视网膜变性；更优选的，所述的视网膜变性为进行性视网膜变性。
优选的，所述的视网膜变性为遗传性视网膜变性(IRD)。
优选的，所述的视网膜变性是模型动物自身的疾病或者是由于基因操作使模型动物患视网膜变性。
优选的，所述的眼部疾病包含LCA、RP、arRP、EORD、EORP、PPRPE、rettelangiectasia和/或choroideremia like fundus。
优选的，所述的眼部疾病包含眼部炎症，例如葡萄膜炎、青光眼、和年龄相关的黄斑变性(AMD)、玻璃体炎，脉络膜炎、视网膜炎，视网膜血管炎，视神经炎，还有葡萄膜炎、白塞病、伏格特-小柳-原田综合征、葡萄膜炎、视网膜病变、交感性眼炎、白内障、结膜炎、青光眼等。
优选的，所述的模型是非人动物，优选猴、犬、黑猩猩、大鼠、小鼠。
优选的，所述的模型载体是细胞、组织或器官，所述的细胞、组织或器官来源于人或非人动物。
优选的，所述的细胞为原代细胞或细胞系。
优选的，所述的组织为眼部组织，所述的器官为眼部器官。
优选的，所述的组织或器官为再生组织或器官。
优选的，所述的模型存在基因的致病突变。
优选的，所述的发生了致病突变的基因为与维持视网膜屏障结构有关的基因，所述的视网膜屏障为外血-视网膜屏障和/或内血-视网膜屏障。
优选的，所述的模型载体中有以下一个或两个以上基因发生了突变：ABCA4、ABCC6、 ABCC9、ACBD5、ACO2、ACO2、ACTG1、ADGRV1、AHI1、AIPL1、ALMS1、AMY2B、APC、ARFGEF1、ARL13B、ARL13B、ARL6、ARMC9、ATOH7、B9D1、BAG3、BBS1、BBS1、BBS2、BBS5、BEST1、C2CD3、CA4、CABP4、CACNA1F、CBS、CC2D2A、CDH23、CDH23、CDHR1、CEMIP2、CEP104、CEP250、CEP290、CEP290、CEP41、CEP78、CERKL、CFAP410、CFAP418、CHM、CLCC1、CLCN7、CLN3、CLN5、CLN8、CLRN1、CLRN1、CNGA1、CNGA1、CNGA3、CNGB1、CNGB3、CNNM4、COL11A1、COL11A2、COL18A1、COL2A1、COL4A1、COL9A1、COL9A2、CP、CP、CPLANE1、CRB1、ERCC4、CSPP1、CTNNA1、CYP4V2、DHDDS、DYNC2H1、DYNC2I1、DYNC2I2、ENPP1、ERCC4、EVC2、EYS、EYS、F5、FAM161A、FBN1、FKRP、FKTN、FLG、FLVCR1、FOXE3、FUZ、GLB1、GMPPB、GNAT1、GRK1、GRM6、GUCA1A、GUCA1B、GUCY2D、HADHA、HGSNAT、HPS3、HPS5、IDH3B、IFT122、IFT140、IFT140、IFT43、IFT52、IFT74、IFT80、IFT80、IFT81、IFT88、IKBKG、IMPDH1、IMPG2、INPP5E、INTU、IQCB1、IQCE、IREB2、KCNJ13、KCNQ1、KCNV2、KIAA0586、KIAA0753、KIF7、KIZ、KIZ-AS1、KLHL7、KRIT1、LBR、LCA5、LOC101927157、LOC111365204、LRP2、LRP5、MAK、MAPKAPK3、MATK、MCOLN1、MERTK、MKS1、MPDZ、MT-ATP6、MT-CO3、MT-TE、MT-TL1、MTHFR、MUTYH、MYO7A、MYO7A、NMNAT1、NPHP1、NR2E3、OCA2、OTX2、PANK2、PAX6、PCARE、PCDH15、PDE6A、PDE6B、PDE6B、PDE6D、PEX1、PEX1、PEX12、PEX26、PEX6、PHF3、PITPNM3、PKD2、PLA2G5、POC5、POMT1、PRCD、PRDM13、PROM1、PRPF3、PRPF31、PRPF8、PRPH2、RAD51C、RBP3、RBP4、RD3、RDH12、RDH5、RGR、RGR、RHO、RIMS1、RLBP1、ROM1、RP1、RP1L1、RP2、RPE65、RPE65、RPGR、RPGRIP1、RPGRIP1L、RS1、SACS、SAG、SCAPER、SDCCAG8、SIX6、SLC19A1、SLC22A5、SLC26A4、SLC2A9、SLTM、SNRNP200、SPAG17、SPATA7、SPG11、TFAP2A、TGFB2、TGFBR2、TMEM107、TMEM237、TMEM67、TOGARAM1、TOPORS、TPP1、TRAF3IP1、TREX1、TRIM59-IFT80、TSPAN12、TTC21B、TTC21B、TTC8、TULP1、USH1C、USH2A、USH2A、USH2A、USH2A、USH2A-AS1、VAC14、VCAN、VCAN、VCAN-AS1、VHL、VPS13B、WDR19、WDR19、WDR35、WDR73、YARS1、ZFYVE26、ZFYVE26、ZNF408的一种或两种以上的组合。
在一个具体实施方式中，所述的模型载体发生了致病突变的眼部疾病相关的基因中包含CRB1基因。
优选的，所述的模型载体的CRB1基因的突变包含如下的一种或两种以上的突变：c.107C＞G、c.111delT、c.135C＞G、c.257_258dupTG、c.258C＞T、c.428_432delGATTC、c.430T＞G、c.470G＞C、c.481dupG、c.482C＞T、c.584G＞T、c.613_619del、c.717_718insG、c.750T＞G、c.915T＞A、c.929G＞A、c.936T＞G、c.998G＞A、c.1084C＞T、c.1125C＞G、c.1148G＞A、c.1208C＞G、c.1269C＞A、c.1298A＞G、c.1313G＞A、c.1438T＞C、c.1438T＞G、c.1576C＞T、c.1604T＞C、c.1690G＞T、c.1733T＞A、c.1750G＞T、c.1760G＞A、c.1834T＞C、c.1963delC、c.2025G＞T、c.2042G＞A、c.2128G＞C、c.2129C＞T、c.2185_2186insAlu、c.2219C＞T、 c.2222T＞C、c.2234C＞T、c.2245_2247del 3bp(TCA)、c.2258T＞C、c.2290C＞T、c.2365_2367del AAT，in frame deletion、c.2401A＞T、c.2438_2439ins＞100A、c.2441_2442del、c.2465G＞A、c.2479G＞T、c.2506C＞A、c.2509G＞C、c.2536G＞A、c.2548_2551delGGCT、c.2548G＞A、c.2555T＞C、c.2611_2613insT、c.2671T＞G、c.2676delG、c.2681A＞G、c.2688T＞A、c.2816G＞A、c.2843G＞A、c.2853dupT、c.2884_2886delTTA、c.2957A＞T、c.2966T＞C、c.2983G＞T、c.3002A＞T、c.3008T＞C、c.3035T＞C、c.3037C＞T、c.3074G＞A、c.3074G＞T、c.3122T＞C、c.3212T＞C、c.3296C＞A、c.3299T＞C、c.3299T＞G、c.3307G＞A/C、c.3320T＞C、c.3320T＞G、c.3331G＞T、c.3343_3352del、c.3347delT、c.3343_3352del、c.3347delT、c.3427delT、c.3482A＞G、c.3493T＞C、c.3655T＞G、c.3541T＞C、c.3542dupG、c.3593A＞G、c.3613G＞A、c.3653G＞T、c.3659_3660delinsA、c.3664C＞T、c.3668G＞C、c.3676G＞T、c.3713_3716dup、c.3879G＞A、c.3914C＞T、c.3949A＞C、c.3961T＞A、c.3988delG、c.3988G＞T、c.3995G＞T、c.3996C＞A、c.3997G＞T、c.4094C＞A、c.4121_4130del、c.4142C＞T、c.4148G＞A、c.2128+2T＞G、c.2842+5G＞A、c.3878+1G＞T、c.4005+1G＞A、c.4005+2T＞G、c.4006-2A＞G、c.4006-1G＞T、c.619G＞A、c.614T＞C、c.1472A＞T、c.1903T＞C、c.2809G＞A、c.3103C＞T、c.4082G＞A、c.4060G＞A、c.866C＞T、c.1463T＞C、c.2035C＞G、c.2306_2307GC＞AG、c.2306G＞A、c.2714G＞A、c.2875G＞A、c.3992G＞A。
进一步优选的，所述的模型或模型载体的CRB1基因的突变包含如下的一种或两种以上的突变：c.4006-1G＞T、c.3686G＞C、(p.Cys1229Ser)、c.2842+1delinsAA、c.4060G＞A、(p.Ala1354Thr)、c.3991C＞T、(p.Arg1331Cys)、c.3014A＞T、(p.Asp1005Val)、c.4005+1G＞A、c.2680_2684del、(p.Asn894fs)、c.1733T＞A、(p.Val578Glu)、c.455G＞A、(p.Cys152Tyr)、c.3462_3463del、(p.Cys1154_Glu1155delinsTer)、c.3037C＞T、(p.Gln1013Ter)、c.2673C＞A、(p.Cys891Ter)、c.2230C＞T、(p.Arg744Ter)、c.3676G＞T、(p.Gly1226Ter)、c.2842+5G＞A、c.2842T＞C、(p.Cys948Arg)、c.3988del、(p.Glu1330fs)、c.2506C＞A、(p.Pro836Thr)、c.2291G＞A、(p.Arg764His)、c.1576C＞T、(p.Arg526Ter)、c.613_619del、(p.Ile205fs)、c.3320T＞C、(p.Leu1107Pro)、c.2688T＞A、(p.Cys896Ter)、c.2555T＞C、(p.Ile852Thr)、c.2222T＞C、(p.Met741Thr)、c.1148G＞A、(p.Cys383Tyr)、c.2843G＞A、(p.Cys948Tyr)、c.4121_4130del、(p.Ala1374fs)、c.3307G＞A、(p.Gly1103Arg)、c.484G＞A、(p.Val162Met)、c.2401A＞T、(p.Lys801Ter)、c.2234C＞T、(p.Thr745Met)、c.2290C＞T、(p.Arg764Cys)、c.3122T＞C、(p.Met1041Thr)。
优选的，所述的模型载体的CRB1基因的突变为Rd8突变。
优选的，所述的突变为纯和突变或杂合突变。
优选的，所述的模型载体体内先天存在如前所述的基因的突变或者所述的突变是由于基因重组操作而后天携带的。
优选的，所述的模型载体体内存在人源化CRB1基因或人CRB1基因，其内源CRB1基因缺失或不表达。
优选的，所述的非人动物具有结肠上皮屏障缺陷和/或相关的结肠壁炎症。
在一个具体实施例中，所述的模型体内Occludin蛋白的显著缺失，在一个具体实施例中，所述的模型体内Occludin蛋白显著缺失和Claudin1表达不明显。
所述微生物为细菌、古细菌、原生生物、真菌或病毒中的一种或两种以上的组合，优选的，所述微生物为细菌，所述细菌选自：Anearostipes、双歧杆菌(Bifidobacterium)、巨单胞菌(Megamonas)、亚硝基单胞菌(Nitrosomonas)，颤螺旋菌(Oscillibacter)、塔特姆菌(Tatumella)、硫杆菌(Thiobacillussp.)、梭菌属(Clostridium)、不动杆菌属(Acinetobacter)、链球菌属(Streptococcus)、曼氏杆菌属(Mannheimia)、纤维杆菌属(Fibrobacter)、普氏菌属(Prevotella)、弯曲杆菌属(Campylobacter)、放线菌属(Actinomyces)、薄层菌属(Hymenobacter)、埃希氏杆菌属(Escherichia)、泰氏菌属(Tissierella)、克雷白氏杆菌属(Klebsiella)、卟啉单胞菌属(Porphyromonas)、固氮螺菌属(Azospira)、海水菌属(Aquimarina)、无色菌属(Achromobacter)、嗜酸硫杆菌属(Acidithiobacillus)、伯克霍尔德菌属(Burkholderia)、海杆菌属(Marinobacter)、密螺旋体属(Treponema)、孢裹放线菌属(Actinosporangium)、弧菌属(Vibrio)、瘤胃球菌属(Ruminococcus)、甲烷短杆菌(Methanobrevibacter)、志贺氏杆菌(Shigella)、弗兰克氏菌属(Frankia)、链霉菌属厌氧原体属(Anaeroplasma)、粪球菌属(Coprococcus)中的一种或两种以上。
具体的，所述细菌选自：Anearostipeshadrus、Bifidobacterium pseudocatenulatum、Nitrosomonas sp.Is79A3、Oscillibactervalericigenes、Tatumella sp.TA1、Megamonasfuniformis、Thiobacillus denitrificans、破伤风梭菌、产气荚膜梭菌、肉毒梭菌、醋酸钙不动杆菌、鲁菲不动杆菌、鲍曼不动杆菌、溶血不动杆菌、琼氏不动杆菌、约翰逊不动杆菌、化脓性链球菌、溶血性链球菌、产琥珀酸丝状杆菌、肠道丝状杆菌、非解糖卟啉单胞菌、牙髓卟啉单胞菌、牙龈卟啉单胞菌、空肠弯曲菌、结肠弯曲菌、海鸟弯曲菌、乌普萨拉弯曲菌、简明弯曲菌、胎儿弯曲菌、衣氏放线菌、奈氏放线菌、溶齿放线菌、粘稠放线菌、纽氏放线菌、大肠埃希菌、蟑螂埃希菌、弗格森埃希菌、赫尔曼埃希菌、伤口埃希菌、极尖泰氏菌、肺炎克雷伯氏菌、臭鼻克雷伯氏菌、巴西固氮螺菌、无色杆菌、脱氮硫杆菌、氧化亚铁硫杆菌、氧化硫硫杆菌、那不勒斯硫杆菌、伯克霍尔德菌、海洋分枝杆菌、苍白密螺旋体、猪痢疾密螺旋体、梅氏弧菌、白色瘤胃球菌、生黄瘤胃球菌、瘤胃甲烷短杆菌、痢疾志贺菌、福氏志贺菌、鲍氏志贺菌、宋内志贺菌、弗兰克氏菌、规则粪球菌、白色链霉菌、门多萨假单胞菌，栖息微球菌，脂环素反硝化菌，氧化木糖无色杆菌，鞘脂单胞杆菌，脓肿分枝杆菌，金黄节杆菌，普氏菌，草木樨中华根瘤菌，酸性酵母，表皮葡萄球菌，铜绿假单胞菌，金黄色葡萄球菌，溶血性葡萄球菌，恶臭假单胞菌，嗜麦芽寡养单胞菌，蜡状芽孢杆菌，巨大芽孢杆菌，罗氏乳酸杆菌，阴道嗜血杆菌，蜜蜂屎肠球菌，正哈氏嗜纤维菌，地衣芽孢杆菌，白叶枯菌，鲍曼不动杆菌，醋酸钙不动杆菌，睾丸酮丛毛单胞菌，堪萨斯分枝杆菌，斯润金芽孢杆菌，柯氏柠檬酸杆菌，发酵成对杆菌，粘 质沙雷氏菌，维氏鞘氨醇单胞菌，肺炎克雷伯菌，荧光假单胞菌，皮氏罗尔斯顿菌，卷曲乳杆菌，伯克霍尔德菌，德氏乳杆菌，Meiothermussilvanus(D)，大肠杆菌，藤黄微球菌，枯草芽孢杆菌，粘金色棒状杆菌，大芬戈尔德菌中的一种或两种以上。
优选的，所述的感染方法包含是让微生物与模型载体待感染的部位直接接触或间接接触，所述的间接接触是指所述的微生物和待感染的部位之间存在血视网膜屏障，优选的，为外血-视网膜屏障或内血-视网膜屏障。
在一个具体实施方式中，所述的感染方法包含通过外周血使肠道细菌感染眼部。具体的，非人动物模型的肠上皮屏障收到显著损伤，致使肠道细菌进入外周血。在一个模型体内，视网膜屏障也收到了显著受损，使得进入外周血的肠道细菌感染视网膜；在一个具体实施方式中，所述的非人动物模型发生了CRB1基因的突变；在一个具体实施方式中，所述的CRB1基因的突变是Rd8突变。
所述有炎症的模型载体来自如前所述的方法制备得到的疾病模型，或，用微生物感染来自立体的来自如前所述的非人动物的眼部细胞、组织或器官得到的
本发明提供一种如前所述的方法在评估眼部疾病靶向治疗疗效中的应用，所述的眼部疾病包含如前所述的眼部疾病。
在一个具体实施方式中，对如前所述的模型或模型载体进行针对如前所述的基因突变的靶向治疗，将经过靶向治疗和未经过靶向治疗的模型或模型载体分为两组，分别按照如前所述的方法建立眼部疾病模型，如果相比之下，经过靶向治疗的组不能成功建模，说明靶向治疗取得了有益的效果。
在一个具体实施方式中，所述靶向治疗靶向如下一种基因或两种以上的基因的组合：ABCA4、ABCC6、ABCC9、ACBD5、ACO2、ACO2、ACTG1、ADGRV1、AHI1、AIPL1、ALMS1、AMY2B、APC、ARFGEF1、ARL13B、ARL13B、ARL6、ARMC9、ATOH7、B9D1、BAG3、BBS1、BBS1、BBS2、BBS5、BEST1、C2CD3、CA4、CABP4、CACNA1F、CBS、CC2D2A、CDH23、CDH23、CDHR1、CEMIP2、CEP104、CEP250、CEP290、CEP290、CEP41、CEP78、CERKL、CFAP410、CFAP418、CHM、CLCC1、CLCN7、CLN3、CLN5、CLN8、CLRN1、CLRN1、CNGA1、CNGA1、CNGA3、CNGB1、CNGB3、CNNM4、COL11A1、COL11A2、COL18A1、COL2A1、COL4A1、COL9A1、COL9A2、CP、CP、CPLANE1、CRB1、ERCC4、CSPP1、CTNNA1、CYP4V2、DHDDS、DYNC2H1、DYNC2I1、DYNC2I2、ENPP1、ERCC4、EVC2、EYS、EYS、F5、FAM161A、FBN1、FKRP、FKTN、FLG、FLVCR1、FOXE3、FUZ、GLB1、GMPPB、GNAT1、GRK1、GRM6、GUCA1A、GUCA1B、GUCY2D、HADHA、HGSNAT、HPS3、HPS5、IDH3B、IFT122、IFT140、IFT140、IFT43、IFT52、IFT74、IFT80、IFT80、IFT81、IFT88、IKBKG、IMPDH1、IMPG2、INPP5E、INTU、IQCB1、IQCE、IREB2、KCNJ13、KCNQ1、KCNV2、KIAA0586、KIAA0753、KIF7、KIZ、KIZ-AS1、KLHL7、KRIT1、LBR、LCA5、LOC101927157、 LOC111365204、LRP2、LRP5、MAK、MAPKAPK3、MATK、MCOLN1、MERTK、MKS1、MPDZ、MT-ATP6、MT-CO3、MT-TE、MT-TL1、MTHFR、MUTYH、MYO7A、MYO7A、NMNAT1、NPHP1、NR2E3、OCA2、OTX2、PANK2、PAX6、PCARE、PCDH15、PDE6A、PDE6B、PDE6B、PDE6D、PEX1、PEX1、PEX12、PEX26、PEX6、PHF3、PITPNM3、PKD2、PLA2G5、POC5、POMT1、PRCD、PRDM13、PROM1、PRPF3、PRPF31、PRPF8、PRPH2、RAD51C、RBP3、RBP4、RD3、RDH12、RDH5、RGR、RGR、RHO、RIMS1、RLBP1、ROM1、RP1、RP1L1、RP2、RPE65、RPE65、RPGR、RPGRIP1、RPGRIP1L、RS1、SACS、SAG、SCAPER、SDCCAG8、SIX6、SLC19A1、SLC22A5、SLC26A4、SLC2A9、SLTM、SNRNP200、SPAG17、SPATA7、SPG11、TFAP2A、TGFB2、TGFBR2、TMEM107、TMEM237、TMEM67、TOGARAM1、TOPORS、TPP1、TRAF3IP1、TREX1、TRIM59-IFT80、TSPAN12、TTC21B、TTC21B、TTC8、TULP1、USH1C、USH2A、USH2A、USH2A、USH2A、USH2A-AS1、VAC14、VCAN、VCAN、VCAN-AS1、VHL、VPS13B、WDR19、WDR19、WDR35、WDR73、YARS1、ZFYVE26、ZFYVE26、ZNF408。
在一个具体实施方式中，所述的靶向治疗靶向CRB1基因的如下突变的一种或两种以上：c.257_258dupTG、c.258C＞T、c.428_432delGATTC、c.430T＞G、c.470G＞C、c.481dupG、c.482C＞T、c.584G＞T、c.613_619del、c.717_718insG、c.750T＞G、c.915T＞A、c.929G＞A、c.936T＞G、c.998G＞A、c.1084C＞T、c.1125C＞G、c.1148G＞A、c.1208C＞G、c.1269C＞A、c.1298A＞G、c.1313G＞A、c.1438T＞C、c.1438T＞G、c.1576C＞T、c.1604T＞C、c.1690G＞T、c.1733T＞A、c.1750G＞T、c.1760G＞A、c.1834T＞C、c.1963delC、c.2025G＞T、c.2042G＞A、c.2128G＞C、c.2129C＞T、c.2185_2186insAlu、c.2219C＞T、c.2222T＞C、c.2234C＞T、c.2245_2247del 3bp(TCA)、c.2258T＞C、c.2290C＞T、c.2365_2367del AAT，in frame deletion、c.2401A＞T、c.2438_2439ins＞100A、c.2441_2442del、c.2465G＞A、c.2479G＞T、c.2506C＞A、c.2509G＞C、c.2536G＞A、c.2548_2551delGGCT、c.2548G＞A、c.2555T＞C、c.2611_2613insT、c.2671T＞G、c.2676delG、c.2681A＞G、c.2688T＞A、c.2816G＞A、c.2843G＞A、c.2853dupT、c.2884_2886delTTA、c.2957A＞T、c.2966T＞C、c.2983G＞T、c.3002A＞T、c.3008T＞C、c.3035T＞C、c.3037C＞T、c.3074G＞A、c.3074G＞T、c.3122T＞C、c.3212T＞C、c.3296C＞A、c.3299T＞C、c.3299T＞G、c.3307G＞A/C、c.3320T＞C、c.3320T＞G、c.3331G＞T、c.3343_3352del、c.3347delT、c.3343_3352del、c.3347delT、c.3427delT、c.3482A＞G、c.3493T＞C、c.3655T＞G、c.3541T＞C、c.3542dupG、c.3593A＞G、c.3613G＞A、c.3653G＞T、c.3659_3660delinsA、c.3664C＞T、c.3668G＞C、c.3676G＞T、c.3713_3716dup、c.3879G＞A、c.3914C＞T、c.3949A＞C、c.3961T＞A、c.3988delG、c.3988G＞T、c.3995G＞T、c.3996C＞A、c.3997G＞T、c.4094C＞A、c.4121_4130del、c.4142C＞T、c.4148G＞A、c.2128+2T＞G、c.2842+5G＞A、c.3878+1G＞T、c.4005+1G＞A、c.4005+2T＞G、c.4006-2A＞G、c.4006-1G＞T、c.619G＞A、c.614T＞C、c.1472A＞T、c.1903T＞C、c.2809G＞A、c.3103C＞T、c.4082G＞A、c.4060G＞A、c.866C＞T、c.1463T＞C、c.2035C＞G、c.2306_2307GC＞AG、c.2306G＞A、c.2714G＞A、c.2875G＞A、c.3992G＞A。
在一个具体实施方式中，所述的靶向治疗药物包含经过修饰的细胞、经过修饰的蛋白、靶向 如前所述的基因或靶向如前所述的突变位点的RNA，和/或靶向如前所述的基因或靶向如前所述的突变位点的DNA。
本发明提供一种如前所述的方法制备得到的疾病模型在眼部疾病相关的研究中的应用。所述的眼部疾病包含如前所述的眼部疾病。所述的研究包括与遗传性视网膜变性相关的疾病与肠道菌群的相互响应等。
在一个具体实施方式中，所述的疾病模型感染了一种肠道细菌，当其所携带的致病突变被细胞治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。在一个具体实施方式中，所述的疾病模型感染了一种肠道细菌，当其所携带的致病突变被RNA治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。在一个具体实施方式中，所述的疾病模型感染了两种以上的肠道细菌，当其所携带的致病突变被细胞治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。在一个具体实施方式中，所述的疾病模型感染了两种肠道细菌，当其所携带的致病突变被RNA治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。
优选的，所述的致病突变发生与如前所述的基因，或，所述的致病突变为如前所述的CRB基因的突变。
本发明提供一种如前所述的方法制备得到的疾病模型载体在眼部疾病相关的研究中的应用。所述的眼部疾病包含如前所述的眼部疾病。所述的研究包括与遗传性视网膜变性相关的疾病与肠道菌群的协同作用等。
在一个具体实施方式中，所述的疾病模型载体感染了一种肠道细菌，当其所携带的致病突变被细胞治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。在一个具体实施方式中，所述的疾病模型载体感染了一种肠道细菌，当其所携带的致病突变被RNA治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。在一个具体实施方式中，所述的疾病模型载体感染了两种以上的肠道细菌，当其所携带的致病突变被细胞治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。在一个具体实施方式中，所述的疾病模型载体感染了两种肠道细菌，当其所携带的致病突变被RNA治疗的情况下，观察给药和不给药的疗效，所述的药物为小分子药物，优选为广谱抗生素或针对所感染的细菌的抗生素。
优选的，所述的致病突变发生与如前所述的基因，或，所述的致病突变为如前所述的CRB基因的突变。
本发明提供一种如前所述的疾病模型或疾病模型载体在眼部疾病相关药物筛选中的应用。所述的药物包含小分子药物，化学药物，高分子药物，生物药物或天然药物(例如中药或中药提取物)、细胞药物、RNA药物、DNA药物的一种或两种以上的组合。
所述的眼部疾病包含如前所述的眼部疾病。
优选的，小分子化合物为抗生素，所述的抗生素为一般为本领域技术人员所熟知的广谱抗生素药物。
优选的，所述的小分子化合物为对特定的细菌具有针对性的非广谱性的抗生素。
优选的，所述的细胞包含经过修饰的免疫细胞，例如T细胞、B细胞或者干细胞的一种或两组以上的组合。
优选的，所述的RNA包含mRNA、siRNA、sgRNA、miRNA、ASO和/或复制子RNA。
在一个具体实施方式中，对所述的疾病模型或疾病模型载体进行靶向治疗，同时对经过靶向治疗的疾病模型或疾病模型载体和未经过靶向治疗的疾病模型或疾病模型载体施与如前所述的药物或不给药，观察几组的炎症进展，评估靶向治疗的药物疗效。
在一个具体实施方式中，对所述的疾病模型或疾病模型载体进行靶向治疗，同时对经过靶向治疗的疾病模型或疾病模型载体和未经过靶向治疗的疾病模型或疾病模型载体施与如前所述的药物或不给药，观察几组的炎症进展，评估小分子药物的疗效。
附图说明
图1：Crb1 rd8/rd8(rd8)-SPF小鼠的基因型和表型。其中，图1A为Crb1 rd8/rd8(rd8)和Crb1 wt/wt(C57BL/J，简称wt)小鼠的基因型凝胶电泳图，图1B为Rd8-SPF和WT-SPF小鼠的代表性眼底图像，Rd8-SPF小鼠视网膜下鼻象限出现典型的白色斑点，图1C为检测Rd8-SPF小鼠E18时双眼病理变化的H&E染色。
图2：Rd8-SPF小鼠发生视网膜异常及视网膜病变的潜在机制。其中图2A为H&E染色检测Rd8-SPF和WT-SPF小鼠在E18、P12(睁眼前)、P15(睁眼后)和8周(8W)的双眼病理变化，Rd8小鼠表现出典型的视网膜异常，包括进行性视网膜发育不良(皱褶和假花环)和变性，而WT小鼠表现出正常的视网膜结构；图2B为Rd8-和WT-SPF小鼠在E18、P12、P15和8W时眼睛有或无损伤的统计数据，从P12、P15和8W的Rd8小鼠的所有视网膜中都可以看到典型的病变，但WT-SPF小鼠中没有任何一个，WT-SPF：在E18、P12、P15和8W时，每组n＝6；Rd8-SPF：E18处n＝32，P12处n＝6，P15处n＝8；图2C为Rd8小鼠视网膜上(无病变)区和下(有病变)区DEGs火山图分析。S1amf1(信号淋巴细胞活化分子家族成员1)和Ncf4(中性粒细胞胞浆因子)是Rd8-SPF小鼠视网膜病变中增殖倍数最高的两个基因；图2D为DEGs的IPA功能分析；图2E为免疫荧光染色显示Rd8小鼠视网膜病变区有丰富的IBA1+小胶质细胞(红色)。
图3：RNA序列分析比较Rd8-SPF小鼠视网膜上、下区基因表达谱。其中，图3A为Rd8-SPF小鼠上(无病变)和下(有病变)区域的图示；图3B为RNA-seq分析发现Rd8-SPF小鼠视网膜上、下区存在至少2倍的表达差异(P＜0.05)；图3C为Rd8-和WT-SPF小鼠视网膜上下区179DEGs的表达模式。
图4：Rd8-SPF小鼠视网膜病变内细菌的鉴定。其中，图4A为主坐标分析(PCoA)，显示Rd8小鼠视网膜组织中细菌组成与WT小鼠有显著差异；图4B通过宏基因组测序鉴定Rd8小鼠视网膜上(S)和下(I)组织的微生物种类组成(n＝4)；图4C为荧光原位杂交法检测Rd8-和WT-SPF小鼠(4周龄)视网膜细菌16srDNA和vanco-bodipy；图4D用透射电镜(TEM)观察Rd8小鼠视网膜病变内细菌的分布，阳性对照为大肠菌群；
图5：Rd8-SPF小鼠视网膜粘附连接的破坏。其中，图5A为Rd8-和WT-SPF小鼠视网膜CRB1(红色)的免疫荧光染色，BM为Bruch膜，CC为绒毛膜毛细血管，BL为基膜；图5B为Rd8-和WT-SPF小鼠视网膜外界膜粘附连接的透射电镜观察，红色箭头为粘附连接，AJ指粘附连接，OLM为外界膜，ONL为外核层，IS指内段；图5C为透射电镜观察Rd8-SPF小鼠视网膜色素上皮(RPE)基底层粘连溶解、绒毛膜毛细血管基底层扭曲、胶原层紊乱，CC为绒毛膜毛细血管，CH为脉络膜，BL为基膜；图5D为Rd8-和WT-SPF小鼠Bruch膜厚度的统计分析****P＜0.0001。
图6A：为透射电镜(TEM)显示Rd8-SPF小鼠外界膜(OLM)粘附连接断裂(AJ)和外核层(ONL)。
图6B：透射电镜(TEM)显示的Rd8-SPF小鼠和WT-SPF小鼠Brunch膜的厚度。
图7：Rd8-SPF小鼠结肠上皮屏障缺陷及其相关炎症。其中，图7A为Rd8和WT小鼠胃肠道不同部位Rd8视网膜中细菌的相对丰度(n＝5)；图7B-D为Rd8-和WT-SPF小鼠结肠肠细胞CRB1蛋白(B)、鬼笔环化蛋白(C)和闭塞蛋白(D)的免疫荧光染色；图7E为Rd8-和WT-SPF小鼠咬合蛋白相对强度的统计分析；图7F为westernblot检测Rd8-和WT-SPF小鼠结肠肠上皮细胞Claudin1的表达；图7G为Rd8-和WT-SPF小鼠Claudin1相对强度的统计分析；图7H为透射电镜观察Rd8-和WT-SPF小鼠结肠上皮间的贴壁连接和紧密连接；图7I-L为Rd8-和WT-SPF小鼠上皮微绒毛数(I)、微绒毛长度(J)、微绒毛宽度(K)和完整粘附连接总数(L)的统计分析；图7M-N为比较Rd8-和WT-SPF小鼠Tnfa、Il1b、Il12a、(M)和Mucin2(N)的mRNA表达水平。
图8：Rd8-SPF小鼠胃肠道不同部位菌群的微生物种类组成。其中，图8A-F为基于Bray-Curtis距离的WT(n＝5)和Rd8(n＝5)小鼠胃肠道样品微生物种类组成的主坐标分析(PCoA)，包括胃(图8A)、空肠(图8B)、回肠(图8C)、盲肠(图8D)、结肠(图8E)和直肠(图8F)；图8G为PCoA区分Rd8小鼠和WT-SPF小鼠下消化道(盲肠、结肠 和直肠)的微生物组成(H-J)比较Rd8和WT小鼠盲肠(H)、结肠(I)和直肠(J)中粘液阿克曼菌的相对丰度。数据表示为平均值±SEM*P＜0.05。
图9：Rd8小鼠盲肠的紧密连接和粘附连接。其中，图9A为Rd8-和WT-SPF小鼠盲肠肠细胞CRB1蛋白(绿色)的免疫荧光染色；图9B为Rd8-和WT-SPF小鼠盲肠肠细胞闭塞素(红色)的免疫荧光染色；图9C为Rd8-和WT-SPF小鼠咬合蛋白相对强度的统计分析*P＜0.05；图9D为westernblot检测Rd8-和WT-SPF小鼠盲肠Claudin1的表达；图9E为Rd8-和WT-SPF小鼠Claudin1相对强度的统计分析，NS代表不重要；图9F为透射电镜检查显示盲肠上皮屏障处有正常的紧密连接和粘着连接，MV为微泡，MC为线粒体。
图10：图10A为透射电镜观察Rd8-和WT-SPF小鼠结肠上皮与紧密连接(TJ)间的粘附连接(AJ)，MV为微泡，MC为线粒体；图10B为流式细胞仪检测Rd8和WT小鼠外周血中荧光+细菌/细胞的频率。
图11：Rd8-SPF小鼠肠上皮屏障功能破坏。其中，图11A为肠道FICT-葡聚糖通透性测定显示Rd8小鼠血清荧光强度明显高于WT小鼠***P＜0.001；图11B为用vanco-bodipy标记粪便微生物群移植法比较Rd8和WT小鼠外周血中荧光+细菌/细胞的百分比*P＜0.05；图11C-D为在荧光显微镜下(C)和免疫荧光染色(D)均能在Rd8小鼠视网膜病变中检测到vanco-bodipy+细菌；图11F-G为比较DSS治疗13d后Rd8和WT小鼠的结肠长度、血清细菌16srrna(F)和细菌LPS(G)水平****P＜0.0001；图11H为每天监测用2.5％DSS处理的Rd8(n＝20)和WT(n＝19)小鼠的体重；图11I为Rd8(n＝20)和WT(n＝19)小鼠经2.5％DSS处理后的Kaplan-Meier生存曲线。
图12：Rd8GF和Rd8GF SPF小鼠的视网膜表型。其中，图12A为Rd8-SPF和Rd8GF小鼠在4周、8周、12周和16周时的代表性眼底图像；图12B为Rd8-GF小鼠E18、P12、P15、8W双眼视网膜组织学观察；图12C为Rd8-GF小鼠视网膜细菌16srDNA和vanco-bodipy的荧光原位杂交染色；图12D为Rd8-SPF、Rd8GF和WT-SPF小鼠视网膜中IBA1(红色)的免疫荧光染色；图12E为Rd8-SPF、Rd8GF和WT-SPF小鼠ONL中IBA1+小胶质细胞的百分比***P＜0.001；NS代表不重要；图12F为Rd8-SPF、Rd8-GF和WT-SPF小鼠视网膜ZO-1(红色)和Phalloidin(绿色)蛋白的免疫荧光染色；图12G为H&E染色检测出生后SPF环境中饲养的Rd8-GF小鼠(Rd8-GF-SPF小鼠)P15和8W视网膜病变。
图13没食子酸辛酯(化合物6)灌胃治疗Crb1 rd8/rd8小鼠眼底退行性视网膜病变实验中灌胃给药2周和4周后眼底浅色斑点计数变化
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述。在如下提供的实施例中，仅采用了将Crb1基因突变的小鼠饲养于SPF环境下的建模方法，通过验证其视网膜局部炎症反 应的存在和细菌在病变部位的存在，确定所述的模型视网膜感染了细菌。进一步通过接下来的实验，验证所述的细菌来自肠道。这个具体实施例并不排除其他的建模方法，比如饲养于微生物条件更复杂的环境里，或者向眼部组织施与来自肠道的微生物或与肠道微生物相同的微生物，让眼部组织直接或间接与如前所述的微生物接触等。
显然，所描述的实施例仅是本发明的部分实施例，而不是全部。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
1.老鼠
携带Rd8突变的C57BL/6N小鼠(Crb1 rd8/Rd8，命名为Rd8小鼠)和C57BL/6J小鼠(Crb1 wt/wt，命名为wt小鼠)购自北京维通利华实验动物技术有限公司，并在中山眼科中心动物设施的无特定病原体(SPF)条件下进行维护。孙中山大学附属第一附属医院的动物设施，用雌性RD8小鼠的胚胎产生无菌(GF)RD8小鼠。GF小鼠保持无菌状态，设施工作人员每周对粪便样本进行微生物和寄生虫检测，以确保GF单元的无菌性。如前所述进行小鼠基因分型(Mattapallil等人，2012)。两个小鼠品系的Crb1基因型得到证实(图4A)。所有动物实验均经中山眼科中心机构动物护理和使用委员会批准，并遵守《ARVO眼科和视力研究动物使用声明》。
2.方法
2.1组化
小鼠颈椎脱位处死，眼球摘除，用4％多聚甲醛(PFA)在4℃磷酸盐缓冲液(PBS)中固定24h。样品用PBS洗涤3次，在一系列醇中脱水，在二甲苯中脱水2次，然后包埋在石蜡中，并用切片机在10μm处连续切片(RM 223；Leica，Wetzlar，Hesse-Darmstadt，Germany)。切片用苏木精和伊红(H&E)染色。H&E图像由Imager.Z2(蔡司)获得。
取眼，室温下放置于4％PFA中5min，然后解剖并固定眼罩45min，取结肠组织，室温下固定于4％PFA中4h，PBS冲洗后，用30％蔗糖渗透分离的眼罩和结肠过夜进行冷冻保护，嵌入OCT化合物(Cat.4583；SAKURA，USA)，并储存在-80℃切片前。在12μm处切割切片用于所有免疫染色目的。
用10％驴血清/PBST(0.1％tritonx-100/PBS)阻断组织切片30分钟，然后在4℃下与一级抗体孵育过夜。在用PBST洗涤后，用荧光染料结合的二级抗体孵育切片，并用Fluoromount-G(Southern Biotech，Birmingham，AL，USA)固定。采用相同的免疫组织化学方法进行Phalloidin(A12379；Thermo-Fisher)染色，除了遗漏二级抗体。用蔡司共聚焦显微镜(蔡司LSM880；蔡司，Oberkochen，德国)和Imager.Z2配备ApoTome(蔡司)。本研究中使用的主要抗体是：抗Crb1(PA5-66373，ThermoFisher；1∶50)，抗Iba1(ab178846，Abcam；1∶500)，抗-ZO-1(61-7300，ThermoFisher；1∶500)，抗Occludin(OC-3F10，Invitrogen；1∶200)， AlexaFluor 488 phalloidin(A12379，ThermoFisher；1∶500).
2.2眼底摄影
小鼠被麻醉，瞳孔扩大。定期应用羟丙甲纤维素滴眼液保持角膜湿润。使用Micron IV小鼠眼底照相机(Phoenix Research Laboratories，Inc.，Pleasanton，CA，USA)获得小鼠眼底照片。
2.3视网膜上下部RNA-seq分析
用MasterPure TM全DNA和RNA纯化试剂盒(epicentre)从视网膜上下提取总RNA。用Qbit-RNA-HS分析试剂盒测定RNA浓度。测序文库是按照制造商提供的标准协议，使用VAHTS TM Total RNA seq(H/M/R)库准备试剂盒(Vazyme，中国)制备，并在MGISEQ 2000RS平台上测序。
原始读数首先由FastQC(v0.11.8)和cutadapt(v1.15)进行质量控制评估。使用HISAT2(v2.1.0)将干净的读数与小鼠基因组(mm10)对齐。将基因表达数据导入R软件(v3.6.1)的DESeq2包进行差异表达分析。将差异表达基因(DEGs)导入智能通路分析(IPA)进行功能富集分析。
2.4宏基因组测序
收集视网膜样本，并使用MasterPure TM完整DNA和RNA纯化试剂盒(epicentre)提取DNA。收集胃、空肠、回肠、盲肠、结肠和直肠的内容物，并使用QIAampPowerFecal DNA试剂盒(QIAGEN)提取DNA。浓度测量后，按照制造商提供的标准方案，使用VAHTS TM MGI通用DNA文库制备试剂盒(Vazyme，中国)对DNA进行测序文库制备。用MGISEQ-2000RS进行宏基因组测序。原始读数通过Trimmomatic(v0.36)和PRINSEQ(v0.20.4)进行质量过滤。使用KneadData删除鼠标读取(v0.6.1)(https：//bitbucket.org/biobakery/kneaddata).使用Kraken 2(v2.0.9)将非鼠标清除读取映射到预构建的MiniKraken数据库。分类结果用0.20的置信度进行筛选。阴性空白对照与样品一起处理。阴性空白对照组中存在的所有物种均被去除。
2.5 FITC-葡聚糖体内肠道通透性测定
用FITC标记的葡聚糖法进行体内通透性测定以评价屏障功能。隔夜取出食物和水，8周大的小鼠每100克(体重)口服50毫克FITC标记的葡聚糖(FD-70；Sigma-Aldrich)。给药后5h采集血清，测定每个样品的荧光强度(激发，492nm；发射，525nm)。
2.6流式细胞术
WT和Rd8小鼠禁食过夜，并灌胃给予1 x 109E。大肠杆菌(设计为一致表达RFP)。灌胃给药6小时后，对小鼠实施安乐死，将400μL外周血轻轻移液到含有4mL ACK溶解缓冲液(Gibco，美国)的试管中，并在RT下培养3-5分钟。在300x g离心5分钟后，将细胞固定并渗透(Cytofix/perm溶液，BD Biosciences，USA)，然后通过流式细胞仪 (MACSQuantAnalyzer 10，MiltenyiBiotec，Germany)分析。
2.7电子显微镜组织制备
安乐死后立即收集结肠和眼睛，并在室温下在磷酸盐缓冲的戊二醛-多聚甲醛溶液中固定1h。结肠被切成2毫米的块。眼前段切除，后段切割成2mm×2mm块。解剖后的组织在新鲜固定液中放置12h，用1％四氧化锇固定，脱水后包埋于epon-resin中。在光学显微镜下用甲苯胺蓝染色，在微米厚的切片上预先筛选感兴趣的区域。然后收集80nm的超声图像，用醋酸铀和柠檬酸铅复染。用透射电子显微镜观察超声切片。
2.8荧光原位杂交(FISH)
本研究使用了以下寡核苷酸探针：EUB338，5′-GCTGCCTCCGTAG-GAGT-3′(Amann等人，1990)。探针的5′端带有一个伯氨基，四甲基罗丹明异硫氰酸酯与该氨基共价结合。将染料寡核苷酸结合物(100μM)储存在-20℃下。
预固定的视网膜切片用DEPC处理的PBS冲洗3次。在用0.2％Triton X-100/DEPC处理的PBS处理后，在37℃下将切片与探针(500nM)杂交过夜，并用Fluoromount-G安装。
2.9实时定量PCR检测结肠组织中基因表达水平
新鲜的小鼠结肠组织(～1cm)在液氮中快速冷冻，研磨并用RNA提取裂解缓冲液裂解。然后使用Qiagen RNeasy Plus试剂盒纯化总RNA，并使用Takara PrimeScript RT试剂盒和gDNA擦除器将其反向转录为cDNA。qPCR检测相应基因的表达水平。数据标准化为β-肌动蛋白。
2.10 QPCR定量测定血浆中16srrna基因水平
经2.5％DSS处理13天后，从WT和Rd8小鼠全血中分离血浆。大约50μL血浆用于使用MasterPure分离总核酸 TM完整的DNA和RNA纯化试剂盒(epicentre，美国)。将沉淀的核酸溶解在20μL无核酸酶的水中。qPCR分析(ChamQ-SYBR-Color-qPCR-Master-Mix，Vazyme，中国)使用LightCycler 96系统(美国罗氏)进行。由于所有样品中的DNA浓度都极低，因此使用等体积的每个样品作为模板(20μL中的4μL)。使用以下通用16S rRNA基因引物测量细菌总负荷：27F 5’-AGAGTTTGATCCTGGCTCAG-3’，534R 5’-GCATTACCGCGGCTGCTGG-3’.
2.11酶联免疫吸附试验(ELISA)
每一个样品直接用100μL血浆进行测量。用酶联免疫吸附试剂盒(SEB526Ge；Cloud-Clone Corp.，USA)测定血浆LPS浓度。
2.12荧光团vanco-bodipy标记肠道细菌在Rd8小鼠体内的定殖
新鲜粪便样本收集在带有无菌1xPBS的50ml锥形管中，并旋转直至均质。内容物用0.22μm过滤器(Millipore)过滤以去除粪便残留物，并离心以获得肠道微生物群，然后在 RT下与vanco-bodipy孵育30分钟。用vanco-bodipy标记的肠道细菌在PBS中以1x10 8cfu/小鼠灌胃。灌胃24小时后，取小鼠视网膜切片观察。
2.13右旋糖酐硫酸钠(DSS)诱导结肠炎的实验研究
通过饮用水长期口服2.5％DSS(MW 36000-50000d，Yeasen，China)诱导小鼠肠道炎症。第0天至第13天每天监测体重，第13天处死小鼠，测量结肠长度。为了生存分析，小鼠被允许在其饮用水中随意饮用2.5％DSS 43天，并且在43天期间每24小时监测小鼠的死亡率状态。
2.14肠道共生体耗竭
氨苄西林的广谱抗生素混合物(A；1克/升；Sigma)，甲硝唑(M；1克/升；新霉素(N；1克/升；Sigma)和万古霉素(V；500毫克/升；在饮用水中给怀孕的母鼠喂食Sigma(AMNV)，断奶后继续给幼崽喂食。对照组小鼠被安置在同一机架上的常规装置中。
3.实施例
实施例1建模
观察Crb1rd8/rd8(rd8)和Crb1wt/wt(C57BL/J，命名为wt)小鼠的视网膜微环境特征(图1A)。在无特定病原体(Rd8-SPF)环境中饲养的Rd8小鼠，观察其表型，发现其呈现所有典型的视网膜表现，包括眼底镜检查下眼下鼻象限的白斑(图1B)，以及进行性视网膜发育不良(皱褶和假花环)和视网膜组织学变性(H&E染色)(图2A)。结果显示32只Rd8小鼠中有7只在出生前出现轻微的视网膜发育不良(E18)(图2A和图2B)。此外，E18处的所有异常都是单侧发生的(图2A和图1C)，而在P12(睁眼前)、P15(睁眼后)和8周龄(8W)Rd8小鼠的所有视网膜中都可以看到视网膜皱褶和假花环等典型病变，但在WT-SPF小鼠中没有任何一只(图2A和图2B)。数据表明Rd8小鼠的视网膜异常早在胚胎E18时就发生了，眼内环境在Crb1突变的遗传影响下能够驱动视网膜表型。
实施例2检测建模后的小鼠(Rd8-SPF)视网膜是否存在病变内病原体及其相关的局部免疫反应
使用RNA-seq技术进行转录组学分析，比较Rd8-SPF小鼠上(无病变)和下(有病变)区域的基因表达谱(图3A)。在去除WT-SPF小鼠视网膜上下区域之间具有差异表达模式(2倍变化和P＜0.05)的基因后，显示在Rd8-SPF小鼠中发现179个基因(DEG)在视网膜上下区域之间具有至少2倍的表达差异(P＜0.05)(图3B和图2C)。在Rd8-SPF小鼠中，这些179个DEG中的大多数在损伤的下半区高度表达(图3C)。使用Ingenuity Pathway analysis(IPA)工具对这些DEG进行的功能分析显示，参与细菌和病毒识别的基因在Rd8-SPF小鼠视网膜病变中高度表达的所有DEG中显著富集(图2D)。重要的是，病变增加倍数最多的前两个基因Ncf4和Slamf1都是吞噬细胞抗菌反应的调节因子。数据表明，Rd8视网膜中存在病变内病原体及其相关的局部免疫反应，这些结果与具有促炎功能的基因的丰富表达(图2D) 和IBA1+小胶质细胞向视网膜病变区域的浸润(图2E)相结合。
实施例3检测建模后的小鼠视网膜病变部位是否存在细菌
对WT-SPF(n＝5，年龄＝4周)和Rd8-SPF(n＝4，年龄＝4周)小鼠的视网膜组织进行宏基因组分析。分析发现，WT和Rd8小鼠的视网膜中细菌DNA含量极低，在所有质量控制和去污步骤后，均未检测到病毒或真菌DNA。然而，如图4A所示，主坐标分析(PCoA)表明WT-SPF和Rd8-SPF视网膜的细菌组成存在明显差异。重要的是，对Rd8-SPF(n＝4，年龄＝4周)小鼠视网膜上下区域进行的进一步宏基因组分析显示，在视网膜下区域有7种细菌显著富集，包括无角绦虫hadrus、假链球菌Bifidobacterium pseudocatenulatum、漏斗状巨单胞菌Megamonasfuniformis、亚硝基单胞菌Is79A3，产缬草Oscillibacter、Tatumella sp.TA1和脱氮硫杆菌(图4B)。为了直接观察视网膜病变中是否存在细菌，对Rd8-SPF小鼠(4周龄)进行荧光原位杂交(FISH)和vanco-bodipy染色分析，特别是对革兰氏阳性细菌的细胞壁进行染色。如图4C所示，细菌只能在病变部位发现，而不能在正常视网膜区域发现。使用透射电子显微镜(TEM)进一步证实了病变内细菌的存在(图4D)。数据表明，细菌可以在Rd8-SPF小鼠的视网膜病变中发现。
实施例5证明Rd8-SPF小鼠视网膜的主要缺陷是外血-视网膜屏障
免疫荧光染色数据证实了Rd8视网膜外界膜CRB1蛋白表达减少或缺失(图5A)。数据证实在Bruch膜上可以发现CRB1蛋白的弱表达(图5A)。利用透射电镜，发现在Rd8-SPF小鼠的视网膜病变部位，外界膜上的粘附连接被破坏，这与外核层的向外迁移有关(图5B和图6A)。透射电镜检查还显示Rd8-SPF视网膜中视网膜色素上皮(RPE)基膜处的溶解粘附连接和扭曲的绒毛膜毛细血管基膜，以及它们之间的胶原层的紊乱，这两种情况在任何WT-SPF小鼠中均未发现(图5C和图6B)。这与Rd8-SPF小鼠的Bruch膜破裂和Bruch膜厚度显著减少有关(图5C、图6B和图5D)。另一方面，透射电镜检查没有发现视网膜毛细血管内皮细胞和视网膜色素上皮细胞之间紧密连接的任何变化。因此，结果提示Rd8-SPF小鼠视网膜的主要缺陷是外血-视网膜屏障，而不是内血-视网膜屏障。
实施例6对肠道不通部位的微生物群进行宏基因组分析
在Rd8视网膜中发现的所有七种细菌(图4B)以前都是胃肠道(GI)细菌。因此，对WT-SPF(n＝5)和Rd8-SPF(n＝5)小鼠胃肠道不同部位(包括胃、空肠、回肠、盲肠、结肠和直肠)的微生物群进行宏基因组分析(图8A-F)。Rd8-SPF小鼠下消化道中的微生物成分与WT-SPF小鼠中的微生物成分明显不同(图8G)。在盲肠(图8H)、结肠(图8I)和直肠(图8J)的WT和Rd8肠道菌群中，Akkermansiamucinphila被确定为最不同的细菌种类，尽管在Rd8视网膜中没有追踪到(图4B)。实际上，Rd8视网膜中的7种细菌都在WT和Rd8小鼠的下消化道中发现，盲肠中的细菌最多(图7A)。然而，在Rd8小鼠的上消化道中几乎 检测不到它们。这些数据表明，这些视网膜细菌存在于Rd8-SPF而不是在WT-SPF小鼠的胃肠道菌群。
通过免疫荧光染色鉴定了野生型小鼠盲肠肠细胞中CRB1蛋白的表达，而在Rd8小鼠中其表达明显减弱(图9A)。此外，观察到Rd8小鼠盲肠中Occludin(图9B-C)表达显著缺失，而Claudin1(图9D-E)表达不明显。进一步的透射电镜检查显示盲肠上皮屏障处有正常的紧密连接和粘附连接(图9F)。
实施例7检查Rd8小鼠结肠是否存在屏障缺陷
与盲肠的结果相似，发现CRB1蛋白在结肠肠上皮细胞的顶面和底面有明显的表达(图7B)。CRB1蛋白的丢失与Phalloidin(图7C)和Occludin(图7D和图4E)的表达显著减少相关，但与Claudin1(图7F和图4G)蛋白的表达无关。重要的是，利用透射电镜，观察到大多数细胞中结肠上皮间的粘附连接无法定位，而Rd8小鼠中的紧密连接似乎正常(图7H和图S6A)。在Rd8小鼠结肠上皮中，除连接改变外，还观察到线粒体空泡化。尽管上皮微绒毛的数量没有变化(图7I)，但Rd8小鼠的微绒毛变得更长(图7J)和更细(图7K)，与WT小鼠相比，完整粘附连接的总数显著减少(图7L)。连接和微绒毛的超微结构改变也伴随着结肠壁中I112a表达的显著升高(图7M)，而Tnfa、Il1b和黏蛋白2的表达没有任何变化(图7N)。综上所述，数据表明Rd8小鼠具有结肠上皮屏障缺陷及其相关的结肠壁炎症。
实施例8检查肠上皮屏障缺陷是否会导致Rd8小鼠肠道通透性改变和微生物群像周围血流和视网膜组织迁移
对WT和Rd8小鼠进行肠FICT-dextran通透性测定。如图11A所示，与WT小鼠血液中荧光强度相比，给予FICT右旋糖酐后5小时，Rd8小鼠外周血中荧光显著增加。此外，使用Vancompy标记的粪便微生物群移植试验，发现Rd8小鼠外周血中荧光+细菌/细胞的显著升高，与WT小鼠在粪便移植后24小时相比(图10B和图11B)。重要的是，Rd8小鼠视网膜病变中可检测到Vancomopy+细菌的出现(图11C)，但WT视网膜病变中没有(未显示数据)，Rd8小鼠视网膜组织的免疫荧光染色进一步证实了这一点(图11D)。这些数据表明，肠道对多糖分子和细菌细胞的通透性增加，导致细菌从肠腔转移到血流和视网膜病变。
实施例9 Rd8在增加肠道通透性的情况下对肠道应激的反应实验
将WT和Rd8小鼠暴露于含1.5％右旋糖酐硫酸钠(DSS)的饮用水中，引起WT小鼠的轻微结肠炎。DSS治疗13天后，发现Rd8小鼠的结肠长度明显短于野生型小鼠(图11E)，Rd8小鼠血液中的细菌比野生型小鼠血液中的细菌多，细菌16S rRNA(图11F)和细菌LPS(图11G)的血清水平表明了这一点。
实施例10细菌对Rd8小鼠视网膜表型的逆转作用
虽然在Rd8小鼠视网膜中发现了由外血-视网膜屏障和肠上皮屏障破坏引起的病变内细菌， 但这些细菌是Rd8小鼠视网膜变性的原因还是后果尚不清楚。因此，在无菌(GF)条件下重新分离Rd8小鼠，并检测其视网膜变性表型是否发生改变。如图12A所示，在Rd8-SPF小鼠中发现的视网膜病变(白斑)在无菌Rd8(Rd8GF)小鼠中几乎没有观察到。Rd8-GF小鼠的视网膜组织学显示正常发育的视网膜组织(图12B)没有Rd8-SPF小鼠中发现的典型病变(图2A和图1C)，这证实了Rd8-GF小鼠中缺乏视网膜变性。Rd8GF小鼠中无法检测到视网膜细菌的事实(图12C)与Rd8GF小鼠中视网膜外核层(ONL)(图12D和图12E)中小胶质细胞的急剧减少有关，尽管ZO-1和Phalloidin蛋白染色显示外界膜的破坏，在Rd8-SPF和Rd8GF小鼠中均发现(图12F)。此外，当出生后在SPF环境中饲养Rd8GF小鼠(Rd8GF SPF小鼠)时，视网膜病变再次出现(图12G)。这些数据支持Rd8小鼠视网膜变性是细菌依赖性的事实。
实施例11没食子酸辛酯(化合物6)灌胃治疗Crb1 rd8/rd8小鼠眼底退行性视网膜病变的药效学评价
1.1供试品
Figure PCTCN2022114540-appb-000079
配制供试品时，量取已高压灭菌的4mL蓖麻油，称取化合物6粉末1.2g，加入1～2mL蓖麻油，充分研磨，用36mL超纯水将研磨好的药物和剩余的蓖麻油全部转移至50mL管，震荡混匀，静置过夜，即配制成浓度为30mg/mL的化合物6混悬液，将配置好的药液贴好标签于常温保存，一个月内用完。
计算公式：理论称样量(mg)＝供试品理论浓度(mg/mL)×配制体积(mL)
1.2试验动物信息
种属和品系：Crb1 rd8/rd8小鼠
等级：SPF级
数量和性别：18只，雌雄不限
体重范围：16-24g
供应单位：江苏集萃药康生物科技股份有限公司
1.3试验动物的选择
给药开始时选用健康1月龄Crb1 rd8/rd8小鼠进行试验。动物试验开始时，进行裂隙灯检查，出现白内障病变的小鼠不纳入试验；进行眼底检查，有一眼眼底未出现浅色斑点病变的小鼠的双眼均不纳入试验。
1.4试验设计
分组及剂量
将动物按体重分层后随机分为模型对照组和化合物6组。详细设计见下表：
组别 给药剂量(g/kg，i.g.) 眼睛数量
对照组 0 18
化合物6 0.3 18
给药相关信息及剂量设计
给药相关信息
给药途径及方法：灌胃给药，10.0mL/kg体重
给药频率及期限：隔天1次，持续4周
剂量设计
化合物6在小鼠用药剂量在0.3g/kg体重，此用量根据既往临床用药换算得出。
试验方法及步骤
将1月龄的Crb1 rd8/rd8小鼠随机分为模型对照组和化合物6用药组。动物灌胃给予溶媒或化合物6药物，化合物6给药量为0.3g/kg，隔天一次，连续用药4周。记录小鼠灌胃2周和4周的眼底浅色斑点数量进行分析比较。
1.5数据处理和统计分析
以用药后各时间点小鼠眼底浅色斑点数量变化作为参数，采用SPSS软件进行统计分析。统计结果以
Figure PCTCN2022114540-appb-000080
表示；检验水准＝0.05，试验数据的平均值和统计处理后数据均保留小数点后2位。
1.6试验结果
模型对照组小鼠在用药开始、2周和4周眼底均出现浅色斑点，表明模型动物发生眼底退行性视网膜病变。与模型对照组相比，给予化合物6灌胃2周后浅色斑点数量变化为1.31±3.18个，与模型对照组斑点数量变化2.88±3.41个相比无统计学差异。灌胃4周后见C57BL/6N小鼠的眼底浅色斑点数量变化为-3.63±4.06个，与模型对照组斑点数量变化2.24±4.01个相比有统计学差异(图13)。详细结果见下表：
Figure PCTCN2022114540-appb-000081
注：与模型对照组比较，*P＝0.1518，**P＝0.0005。
在试验第2周和第4周，化合物6组有2/18和1/18眼由于麻醉后晶体透明度轻度降低导 致不能清晰观察眼底浅色斑点，不能进行统计学计数。同时在试验进行第4周，模型对照组有1/18眼出现同样的晶体透明度降低而不能清晰观察眼底浅色斑点情况，不排除晶体透明度轻度降低和化合物6的使用相关性。小鼠麻醉后，晶状体会有透明度减低有文献报道，在Crb1 rd8/rd8小鼠中晶状体异常比较常见，有67％的前晶状体囊透明性会降低，当透明度降低到影响眼底观察时，不能进行统计学计数。
化合物6在0.3g/kg剂量下能有效抑制Crb1 rd8/rd8小鼠的眼底退行性视网膜病变。
以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。

Claims (25)

  1. 一种视网膜变性的治疗方法，所述的方法包括向患者的眼部或胃肠道施用微生物抑制剂或杀灭剂。
  2. 权利要求1所述的治疗方法，所述的视网膜变性为进行性视网膜变性；优选的，所述的视网膜变性为遗传性视网膜变性；更优选的，所述的遗传性视网膜变性包括先天性黑蒙(LCA)、色素性视网膜炎(RP)、早发性视杆-视锥细胞营养不良、视杆-视杆营养不良、先天性静止性夜盲和色盲和Stargardt病。
  3. 权利要求1所述的治疗方法，所述微生物为细菌、古细菌、原生生物、真菌或病毒中的一种或两种以上的组合。
  4. 权利要求3所述的治疗方法，所述微生物为细菌，所述细菌选自：Anearostipes、双歧杆菌(Bifidobacterium)、巨单胞菌(Megamonas)、亚硝基单胞菌(Nitrosomonas)，颤螺旋菌(Oscillibacter)、塔特姆菌(Tatumella)、硫杆菌(Thiobacillussp.)、梭菌属(Clostridium)、不动杆菌属(Acinetobacter)、链球菌属(Streptococcus)、曼氏杆菌属(Mannheimia)、纤维杆菌属(Fibrobacter)、普氏菌属(Prevotella)、弯曲杆菌属(Campylobacter)、放线菌属(Actinomyces)、薄层菌属(Hymenobacter)、埃希氏杆菌属(Escherichia)、泰氏菌属(Tissierella)、克雷白氏杆菌属(Klebsiella)、卟啉单胞菌属(Porphyromonas)、固氮螺菌属(Azospira)、海水菌属(Aquimarina)、无色菌属(Achromobacter)、嗜酸硫杆菌属(Acidithiobacillus)、伯克霍尔德菌属(Burkholderia)、海杆菌属(Marinobacter)、密螺旋体属(Treponema)、孢裹放线菌属(Actinosporangium)、弧菌属(Vibrio)、瘤胃球菌属(Ruminococcus)、甲烷短杆菌(Methanobrevibacter)、志贺氏杆菌(Shigella)、弗兰克氏菌属(Frankia)、链霉菌属厌氧原体属(Anaeroplasma)、粪球菌属(Coprococcus)中的一种或两种以上。
  5. 根据权利要求4所述的方法，所述细菌选自：Anearostipeshadrus、Bifidobacterium pseudocatenulatum、Nitrosomonas sp.Is79A3、Oscillibactervalericigenes、Tatumella sp.TA1、Megamonasfuniformis、Thiobacillus denitrificans、Akkermansiamucinphila。
  6. 根据权利要求1所述的方法，所述的微生物抑制剂或杀灭剂包含化合物、多肽、多核苷酸、天然植物或天然植物提取物。
  7. 根据权利要求1所述的方法，所述的微生物抑制剂或杀灭剂为抗生素，优选的，所述的抗生素为β-内酰胺类抗生素；氨基糖苷类抗生素；四环素类抗生素；氯霉素类抗生素；大环内脂类抗生素；糖肽类抗生素；喹诺酮类抗生素；硝基咪唑类抗生素；利福霉素类抗生素；棘白菌素类抗生素；多烯类抗生素；嘧啶类抗生素；烯丙胺类抗生素；氮唑类抗生素；其它抗生素中的一种或者两种以上。
  8. 根据权利要求1所述的方法，所述的微生物抑制剂或杀灭剂为式I(例如，式I-1、式I-2、式I-3、式I-4、式I-5)、式II(例如，式II-1、式II-2、式II-3、式II-4、式II-5、式II-6、式II-7、式II-8、式II-9、式II-10)、式III(例如，式III-1、式III-2、式III-3)、式IV-1或IV-2(例如，式IV-3、式IV-4、式IV-5、式IV-6)的化合物，糖苷(例如，式V)，或其药学上可接受的盐或酯，其中所述糖苷的苷元是酚类化合物、类黄酮、香豆素、苯甲酸或甾醇，其中所述式I、II、III、IV-1、IV-2、V及其子式如说明书所定义。
  9. 根据权利要求8所述的方法，所述的微生物抑制剂或杀灭剂为化合物1-8，所述的具有以下化学结构：
    Figure PCTCN2022114540-appb-100001
  10. 根据权利要求1所述的方法，所述的微生物抑制剂或杀灭剂为天然植物或其提取物，优选的所述的天然植物选自甘草、白芍、连翘、枳壳、地黄、陈皮、三七、鳖甲、红景天、生地、薏仁、白芍、连翘、决明子和甘草中的一种或两种以上的组合，或上述天然植物提取物或其组合。
  11. 根据权利要求1所述的方法，所述的微生物抑制剂或杀灭剂为包含鳖甲、红景天、生地、薏仁、白芍、连翘、决明子和甘草的组合物，优选的，所述的组合物中按照重量分数计，包括鳖甲5-15份、红景天10-30份、生地5-15份、薏仁5-15份、白芍8-20份、连 翘5-15份、决明子5-15份和甘草5-15份，更优选的，所述的组合物包括鳖甲10份、红景天20份、生地10份、薏仁10份、白芍12份、连翘10份、决明子10份和甘草9份。
  12. 权利要求1所述的治疗方法，所述的向患者的眼部施用包括向患者眼部的前房中的房水、悬韧带、睫状体、睫状体和睫状肌、后房中的玻璃体液、视网膜、脉络膜、视神经、晶状体或虹膜中施用。
  13. 权利要求1所述的治疗方法，所述的向患者的胃肠道施用包括向患者的胃、空肠、回肠、盲肠、结肠或直肠中施用。
  14. 微生物抑制剂或杀灭剂在制备治疗视网膜变性的药物中的应用。
  15. 权利要求14所述的应用，所述的视网膜变性为进行性视网膜变性；优选的，所述的视网膜变性为遗传性视网膜变性；更优选的，所述的遗传性视网膜变性包括先天性黑蒙(LCA)、色素性视网膜炎(RP)、早发性视杆-视锥细胞营养不良、视杆-视杆营养不良、先天性静止性夜盲和色盲和Stargardt病。
  16. 权利要求14所述的应用，所述微生物为细菌、古细菌、原生生物、真菌或病毒中的一种或两种以上的组合。
  17. 权利要求16所述的应用，所述微生物为细菌，所述细菌选自：Anearostipes、双歧杆菌(Bifidobacterium)、巨单胞菌(Megamonas)、亚硝基单胞菌(Nitrosomonas)，颤螺旋菌(Oscillibacter)、塔特姆菌(Tatumella)、硫杆菌(Thiobacillus sp.)、梭菌属(Clostridium)、不动杆菌属(Acinetobacter)、链球菌属(Streptococcus)、曼氏杆菌属(Mannheimia)、纤维杆菌属(Fibrobacter)、普氏菌属(Prevotella)、弯曲杆菌属(Campylobacter)、放线菌属(Actinomyces)、薄层菌属(Hymenobacter)、埃希氏杆菌属(Escherichia)、泰氏菌属(Tissierella)、克雷白氏杆菌属(Klebsiella)、卟啉单胞菌属(Porphyromonas)、固氮螺菌属(Azospira)、海水菌属(Aquimarina)、无色菌属(Achromobacter)、嗜酸硫杆菌属(Acidithiobacillus)、伯克霍尔德菌属(Burkholderia)、海杆菌属(Marinobacter)、密螺旋体属(Treponema)、孢裹放线菌属(Actinosporangium)、弧菌属(Vibrio)、瘤胃球菌属(Ruminococcus)、甲烷短杆菌(Methanobrevibacter)、志贺氏杆菌(Shigella)、弗兰克氏菌属(Frankia)、链霉菌属厌氧原体属(Anaeroplasma)、粪球菌属(Coprococcus)中的一种或两种以上。
  18. 权利要求17所述的应用，所述细菌选自：Anearostipeshadrus、Bifidobacterium pseudocatenulatum、Nitrosomonas sp.Is79A3、Oscillibactervalericigenes、Tatumella sp.TA1、Megamonasfuniformis、Thiobacillus denitrificans、Akkermansiamucinphila。
  19. 权利要求14所述的应用，所述的微生物抑制剂或杀灭剂包含化合物、多肽、多核苷酸、天然植物或天然植物提取物。
  20. 权利要求14所述的应用，所述的微生物抑制剂或杀灭剂为抗生素，优选的，所述的抗生素为β-内酰胺类抗生素；氨基糖苷类抗生素；四环素类抗生素；氯霉素类抗生素；大环内脂类抗生素；糖肽类抗生素；喹诺酮类抗生素；硝基咪唑类抗生素；利福霉素类抗生素；棘白菌素类抗生素；多烯类抗生素；嘧啶类抗生素；烯丙胺类抗生素；氮唑类抗生素；其它抗生素中的一种或者两种以上。
  21. 权利要求14所述的应用，所述的微生物抑制剂或杀灭剂为式I(例如，式I-1、式I-2、式I-3、式I-4、式I-5)、式II(例如，式II-1、式II-2、式II-3、式II-4、式II-5、式II-6、式II-7、式II-8、式II-9、式II-10)、式III(例如，式III-1、式III-2、式III-3)、式IV-1或IV-2(例如，式IV-3、式IV-4、式IV-5、式IV-6)的化合物，糖苷(例如，式V)，或其药学上可接受的盐或酯，其中所述糖苷的苷元是酚类化合物、类黄酮、香豆素、苯甲酸或甾醇，其中所述式I、II、III、IV-1、IV-2、V及其子式如说明书所定义。
  22. 权利要求14所述的应用，所述的微生物抑制剂或杀灭剂为化合物1-8，具有以下化学结构：
    Figure PCTCN2022114540-appb-100002
  23. 权利要求1所述的应用，所述的微生物抑制剂或杀灭剂为天然植物或其提取物，优选的所述的天然植物选自甘草、白芍、连翘、枳壳、地黄、陈皮、三七、鳖甲、红景天、 生地、薏仁、白芍、连翘、决明子和甘草中的一种或两种以上的组合，或上述天然植物提取物或其组合。
  24. 权利要求1所述的应用，所述的微生物抑制剂或杀灭剂为包含鳖甲、红景天、生地、薏仁、白芍、连翘、决明子和甘草的组合物，优选的，所述的组合物中按照重量分数计，包括鳖甲5-15份、红景天10-30份、生地5-15份、薏仁5-15份、白芍8-20份、连翘5-15份、决明子5-15份和甘草5-15份，更优选的，所述的药物组合物包括鳖甲10份、红景天20份、生地10份、薏仁10份、白芍12份、连翘10份、决明子10份和甘草9份。
  25. 权利要求1所述的应用，所述药物为眼部给药制剂或胃肠道给药制剂，优选的，所述的眼部给药制剂为滴眼剂、眼膏剂、眼用凝胶剂、眼用膜剂、洗眼剂、眼内注射剂，优选的，所述的胃肠道给药制剂为片剂、丸剂、粉剂、颗粒剂、胶囊剂、锭剂、糖浆剂、溶液剂、乳剂、混悬剂、控制释放制剂、气雾剂、膜剂。
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