KR102287829B1 - Antifungal composition comprising aripiprazole - Google Patents
Antifungal composition comprising aripiprazole Download PDFInfo
- Publication number
- KR102287829B1 KR102287829B1 KR1020200009139A KR20200009139A KR102287829B1 KR 102287829 B1 KR102287829 B1 KR 102287829B1 KR 1020200009139 A KR1020200009139 A KR 1020200009139A KR 20200009139 A KR20200009139 A KR 20200009139A KR 102287829 B1 KR102287829 B1 KR 102287829B1
- Authority
- KR
- South Korea
- Prior art keywords
- candida
- aripiprazole
- pathogenic fungi
- composition
- pathogenic
- Prior art date
Links
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 105
- 239000012871 anti-fungal composition Substances 0.000 title claims description 8
- 244000053095 fungal pathogen Species 0.000 claims abstract description 66
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 28
- 230000032770 biofilm formation Effects 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 15
- 244000000010 microbial pathogen Species 0.000 claims abstract description 5
- 241000222122 Candida albicans Species 0.000 claims description 73
- 229940095731 candida albicans Drugs 0.000 claims description 73
- 230000015572 biosynthetic process Effects 0.000 claims description 30
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 24
- 230000000694 effects Effects 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 229930182558 Sterol Natural products 0.000 claims description 10
- 230000000843 anti-fungal effect Effects 0.000 claims description 10
- 150000003432 sterols Chemical class 0.000 claims description 10
- 235000003702 sterols Nutrition 0.000 claims description 10
- 108010013803 Sterol 14-Demethylase Proteins 0.000 claims description 9
- 230000036541 health Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 235000013376 functional food Nutrition 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 230000037303 wrinkles Effects 0.000 claims description 5
- 241000222173 Candida parapsilosis Species 0.000 claims description 4
- 241000222178 Candida tropicalis Species 0.000 claims description 4
- 241000235645 Pichia kudriavzevii Species 0.000 claims description 4
- 150000003278 haem Chemical class 0.000 claims description 4
- 241000144583 Candida dubliniensis Species 0.000 claims description 3
- 206010053166 Candida sepsis Diseases 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 206010017938 Gastrointestinal candidiasis Diseases 0.000 claims description 3
- 206010018691 Granuloma Diseases 0.000 claims description 3
- 206010027205 Meningitis candida Diseases 0.000 claims description 3
- 208000007027 Oral Candidiasis Diseases 0.000 claims description 3
- 206010046914 Vaginal infection Diseases 0.000 claims description 3
- 201000008100 Vaginitis Diseases 0.000 claims description 3
- 241000222126 [Candida] glabrata Species 0.000 claims description 3
- 208000002479 balanitis Diseases 0.000 claims description 3
- 206010014665 endocarditis Diseases 0.000 claims description 3
- 201000009179 neonatal candidiasis Diseases 0.000 claims description 3
- 208000000143 urethritis Diseases 0.000 claims description 3
- 241001508813 Clavispora lusitaniae Species 0.000 claims description 2
- 208000032343 candida glabrata infection Diseases 0.000 claims description 2
- 229940055022 candida parapsilosis Drugs 0.000 claims description 2
- 208000010195 Onychomycosis Diseases 0.000 claims 1
- 102000017168 Sterol 14-Demethylase Human genes 0.000 claims 1
- 201000005882 tinea unguium Diseases 0.000 claims 1
- 239000003429 antifungal agent Substances 0.000 abstract description 20
- 230000002401 inhibitory effect Effects 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 6
- 206010017533 Fungal infection Diseases 0.000 abstract description 5
- 230000001717 pathogenic effect Effects 0.000 abstract description 5
- 208000031888 Mycoses Diseases 0.000 abstract description 4
- 230000000069 prophylactic effect Effects 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 21
- 229960004125 ketoconazole Drugs 0.000 description 21
- 241000233866 Fungi Species 0.000 description 19
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 18
- 102100021695 Lanosterol 14-alpha demethylase Human genes 0.000 description 17
- 210000000170 cell membrane Anatomy 0.000 description 10
- 101710146773 Lanosterol 14-alpha demethylase Proteins 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 235000013305 food Nutrition 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- 239000001965 potato dextrose agar Substances 0.000 description 9
- 238000010186 staining Methods 0.000 description 9
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 229960004130 itraconazole Drugs 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 238000011156 evaluation Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- -1 isbuconazole Chemical compound 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 4
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 4
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 4
- 101150106008 ERG11 gene Proteins 0.000 description 4
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 101150057219 HWP1 gene Proteins 0.000 description 4
- 102100025133 Potassium voltage-gated channel subfamily H member 7 Human genes 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 4
- 235000013373 food additive Nutrition 0.000 description 4
- 239000002778 food additive Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000002538 fungal effect Effects 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000003032 molecular docking Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 101001077420 Homo sapiens Potassium voltage-gated channel subfamily H member 7 Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000036457 multidrug resistance Effects 0.000 description 3
- 230000007918 pathogenicity Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 150000004291 polyenes Chemical class 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 description 2
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 description 2
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 description 2
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 108700039887 Essential Genes Proteins 0.000 description 2
- 229930183931 Filipin Natural products 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000008686 ergosterol biosynthesis Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 description 2
- 229950000152 filipin Drugs 0.000 description 2
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 208000024386 fungal infectious disease Diseases 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 description 2
- 229940058690 lanosterol Drugs 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 230000037373 wrinkle formation Effects 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- COAYMVLTWXLTOT-UHFFFAOYSA-N 7-[4-[4-[2,3-bis(chloranyl)phenyl]piperazin-1-yl]butoxy]-3,4-dihydro-1h-quinolin-2-one Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl.ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl COAYMVLTWXLTOT-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 244000197813 Camelina sativa Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 101150103048 ERG3 gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000037026 Invasive Fungal Infections Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- 229940123247 Neurotransmitter antagonist Drugs 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 244000117054 Rungia klossii Species 0.000 description 1
- 235000002492 Rungia klossii Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- CJGYSWNGNKCJSB-YVLZZHOMSA-N bucladesine Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 CJGYSWNGNKCJSB-YVLZZHOMSA-N 0.000 description 1
- 229960005263 bucladesine Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 230000002338 cryopreservative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000003235 crystal violet staining Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000012595 freezing medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229960001589 posaconazole Drugs 0.000 description 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011269 tar Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Images
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Abstract
본 발명은 아리피프라졸을 유효성분으로 함유하는 병원성 미생물의 생물막 형성 억제용 조성물에 관한 것으로, 아리피프라졸이 병원성 진균에 대해 생물막의 형성을 억제할 뿐만 아니라, 병원성을 나타내는 균사 형태로의 전환을 억제하는 것을 확인함에 따라, 상기 아리피프라졸 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 조성물은 병원성 진균에 대한 항진균제 및 병원성 진균 감염에 대한 예방 또는 치료용 제제로 제공될 수 있다.The present invention relates to a composition for inhibiting biofilm formation of pathogenic microorganisms containing aripiprazole as an active ingredient. Accordingly, the composition containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient may be provided as an antifungal agent for pathogenic fungi and a prophylactic or therapeutic agent for pathogenic fungal infections.
Description
본 발명은 아리피프라졸을 유효성분으로 함유하는 병원성 진균의 생물막 형성 억제용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting biofilm formation of pathogenic fungi containing aripiprazole as an active ingredient.
진균은 인체에 상재 하거나 토양, 공기 및 물 등 주위 자연환경에 널리 분포되어 있으며, 인간에게 다양한 질병을 유발하는 병원성 진균은 다양한 경로로 인체에 침입한다. 일반적으로 병원성 진균의 감염으로 인한 질병의 발병 여부는 병원균의 감염량, 숙주의 면역 상태 등에 따라 결정되며, 진균 항원의 감작으로 인한 과민성 질환(hypersensitivity diseases), 진균의 독소(mycotoxin)에 의한 진균독소증 및 숙주의 조직에 병원균이 감염하여 일으키는 진균증((mycosis, mycoses)등의 형태로 질병을 일으킨다.Fungi reside in the human body or are widely distributed in the surrounding natural environment such as soil, air, and water, and pathogenic fungi that cause various diseases in humans invade the human body through various routes. In general, the onset of disease due to pathogenic fungal infection is determined by the pathogen's infection amount, the host's immune status, etc. It causes disease in the form of mycosis (mycosis, mycoses) caused by the infection of pathogens and host tissues.
병원성 진균의 주된 감염경로는 피부, 호흡기계통 및 비뇨생식기나 소화기계의 상피 등이 될 수 있고, 이식 수술에 의해 인공 의료 장비 및 이식 장기에 감염되어 침입하여 인체 내부에서 질병을 일으키기 때문에, 병원성 진균의 감염이 의료적 문제를 일으키고 있다. 특히 침습성 진균의 경우 면역기능 저하 환자의 생명을 위협하기 때문에, 이러한 병원성 진균의 감염 및 확산을 억제하기 위해서 수술 직후 환자에게 항진균제가 투여되는 경우도 있다.The main route of infection of pathogenic fungi can be the skin, respiratory system, and epithelium of the genitourinary or digestive system. infection is causing medical problems. In particular, since invasive fungi threaten the lives of patients with weakened immune function, antifungal agents are sometimes administered to patients immediately after surgery in order to suppress the infection and spread of these pathogenic fungi.
병원성 진균의 감염을 치료하기 위한 약제로는 다양한 항진균제가 개발되고 있으며, 보리코나졸, 이사부코나졸, 포사코나졸, 및 이트라코나졸과 같은 아졸계 항진균제가 대부분이며, 일부에서는 침습성 진균 감염에 대항하기 위해 국소 및 전신성 항진균제로 제공되고 있다. 그러나 아졸계 항균제가 사용될수록 이에 대한 내성을 갖는 병원성 진균이 보고되고 있다.Various antifungal agents have been developed as agents for treating pathogenic fungal infections, and azole antifungal agents such as voriconazole, isbuconazole, posaconazole, and itraconazole are mostly used, and some are used to combat invasive fungal infections. It is available as a topical and systemic antifungal agent. However, as azole-based antibacterial agents are used, pathogenic fungi having resistance to them have been reported.
일부 병원성 진균은 세포 표면에 다당류(polysaccharides) 또는 단백질로 구성되는 점액질이 세포 주위를 둘러 싸는 생물막을 형성하여 의료 기기 및 인체 부위 표면에 부착하여 성장한다. 진균의 생물막은 항진균제 및 면역인자로부터 진균을 보호하는 작용을 하기 때문에 생물막이 형성된 병원성 진균은 대부분의 항진균제에 대한 내성을 나타낸다.Some pathogenic fungi form a biofilm in which mucus composed of polysaccharides or proteins on the cell surface surrounds the cells, and grows by attaching to the surface of medical devices and human body parts. Since the biofilm of the fungus acts to protect the fungus from antifungal agents and immune factors, the pathogenic fungi with the biofilm formed show resistance to most antifungal agents.
또한, 병원성 진균은 이들을 사멸시키는 항진균제에 대항하기 위해 돌연변이를 일으키기도 하며, 이러한 병원성 진균의 진화는 생물막 성장 및 다중약물내성과 같은 특징을 나타내기 때문에 환자의 생명을 위협하는 슈퍼 감염을 일으킬 수 있다. 따라서 이러한 다중약물내성을 갖는 병원성 진균에 대항하기 위해서는 진균의 성장을 억제할 뿐만 아니라 생물막 형성을 억제하거나, 병원성을 상실하게 하는 약제가 개발되고 있다. In addition, pathogenic fungi may mutate to fight antifungal agents that kill them, and the evolution of these pathogenic fungi exhibits features such as biofilm growth and multidrug resistance, which can lead to life-threatening super-infections in patients. . Therefore, in order to combat pathogenic fungi having multi-drug resistance, drugs that inhibit the growth of fungi as well as inhibit biofilm formation or lose pathogenicity have been developed.
한편, 최근에는 기존 약제를 약리학적으로 별개의 분야에 적용함으로써, 약제의 새로운 용법을 제시하는 연구가 진행되고 있다. 항정신병 약물은 세균에 대한 항균 활성이 나타나는 경우가 있으며, 이를 통해 항균제로 용도를 변경할 수 있는 가능성을 제시하는 연구가 보고되고 있으나, 항진균제에 대한 연구는 미비한 실정이다.On the other hand, recently, by applying the existing drug to a pharmacologically separate field, research to suggest a new use of the drug is in progress. Antipsychotic drugs may exhibit antibacterial activity against bacteria, and there have been reports of studies suggesting the possibility of changing their use to antibacterial agents. However, studies on antifungal agents are insufficient.
본 발명자들은 이와 같은 점을 감안하여 항정신병 약제인 아리피프라졸이 진균의 생물막 형성 및 성장을 억제하는 등의 항진균 활성을 확인함으로써 새로운 항진균제 및 생물막 억제제로 사용될 수 있는 본 발명을 완성하였다.The present inventors have completed the present invention that can be used as a new antifungal agent and biofilm inhibitor by confirming the antifungal activity, such as the antipsychotic drug aripiprazole inhibits the biofilm formation and growth of fungi in view of this point.
본 발명은 아리피프라졸을 유효성분을 포함하여 병원성 진균의 생물막 형성 및 성장을 억제하는 것을 확인함으로써, 새로운 항진균제로 사용 가능한 항진균용 조성물을 제공하는 것이다.The present invention is to provide an antifungal composition that can be used as a novel antifungal agent by confirming that aripiprazole, including an active ingredient, inhibits the biofilm formation and growth of pathogenic fungi.
본 발명은 아리피프라졸 또는 이의 염을 유효성분으로 함유하는 병원성 진균에 대한 항진균용 조성물을 제공한다.The present invention provides an antifungal composition for pathogenic fungi containing aripiprazole or a salt thereof as an active ingredient.
또한, 본 발명은 아리피프라졸 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 병원성 진균에 의해 유발되는 질환에 대한 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by pathogenic fungi containing aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 아리피프라졸 또는 이의 염을 유효성분으로 함유하는 병원성 진균에 의해 유발되는 질환에 대한 예방 또는 개선용 건강식품을 제공한다.In addition, there is provided a health food for preventing or improving diseases caused by pathogenic fungi containing aripiprazole or a salt thereof as an active ingredient.
본 발명에 따르면, 아리피프라졸은 병원성 진균에 대해 생물막의 형성을 억제할 뿐만 아니라, 병원성을 나타내는 균사 형태로의 전환을 억제하는 것이 확인됨에 따라, 상기 아리피프라졸 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 조성물은 병원성 진균에 의해 유발되는 질환에 대한 예방 또는 치료용으로 사용될 수 있는 항진균제로 제공될 수 있다.According to the present invention, aripiprazole or a pharmaceutically acceptable salt thereof is used as an active ingredient as it has been confirmed that aripiprazole not only inhibits the formation of a biofilm against pathogenic fungi, but also inhibits conversion to a pathogenic mycelial form. The composition containing it can be provided as an antifungal agent that can be used for preventing or treating diseases caused by pathogenic fungi.
도 1은 항진균제로서 아리피프라졸이 병원성 진균에서 약동학적으로 작용하는 기작을 도식화한 그림이다. 아리피프라졸 구조에서 분홍색 화살표는 방향족 고리에 있는 2개의 염소 원자(분홍색 원)을 나타내고, 녹색 화살표는 H-결합(공여체/수용체)의 산소 원자(녹색 상자)를 나타내고, 검정색 화살표는 헴(Heme) 그룹을 포함하는 모이어티(검정색 박스), 측쇄(빨간 점선 박스) 및 Try118 상호작용 고리를 나타낸다.
도 2는 병원성 진균에 아리피프라졸을 처리함에 따른 생물막 형성 및 성장에 대한 억제 효과를 측정한 그래프이다.
도 3은 병원성 진균에 아리피프라졸을 처리함에 따른 균사 형성에 대한 억제 효과를 확인한 사진이다. 사이즈바는 100 μm을 의미한다.
도 4는 병원성 진균에 아리피프라졸을 처리함에 따른 콜로니 주름 형성에 대한 억제 효과를 확인한 사진이다.
도 5는 혐기성 조건에서 병원성 진균에 아리피프라졸을 처리함에 따른 효모-균사 전환에 대한 억제 효과를 확인한 사진이다. 사이즈바는 20 μm을 의미한다.
도 6은 병원성 진균에 아리피프라졸을 처리함에 따른 응집화에 대한 억제 효과를 확인한 사진이다. 사이즈바는 100 μm을 의미한다.
도 7은 병원성 진균에 아리피프라졸을 처리함에 따른 cAMP 경로에 미치는 영향을 확인한 사진이다. 사이즈바는 20 μm을 의미한다.
도 8은 병원성 진균에 아리피프라졸을 처리함에 따른 항산화 활성을 확인한 사진이다. 사이즈바는 100 μm을 의미한다.
도 9는 병원성 진균에 아리피프라졸을 처리함에 따른 세포막 스테롤의 변화를 확인한 사진이다. 사이즈바는 20 μm을 의미한다. 노란색 화살촉은 균사 끝에 집중된 필리핀 염색을 나타내고, 빨간색 화살촉은 효모 세포막을 가로지르는 균일한 필리핀 염색을 나타낸다.
도 10은 병원성 진균에 아리피프라졸을 처리함에 따른 가성균사 요소의 변화를 확인한 사진이다. 사이즈바는 20 μm을 의미한다. 노란색 화살촉은 균사 끝에 집중된 필리핀 염색을 나타내고, 파란색 화살촉은 세포막의 필리핀 반점을 나타낸다.
도 11은 병원성 진균에 아리피프라졸을 처리함에 따른 세포막 손상 정도를 PI 염색으로 확인한 사진이다. 사이즈바는 20 μm을 의미한다.
도 12는 분자 도킹을 이용한 아리피프라졸, 이트라코나졸 또는 케토코나졸이 lanosterol 14-alpha-demethylase (CYP51)과의 상호작용을 3D로 나타내 그림이다. 녹색은 Heme601 보결분자단, 파란색은 아리피프라졸, 검정색은이트?珌ち? 및 케토코나졸을 나타낸다.
도 13은 병원성 진균에 아리피프라졸을 처리함에 따른 ERG3, ERG11 및 HWP1 유전자 발현 변화를 측정한 그래프이다. RND18은 항존유전자(housekeeping)이다.1 is a schematic diagram of the mechanism of pharmacokinetic action of aripiprazole as an antifungal agent in pathogenic fungi. In the aripiprazole structure, the pink arrow indicates the two chlorine atoms (pink circles) in the aromatic ring, the green arrow indicates the oxygen atom (green box) of the H-bond (donor/acceptor), and the black arrow indicates the Heme group. Moieties containing (black box), side chains (red dashed box) and Try 118 interacting ring are shown.
Figure 2 is a graph measuring the inhibitory effect on the biofilm formation and growth according to the treatment of aripiprazole to pathogenic fungi.
3 is a photograph confirming the inhibitory effect on the mycelium formation according to the treatment of aripiprazole on pathogenic fungi. The size bar means 100 μm.
Figure 4 is a photograph confirming the inhibitory effect on colony wrinkle formation according to the treatment of aripiprazole to pathogenic fungi.
5 is a photograph confirming the inhibitory effect on yeast-mycelial conversion by treating the pathogenic fungi with aripiprazole under anaerobic conditions. The size bar means 20 μm.
6 is a photograph confirming the inhibitory effect on aggregation of aripiprazole by treating pathogenic fungi. The size bar means 100 μm.
7 is a photograph confirming the effect on the cAMP pathway according to the treatment of aripiprazole in pathogenic fungi. The size bar means 20 μm.
8 is a photograph confirming the antioxidant activity according to the treatment of aripiprazole to pathogenic fungi. The size bar means 100 μm.
9 is a photograph confirming the change of cell membrane sterol according to the treatment of aripiprazole to pathogenic fungi. The size bar means 20 μm. Yellow arrowheads indicate Filipino staining concentrated at the hyphal tip, and red arrowheads indicate uniform Filipino staining across the yeast cell membrane.
10 is a photograph confirming the change of the pseudomycel element according to the treatment of aripiprazole to pathogenic fungi. The size bar means 20 μm. Yellow arrowheads indicate Filipino staining concentrated at the tip of the mycelium, and blue arrowheads indicate Filipino spots on the cell membrane.
11 is a photograph confirming the degree of cell membrane damage caused by the treatment of aripiprazole to pathogenic fungi by PI staining. The size bar means 20 μm.
12 is a 3D diagram illustrating the interaction of aripiprazole, itraconazole or ketoconazole with lanosterol 14-alpha-demethylase (CYP51) using molecular docking. Green is Heme601 prosthetic group, blue is aripiprazole, and black is yite? and ketoconazole.
13 is a graph measuring ERG3, ERG11 and HWP1 gene expression changes according to the treatment of aripiprazole in pathogenic fungi. RND18 is a housekeeping gene.
본 명세서에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.The terms used in this specification have been selected as currently widely used general terms as possible while considering the functions in the present invention, which may vary depending on the intention or precedent of a person skilled in the art, the emergence of new technology, and the like. In addition, in a specific case, there is a term arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the corresponding invention. Therefore, the term used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, rather than the name of a simple term.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Unless defined otherwise, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related art, and should not be interpreted in an ideal or excessively formal meaning unless explicitly defined in the present application. does not
수치 범위는 상기 범위에 정의된 수치를 포함한다. 본 명세서에 걸쳐 주어진 모든 최대의 수치 제한은 낮은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 낮은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 최소의 수치 제한은 더 높은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 높은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 수치 제한은 더 좁은 수치 제한이 명확히 쓰여져 있는 것처럼, 더 넓은 수치 범위 내의 더 좋은 모든 수치 범위를 포함할 것이다.Numerical ranges are inclusive of the values defined in that range. Every maximum numerical limitation given throughout this specification includes all lower numerical limitations as if the lower numerical limitation were expressly written. Every minimum numerical limitation given throughout this specification includes all higher numerical limitations as if the higher numerical limitation were expressly written. Any numerical limitation given throughout this specification shall include all numerical ranges within the broader numerical range, as if the narrower numerical limitation were expressly written.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 하기 화학식 1로 표시되는 아리피프라졸 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 병원성 진균에 대한 항진균용 조성물을 제공한다.The present invention provides an antifungal composition for pathogenic fungi containing aripiprazole represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 "아리피프라졸"은 화학명으로 7-{4-[4-(2,3-디클로로페닐)피페라진-1-일]부톡시}-3,4-디하이드로퀴노린-2(1H)-원 (7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one)이며, 도파민 작용성 신경전달물질 길항제로서, 정신 분열증 (schizophrenia), 양극성 장애 (bipolar disorder), 임상우울증 (clinical depression) 등의 치료에 사용되는 비전형 항정신제 및 항우울제로서 사용된다.The "aripiprazole" is a chemical name of 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinoline-2(1H)-one ( 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one), a dopaminergic neurotransmitter antagonist, used in schizophrenia (schizophrenia), bipolar disorder, clinical depression (clinical depression) used as an atypical antipsychotic and antidepressant.
상기 "약학적으로 허용 가능한 염"은 제약 분야에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 칼륨, 나트륨 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산, 주석산 및 황산 등으로 제조된 무기산염, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 구연산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트리메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다.The "pharmaceutically acceptable salt" means salts commonly used in the pharmaceutical field, for example, inorganic ionic salts prepared with calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodine Inorganic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid , galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. organic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -There are sulfonic acid salts prepared from toluenesulfonic acid and naphthalenesulfonic acid, amino acid salts prepared from glycine, arginine, lysine, etc., and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc. The types of salts in the present invention are not limited by these listed salts.
상기 병원성 진균은 바람직하게는 칸디다 알비칸스(Candida albicans), 칸디다 크루세이(C. krusei), 칸디다 트로피칼리스(C. tropicalis), 칸디다 글라브라타(C. glabrata), 칸디다 파라프실로시스(C. parapsilosis), 칸디다 두블리니엔시스(C. dubliniensis), 및 칸디다 루시타니에(C. lusitaniae)로 이루어진 군에서 하나 이상 선택될 수 있고, 보다 더 바람직하게는 칸디다 알비칸스(Candida albicans)일 수 있다.The pathogenic fungi are preferably Candida albicans ( Candida albicans ), Candida krusei ( C. krusei ), Candida tropicalis ( C. tropicalis ), Candida glabrata ( C. glabrata ), Candida parapsilosis ( C . parapsilosis), Candida two N-Sys Needle assembly (C. dubliniensis), and the Lucy Candida Tani (may be one or more selected from the group consisting of C. lusitaniae), may be more preferably, Candida albicans (Candida albicans) there is.
상기 아리피프라졸은 병원성 진균의 생물막 형성을 억제할 수 있다. 또한 상기 아리피프라졸은 병원성 진균의 성장을 억제할 수 있고, 병원성 진균의 균사 또는 콜로니 주름 형성을 억제할 수 있다. 또한, 상기 아리피프라졸은 병원성 미생물의 응집체 형성을 억제할 수 있다. 또한, 상기 아리피프라졸은 병원성 미생물의 스테롤 합성을 억제할 수 있다.The aripiprazole can inhibit the biofilm formation of pathogenic fungi. In addition, the aripiprazole may inhibit the growth of pathogenic fungi, and may inhibit the formation of hyphae or colony wrinkles of the pathogenic fungi. In addition, the aripiprazole may inhibit the formation of aggregates of pathogenic microorganisms. In addition, the aripiprazole may inhibit the synthesis of sterols in pathogenic microorganisms.
상기 아리피프라졸은 헴 보결분자단(heme prosthetic group)에 결합하여 라노스테롤 14-알파 데메틸라아제(lanosterol 14-alpha-demethylase)의 활성을 억제할 수 있다.The aripiprazole may bind to a heme prosthetic group to inhibit the activity of lanosterol 14-alpha-demethylase.
상기 라노스테롤 14-알파 데메틸라아제(lanosterol 14-alpha-demethylase)는 진균에서 라노스테롤(lanosterol)을 에르고스테롤(ergosterol)로 전환하여 진균의 세포막 형성에 주요 역할을 한다. The lanosterol 14-alpha demethylase (lanosterol 14-alpha-demethylase) converts lanosterol into ergosterol in the fungus and plays a major role in forming the cell membrane of the fungus.
고농도에서는 라노스테롤 14-알파 데메틸라아제(lanosterol 14-alpha-demethylase)를 불활성화하여 에르고스테롤의 합성을 억제하기 때문에, 병원성 진균의 세포막을 손상시키고, 세포 내용물 유출이 유도되기 때문에 진균을 사멸시킬 수 있다. (도 1)At high concentrations, lanosterol 14-alpha-demethylase is inactivated to inhibit the synthesis of ergosterol, thereby damaging the cell membrane of pathogenic fungi and inducing the outflow of cell contents, thereby killing the fungus. can do it (Fig. 1)
또한, 본 발명은 하기 화학식 1로 표시되는 아리피프라졸 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 병원성 진균에 의해 유발되는 질환에 대한 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by pathogenic fungi containing aripiprazole represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
본 발명의 약학 조성물은 통상의 방법에 따라 액제, 현탁액, 에멀젼, 로션, 연고, 동결건조제 등 다양한 제형으로 제제화될 수 있다.The pharmaceutical composition of the present invention may be formulated in various formulations such as solutions, suspensions, emulsions, lotions, ointments, and freeze-drying agents according to conventional methods.
본 발명의 약학 조성물은 약학적 분야의 통상의 방법에 따라 환자의 신체 내 투여에 적합한 단위투여형의 약학적 제제로 제형화시켜 투여할 수 있으며, 상기 제제는 1회 또는 수회 투여에 의해 효과적인 투여량을 포함한다. 이러한 목적에 적합한 제형으로는 비경구투여 제제로서 주사제, 주입제 등이 바람직하다. 또한, 약학 조성물은 약학적으로 허용가능한 통상의 불활성 담체 및 희석제를 포함할 수 있다. The pharmaceutical composition of the present invention may be formulated and administered in a unit dosage form suitable for administration in the body of a patient according to a conventional method in the pharmaceutical field, and the preparation may be administered effectively by one or several administrations. includes the amount As a formulation suitable for this purpose, an injection, an infusion, etc. are preferable as a preparation for parenteral administration. In addition, the pharmaceutical composition may contain conventional pharmaceutically acceptable inert carriers and diluents.
본 발명의 약학 조성물에 포함될 수 있는 약학적으로 허용가능한 담체 및 희석제는 전분, 당, 및 만니톨과 같은 부형제, 칼슘 포스페이트 등과 같은 충전제 및 증량제, 카르복시메틸셀룰로오스, 히드록시프로필셀룰로오스 등과 같은 셀룰로오스 유도체, 젤라틴, 알긴산염, 및 폴리비닐 피롤리돈 등과 같은 결합제, 활석, 스테아린산 칼슘, 수소화 피마자유 및 폴리에틸렌 글리콜과 같은 윤활제, 포비돈, 크로스포비돈과 같은 붕해제, 폴리소르베이트, 세틸알코올, 및 글리세롤 등과 같은 계면활성제를 포함하나, 이에 한정되지 않는다. 상기 약학적으로 허용되는 담체 및 희석제는 복합 추출물 및 이를 투여받을 수혜자에 대해 생물학적 및 생리학적으로 친화적인 것일 수 있다. 희석제로는 이에 한정되지 않으나, 염수, 수용성 완충액, 용매 및/또는 분산제(dispersion media)를 들 수 있다. 이외에도, 예를 들어, 주사제의 경우에는 보존제, 무통화제, 가용화제 또는 안정화제 등을, 국소투여용 제제의 경우에는 기제(base), 부형제, 윤활제 또는 보존제 등을 추가로 포함할 수 있다. 본 발명의 조성물은 동결되지 않은 채 사용되거나 차후 사용을 위해 동결될 수 있다. 동결되어야 할 경우, 표준 냉동보존제 (예를 들어 DMSO, 글리세롤, 에피라이프 (Epilife®) 세포 동결 배지 (Cascade Biologics))가 동결 전 세포 집단에 첨가될 수 있다.Pharmaceutically acceptable carriers and diluents that may be included in the pharmaceutical composition of the present invention include excipients such as starch, sugar, and mannitol, fillers and extenders such as calcium phosphate, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, gelatin, etc. , alginate, and binders such as polyvinyl pyrrolidone, lubricants such as talc, calcium stearate, hydrogenated castor oil and polyethylene glycol, disintegrants such as povidone, crospovidone, interfacial agents such as polysorbate, cetyl alcohol, and glycerol active agents, but are not limited thereto. The pharmaceutically acceptable carrier and diluent may be biologically and physiologically compatible with the complex extract and the recipient to which it will be administered. Diluents include, but are not limited to, saline, aqueous buffers, solvents, and/or dispersion media. In addition, for example, in the case of injections, preservatives, analgesics, solubilizers or stabilizers, etc., and in the case of formulations for topical administration, a base, excipients, lubricants or preservatives, etc. may be further included. The compositions of the present invention may be used undisturbed or frozen for later use. If frozen, standard cryopreservatives (eg DMSO, glycerol, Epilife ® Cell Freezing Medium (Cascade Biologics)) can be added to the cell population prior to freezing.
유효성분의 투여량은 치료하고자 하는 질환, 질환의 중증도, 투여경로, 환자의 체중, 연령 및 성별 등의 여러 관련 인자에 비추어 결정되어야 하는 것으로 이해되어야 하며, 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.It should be understood that the dosage of the active ingredient should be determined in light of several related factors such as the disease to be treated, the severity of the disease, the route of administration, the patient's weight, age, and sex, and therefore, the dosage should be determined in any way. It does not limit the scope of the invention.
상기 병원성 진균에 의해 유발되는 질환은 칸디다성 피부염, 칸디다성 육아종, 칸디다성 구내염, 칸디다성 질염, 칸디다성 귀두염, 칸디다성 요도염, 칸디다성 장염, 칸디다성 수막염, 칸디다성 심내막염, 칸디다성 패혈증, 칸디다성 손발톱염 및 신생아 칸디다증으로 이루어진 군으로부터 선택될 수 있으며, 이에 제한되는 것은 아니다.Diseases caused by the pathogenic fungus include Candida dermatitis, Candida granuloma, Candida stomatitis, Candida vaginitis, Candida balanitis, Candida urethritis, Candida enteritis, Candida meningitis, Candida endocarditis, Candida sepsis, Candida and may be selected from the group consisting of onychoycosis and neonatal candidiasis, but is not limited thereto.
또한, 본 발명은 하기 화학식 1로 표시되는 아리피프라졸 또는 이의 염을 유효성분으로 함유하는 병원성 진균에 의해 유발되는 질환에 대한 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving diseases caused by pathogenic fungi containing aripiprazole represented by the following formula (1) or a salt thereof as an active ingredient.
[화학식 1][Formula 1]
본 발명은 통상적으로 이용되는 식품으로써 일반적으로 사용될 수 있다. The present invention can be generally used as a commonly used food product.
본 발명의 식품 조성물은 건강기능식품으로서 사용될 수 있다. 상기 "건강기능식품"이라 함은 건강기능식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The food composition of the present invention can be used as a health functional food. The term "health functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body in accordance with the Health Functional Food Act, and "functionality" refers to the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological effects.
본 발명의 식품 조성물은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. The food composition of the present invention may contain conventional food additives, and the suitability as the "food additive" is determined according to the general rules and general test methods of food additives approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the standards and standards related to the item.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류들을 들 수 있다.The items listed in the "Food Additives Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; Mixed preparations such as sodium L-glutamate preparation, noodle-added alkali agent, preservative agent, and tar color agent can be mentioned.
본 발명의 식품 조성물은 병원성 진균에 의해 유발되는 질환의 예방 및/또는 개선을 목적으로, 정제, 캡슐, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing and/or improving diseases caused by pathogenic fungi.
예를 들어, 캡슐 형태의 건강기능식품 중 경질캡슐제는 통상의 경질캡슐에 본 발명에 따른 복합 추출물 및 부형제 등의 첨가제와의 혼합물을 충진하여 제조할 수 있으며, 연질캡슐제는 본 발명에 따른 식품 조성물 및 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캡슐기제에 충진하여 제조할 수 있다. 상기 연질캡슐제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.For example, among health functional foods in the form of capsules, hard capsules can be prepared by filling a mixture with additives such as a complex extract and excipients according to the present invention in a conventional hard capsule, and the soft capsule according to the present invention It can be prepared by filling a mixture with additives such as a food composition and excipients in a capsule base such as gelatin. The soft capsule formulation may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함한다 (대한약전 해설편, 문성사, 한국약학대학협의회, 제 5 개정판, p33-48, 1989).The term definitions for the excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, etc. are described in documents known in the art and include those having the same or similar functions (Explanation of the Korean Pharmacopoeia, Moonseongsa, Korea) Association of Colleges of Pharmacy, 5th ed., p33-48, 1989).
상기 식품의 종류에는 특별한 제한이 없으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the type of food, and includes all health functional foods in the ordinary sense.
이하, 본 발명의 이해를 돕기 위하여 실험예 및 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실험예 및 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실험예 및 실시예에 한정되는 것은 아니다. 본 발명의 실험예 및 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, experimental examples and examples will be described in detail to help the understanding of the present invention. However, the following experimental examples and examples are only to illustrate the content of the present invention, the scope of the present invention is not limited to the following experimental examples and examples. Experimental examples and examples of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.
<실험예> 실험 재료 및 방법<Experimental example> Experimental material and method
하기의 실험예들은 본 발명에 따른 각각의 실시예에 공통적으로 적용되는 실험예를 제공하기 위한 것이다.The following experimental examples are intended to provide experimental examples commonly applied to each embodiment according to the present invention.
1. 효모 균주 및 배양 조건1. Yeast strains and culture conditions
여러 항진균제에 대한 내성을 나타내는 칸디다 알비칸스(Candida albicans)로서 DAY 185, ATCC 10231, ATCC 24433, 및 ATCC 18804 균주를 한국 미생물 센터(Korean Culture Centre of Microorganisms) 또는 American Type Culture Collection에서 분양 받았다. 효모 균주들은 PDA(potato dextrose agar), PDB(potato dextrose broth) 및/또는 RPMI(Roswell Park Memorial Institute medium-1640) 배지에 배양되었다.
아리피프라졸(Aripiprazole), 이트라코나졸(itraconazole), 케토코나졸(ketoconazole) 및 암포테리신 B(amphotericin B)는 시그마사(Sigma Aldrich, USA)로부터 구입하고, DMSO(dimethyl sulphoxide)에 용해하여 사용하였다. Aripiprazole, itraconazole, ketoconazole and amphotericin B were purchased from Sigma Aldrich, USA, and dissolved in DMSO (dimethyl sulphoxide).
이트라코나졸(itraconazole) 및 케토코나졸(ketoconazole)은 곰팡이에 의한 피부질환 및 감염 치료에 사용되는 아졸(azole)계 항진균제이고, 암포테리신 B(amphotericin B)은 진균에 대한 넓은 항균 스펙트럼을 가진 폴리엔계 항진균제이다.Itraconazole and ketoconazole are azole antifungals used to treat skin diseases and infections caused by fungi, and amphotericin B is a polyene antifungal agent with a broad antibacterial spectrum against fungi. .
2. 폴리스티렌 플레이트 생물막(Polystyrene plate biofilm) 분석2. Polystyrene plate biofilm analysis
생물막 분석은 크리스탈 바이올렛 염색법을 사용하여 96-웰 마이크로타이터 플레이트(Microtiter plates)에서 수행하였다. 각각의 칸디다 알비칸스(Candida albicans) 균주들을 PDB 배지에 접종하고, 37℃에 밤새 진탕배양 하였다. 배양물을 새로운 PDB 배지가 분주된 마이크로타이터 플레이트(Microtitre plate)에 다시 접종하고, 아리피프라졸, 이트라코나졸, 또는 케토코나졸을 0 μg/mL, 10 μg/mL, 25 μg/mL, 50 μg/mL 농도로 처리하고, 24 시간 동안 37℃에서 정치 배양하였다.Biofilm analysis was performed in 96-well microtiter plates using crystal violet staining. Each Candida albicans ( Candida albicans ) strains were inoculated in PDB medium, and cultured with shaking at 37°C overnight. The culture was re-inoculated into a microtiter plate with fresh PDB medium, and aripiprazole, itraconazole, or ketoconazole was added at concentrations of 0 μg/mL, 10 μg/mL, 25 μg/mL, and 50 μg/mL. treated and incubated at 37° C. for 24 hours.
플레이트 바닥에 부착된 생물막을 0.1% 크리스탈 바이올렛으로 20분 동안 염색한 후, 멸균수로 반복 세척하고 95% 에탄올에 재현탁하였다. 570 nm에서 XTT 분석을 통해 각각의 플레이트에 대한 OD570을 측정하여 생물막의 형성 정도를 평가하였다.The biofilm attached to the bottom of the plate was stained with 0.1% crystal violet for 20 minutes, washed repeatedly with sterile water and resuspended in 95% ethanol. The degree of biofilm formation was evaluated by measuring OD 570 for each plate through XTT analysis at 570 nm.
3. 최소 억제 농도(MIC) 측정3. Determination of Minimum Inhibitory Concentration (MIC)
아리피프라졸 및 케토코나졸의 최소 억제 농도(MIC)는 14 mL 폴리스티렌 튜브(SPL Life Sciences, Korea)를 이용하여 연속 희석법으로 측정하였다. 각각의 칸디다 알비칸스(Candida albicans) 균주들(DAY 185, ATCC 10231, ATCC 24433, 또는 ATCC 18804)을 배양액에 배양한 후, 아리피프라졸 또는 케토코나졸을 0 μg/mL, 100 μg/mL, 200 μg/mL, 300 μg/mL, 또는 500 μg/mL 농도로 처리하고, 37℃에서 24 시간 동안 250 rpm으로 진탕배양하였다. 620 nm에서 OD620을 측정하였다. The minimum inhibitory concentration (MIC) of aripiprazole and ketoconazole was measured by serial dilution using a 14 mL polystyrene tube (SPL Life Sciences, Korea). After culturing each Candida albicans strain (
4. 스테롤 염색 및 cAMP r 분석4. Sterol Staining and cAMP r Assay
칸디다 알비칸스(Candida albicans) 균주의 막에 존재하는 스테롤 변화는 필리핀(filipin) 염색법으로 분석하였다. 칸디다 알비칸스(Candida albicans) ATCC 10231 균주를 밤새 배양한 후, 아리피프라졸 또는 케토코나졸 50 μg/mL가 첨가된 PDB에 접종하고, 37℃항온조건에서 90분 동안 250 rpm으로 진탕 배양하며, 20 μg/mL 필리핀(Sigma-Aldrich, USA)으로 30분 동안 가성균사를 염색하였다. iRiS?? 디지털 셀 이미징 시스템(Logos Bio Systems, Korea)에서 DAPi 필터를 사용하여 배양된 균주의 형태를 관찰하였다.Candida albicans ( Candida albicans ) Changes in sterols present in the membrane of the strain were analyzed by filipin staining. After culturing Candida albicans
5. PI(Propidium iodide) 염색 분석5. PI (Propidium iodide) staining analysis
칸디다 알비칸스(Candida albicans) 균주의 막이 손상된 정도를 분석하기 위해 PI(Propidium iodide)로 염색하였다. 아리피프라졸 또는 케토코나졸이 250 μg/mL가 첨가된 PDB 또는 첨가제가 없는 PCB에 배양된 칸디다 알비칸스(Candida albicans) ATCC 10231 균주를 펠렛화하고, 1시간동안 30 μM의 PI로 염색하였다. 이후, 증류수로 세척한 후, 녹색 자외선 LED 조건 하에서 형광 현미경(iRiS?? 디지털 셀 이미징 시스템)으로 관찰하였다.Candida albicans ( Candida albicans ) To analyze the degree of damage to the membrane of the strain was stained with PI (Propidium iodide). Candida albicans
6. 분자 도킹(Molecular docking) 분석(6. Molecular docking analysis ( in silicoin silico ))
아졸 표적에 대한 아리피프라졸 유도체 또는 기존 항진균 아졸의 결합 방식을 대비하기 위해, 분자 도킹을 이용한 전산 연구를 수행하였다. Protein Data Bank (PDB: 5V5Z, DOI: 10.2210/pdb5V5Z/pdb)에서 검색된 칸디다 알비칸스(Candida albicans)의 라노스테롤 14-알파 데메틸라아제(anosterol 14-alpha-demethylase; CYP51)와 아리피프라졸 유도체 또는 기존 항진균 아졸 사이의 상호작용은 Schrodinger Maestro 11.4(Schrodinger Software Solutions, USA)을 사용하여 분석하였다. In order to prepare for the binding method of an aripiprazole derivative or an existing antifungal azole to the azole target, a computational study using molecular docking was performed. Lanosterol 14-alpha-demethylase (CYP51) and aripiprazole derivatives of Candida albicans retrieved from Protein Data Bank (PDB: 5V5Z, DOI: 10.2210/pdb5V5Z/pdb) Interactions between antifungal azoles were analyzed using Schrodinger Maestro 11.4 (Schrodinger Software Solutions, USA).
7. 유전자 발현 분석7. Gene Expression Analysis
아리피프라졸을 처리함에 따른 칸디다 알비칸스(Candida albicans) 균주의 ERG3, ERG11 및 HWP1 유전자의 발현 변화는 qRT-PCR로 분석하였다. RND18은 항존유전자(housekeeping)로 사용하였다. RND18의 발현 정도 1을 기준으로 ERG3, ERG11 및 HWP1의 발현 정도를 비교하여 유전자의 발현 정도를 배수로 측정하였다.Changes in the expression of ERG3, ERG11 and HWP1 genes of Candida albicans strains by treatment with aripiprazole were analyzed by qRT-PCR. RND18 was used as a housekeeping gene. By comparing the expression levels of ERG3, ERG11 and HWP1 with respect to the expression level 1 of RND18, the expression level of the gene was measured in multiples.
8. 통계 분석8. Statistical Analysis
모든 실험은 3 반복 수행되었으며, 결과는 평균 ± 표준편차로 나타나며, SPSS version 23 (SPSS Inc., Chicago, IL, USA) Dunnett 테스트에 따른 one-way ANOVA을 이용한 통계분석이 수행되었으며, p 값이 <0.05, <0.01, 또는 <0.0001 일때 유의한 것으로 간주하였다.All experiments were performed in triplicate, and the results are presented as mean ± standard deviation. Statistical analysis using one-way ANOVA according to SPSS version 23 (SPSS Inc., Chicago, IL, USA) Dunnett test was performed, and the p value was <0.05, <0.01, or <0.0001 was considered significant.
실시예 1. 아리피프라졸이 생물막 형성에 미치는 영향 평가Example 1. Evaluation of the effect of aripiprazole on biofilm formation
아리피프라졸이 병원성 진균의 생물막 형성을 억제하는지 확인하기 위해, 칸디다 알비칸스(Candida albicans) 균주의 생물막 형성 억제 정도를 평가하였다.To determine whether aripiprazole inhibits the biofilm formation of pathogenic fungi, Candida albicans ( Candida albicans ) The degree of inhibition of biofilm formation of the strain was evaluated.
칸디다 알비칸스(Candida albicans) ATCC 10231 균주는 케토코나졸을 처리하는 농도에 따라 생물막 형성 및 성장이 억제되는 것으로 확인되었으나, 이트라코나졸을 처리하는 경우 균주의 성장 또는 생물막 형성에 아무런 영향을 미치지 못했다. 이트라코나졸에 완전한 내성을 나타내는 칸디다 알비칸스(Candida albicans) ATCC 10231 균주에 아리피프라졸 또는 케토코나졸을 처리함에 따른 생물막 형성 정도를 실험예의 방법에 따라 확인하였다.Candida albicans ( Candida albicans )
도 2에 나타난 바와 같이, 아리피프라졸은 플리스티렌 표면에 형성된 칸디다 알비칸스(Candida albicans) 균주의 생물막 형성을 방지하였다.As shown in FIG. 2 , aripiprazole prevented the biofilm formation of Candida albicans strains formed on the surface of polystyrene.
아리피프라졸이 10 μg/mL 처리한 경우, 처라히자 않은 대조군에 비해 칸디다 알비칸스(Candida albicans) 균주의 생물막 형성 정도가 60% 이상 현저하게 감소하였고, 25 μg/mL 또는 50 μg/mL 처리한 경우, 각각 80% 또는 90% 정도 감소하였다. When aripiprazole was treated with 10 μg/mL, the degree of biofilm formation of the Candida albicans strain was significantly reduced by more than 60% compared to the control group that was not treated, and when treated with 25 μg/mL or 50 μg/mL, decreased by 80% or 90%, respectively.
반면, 케토코나졸은 칸디다 알비칸스(Candida albicans) 균주의 생물막 형성에 영향을 주지 않았으며, 케토코나졸 50 μg/mL 처리한 경우에 생물막이 50% 감소하였다.On the other hand, ketoconazole did not affect the biofilm formation of Candida albicans strain, and the biofilm was reduced by 50% when treated with ketoconazole 50 μg/mL.
또한, 아리피프라졸은 다중 약물 내성을 나타내는 칸디다 알비칸스(Candida albicans) DAY 185 균주의 생물막 형성을 억제하는 것이 확인되었으며, 상기 결과는 아리피프라졸이 기존 항진균제에 대한 내성을 나타내는 진균의 생물막 형성을 억제하는 효과가 있음을 입증해 주며, 다중약물내성을 나타내는 병원성 진균에 대한 방제 및 항진균 효과가 우수하다는 것을 시사한다. In addition, it was confirmed that aripiprazole inhibits the biofilm formation of Candida albicans
실시예 2. 아리피프라졸이 진균의 성장에 미치는 영향 평가Example 2. Evaluation of the effect of aripiprazole on the growth of fungi
아리피프라졸이 병원성 진균의 성장을 억제하는지 확인하기 위해, 칸디다 알비칸스(Candida albicans) 균주에 대한 아리피프라졸의 MIC 농도를 측정하였다.To determine whether aripiprazole inhibits the growth of pathogenic fungi, the MIC concentration of aripiprazole against Candida albicans strains was measured.
도 2에 나타난 바와 같이, 아리피프라졸을 처리하는 농도에 따라 칸디다 알비칸스(Candida albicans) ATCC 10231 균주의 성장을 억제하는 효과가 증가하였으며, 칸디다 알비칸스(Candida albicans) ATCC 10231 균주가 90% 사멸하는 아리피프라졸 또는 케토코나졸의 농도인 MIC90은 각각 500 μg/mL 이상으로 나타났다.As shown in Figure 2, the effect of inhibiting the growth of Candida albicans
아리피프라졸 및 케토코나졸을 다른 칸디다 알비칸스(Candida albicans) 균주(ATCC 24403 및 ATCC 18804)에 대해서는 MIC90가 100 μg/mL 이하로 균주의 성장을 억제하는 효과가 현저히 우수하였다.For aripiprazole and ketoconazole, other Candida albicans strains (ATCC 24403 and ATCC 18804) had a MIC 90 of 100 μg/mL or less, and the effect of inhibiting the growth of the strain was remarkably excellent.
상기 결과는 아리피프라졸이 칸디다 알비칸스(Candida albicans) 균주에 대한 성장 억제 효과가 케토코나졸과 유사한 메커니즘으로 작용한다는 것을 시사한다.The above results suggest that aripiprazole has a growth inhibitory effect on Candida albicans strains by a mechanism similar to that of ketoconazole.
실시예 3. 아리피프라졸이 진균의 균사 형성에 미치는 영향 평가Example 3. Evaluation of the effect of aripiprazole on the mycelium formation of fungi
아리피프라졸이 병원성 진균의 균사 형성을 억제하는지 확인하기 위해, 아리피프라졸이 처리된 칸디다 알비칸스(Candida albicans) 균주의 콜로니를 관찰하였다.In order to determine whether aripiprazole inhibits the mycelial formation of pathogenic fungi, the colonies of the aripiprazole-treated Candida albicans strain were observed.
칸디다 알비칸스(Candida albicans)는 효모 형태 또는 균사 형태로 전환할 수 있으며, 칸디다 알비칸스(Candida albicans)가 효모 형태에서 균사 형태로 전환되었을 때에 다양한 질환을 유발하는 병원성을 나타낸다. 따라서 칸디다 알비칸스(Candida albicans) 균주의 균사 형성을 억제한다는 것은 칸디다 알비칸스(Candida albicans) 균주의 병원성을 억제하는 것을 의미하며, 칸디다 알비칸스(Candida albicans) 균주에 의해 유발되는 다양한 질병에 대한 예방 또는 방제 효과가 있다는 것을 시사한다.Candida albicans ( Candida albicans ) can be converted to yeast form or mycelial form, Candida albicans ( Candida albicans ) When converted from yeast form to mycelial form, it exhibits pathogenicity causing various diseases. Therefore, Candida albicans (Candida albicans) preventive for various diseases of suppressing the mycelial formation of strain is meant to inhibit virulence of Candida albicans (Candida albicans) strain and induced by Candida albicans (Candida albicans) strains Or suggesting that there is a control effect.
도 3에 나타난 바와 같이, 칸디다 알비칸스(Candida albicans) 균주에 아리피프라졸을 처리하면 가장자리가 매끄럽고 균사 돌기가 형성되지 않았다. 칸디다 알비칸스(Candida albicans) DAY 185 균주의 경우 대조군에서는 균사 필라멘트가 표면에 형성되었으나, 아리피프라졸을 처리하자 이러한 균사 필라멘트가 형성되지 않음을 확인하였다.As shown in Figure 3, Candida albicans ( Candida albicans ) When aripiprazole was treated with a strain, the edges were smooth and mycelial projections were not formed. Candida albicans ( Candida albicans ) In the case of the
또한, 도 4에 나타난 바와 같이, 칸디다 알비칸스(Candida albicans) 대조군의 경우 콜로니에 불규칙한 주름 패턴이 나타났지만, 아리피프라졸을 처리한 균주에서는 이러한 콜로니 주름 패턴이 형성되지 않았다. 칸디다 알비칸스(Candida albicans)에서 콜로니의 주름은 생물막을 형성하는 것과 관련이 있다고 알려져 있으며, 상기 아리피프라졸이 칸디다 알비칸스(Candida albicans) 균주의 콜로니 주름 형성을 억제하는 것은 칸디다 알비칸스(Candida albicans) 균주의 생물막 형성을 억제하는 효과가 있다는 것을 시사한다.In addition, as shown in Figure 4, Candida albicans ( Candida albicans ) In the case of the control group, an irregular wrinkle pattern appeared in the colony, but this colony wrinkle pattern was not formed in the strain treated with aripiprazole. Candida albicans ( Candida albicans ) Colony wrinkles are known to be related to the formation of a biofilm, the aripiprazole Candida albicans ( Candida albicans ) Inhibiting the colony wrinkle formation of the strain Candida albicans ( Candida albicans ) strain suggest that it has the effect of inhibiting the formation of biofilms of
또한, 혐기성 조건에서 칸디다 알비칸스(Candida albicans) 균주에 아리피프라졸을 처리하자 효모-균사 전환이 억제되었다. 도 5에 나타난 바와 같이, 칸디다 알비칸스(Candida albicans) ATCC 10231 균주 및 DAY 185 균주는 대조군에서는 균사의 형태를 나타냈으나, 25 μg/mL 또는 50 μg/mL의 아리피프라졸을 처리하자 균사의 형태가 관찰되지 않았다. In addition, when aripiprazole was treated in Candida albicans strains under anaerobic conditions, yeast-mycelial conversion was inhibited. As shown in Figure 5, Candida albicans ( Candida albicans )
다양한 아졸계 또는 폴리엔계 항진균제가 혐기성 조건에서 칸디다 알비칸스(Candida albicans) 균주가 균사로 전환되는 것을 억제하지 못하였으나, 상기 결과를 고려해 볼 때, 아리피프라졸은 혐기성에서도 효모-균사 전환을 완전히 억제하는 것으로 나타났으며, 이는 기존의 아졸계 또는 폴리엔계 항진균제보다 진균의 병원성을 억제하는 효과가 우수하다는 것을 시사한다. Various azole-based or polyene-based antifungal agents did not inhibit the conversion of Candida albicans strains to mycelium under anaerobic conditions, but considering the above results, aripiprazole was found to completely inhibit yeast-mycelial conversion even anaerobically. appeared, suggesting that the effect of inhibiting the pathogenicity of fungi is superior to that of the existing azole-based or polyene-based antifungal agents.
실시예 4. 아리피프라졸이 응집체 형성에 미치는 영향 평가Example 4. Evaluation of the effect of aripiprazole on aggregate formation
프록(flocs) 또는 응집체(aggregates)는 열악한 환경에서 스트레스를 피하고 세포를 보호할 수 있도록 형성하는 효모의 응집성 클러스터이다. 응집체 형성은 병원성 진균이 인체의 면역 반응을 피하고 장기간 생존하게 하며, 응집을 통한 교배를 촉진하기 때문에 병원성 진균의 확산을 유도한다. 따라서 병원성 진균의 응집체(aggregates) 형성을 억제하면, 병원성 진균을 제거할 뿐만 아니라, 확산되는 것을 억제하는 효과가 나타낸다.Flocs or aggregates are cohesive clusters of yeast that form in harsh environments to avoid stress and protect cells. Aggregate formation induces the spread of pathogenic fungi because the pathogenic fungi avoid the body's immune response and survive long-term, and promote mating through aggregation. Therefore, when the formation of aggregates (aggregates) of the pathogenic fungus is suppressed, the effect of suppressing the spread of the pathogenic fungus as well as removing the pathogenic fungus is exhibited.
칸디다 알비칸스(Candida albicans) ATCC 10231 균주 및 DAY 185 균주에 3% 인간 혈청을 처리하여 응집체 형성을 유도하고, 아리피프라졸이 응집체 형성을 억제하는 지 확인하였다.Candida albicans ( Candida albicans ) The
도 6에 나타난 바와 같이, 3% 인간 혈청이 처리된 칸디다 알비칸스(Candida albicans) 균주에서는 응집체가 발견되었으나, 아리피프라졸이 처리된 균주에서는 응집체가 발견되지 않았다. 또한, 케토코나졸을 처리한 경우 대조군 보다는 응집체를 형성하지 않았으나, 약간의 응집체가 발견되었다. As shown in FIG. 6 , aggregates were found in the Candida albicans strain treated with 3% human serum, but no aggregates were found in the strain treated with aripiprazole. In addition, when ketoconazole was treated, no aggregates were formed than the control, but some aggregates were found.
상기 결과는 아리피프라졸이 케토코나졸 보다 진균의 응집체 형성을 억제하는 효과가 우수하며, 병원성 진균에 대한 제거 및 방제 효과가 우수하다는 것을 시사한다.The above results suggest that aripiprazole is superior to ketoconazole in inhibiting the formation of fungal aggregates, and has superior removal and control effects on pathogenic fungi.
실시예 5. 아리피프라졸이 cAMP 경로 또는 활성 ROS에 미치는 영향 평가Example 5. Evaluation of the effect of aripiprazole on the cAMP pathway or active ROS
아리피프라졸이 칸디다 알비칸스(Candida albicans) 균주의 균사 형성과 관련된 메커니즘에 미치는 영향을 분석하기 위해 아리피프라졸 처리에 따른 ROS/cAMP/PKA 신호 전달 경로 변화를 평가하였다.In order to analyze the effect of aripiprazole on the mechanisms related to mycelial formation in Candida albicans strains, changes in the ROS/cAMP/PKA signaling pathway following aripiprazole treatment were evaluated.
ROS/cAMP/PKA 신호 전달 경로는 칸디다 알비칸스(Candida albicans)에서 균사 형태 전환 및 생물막 형성과 관련된 주요 신호 전달 경로이다. The ROS/cAMP/PKA signaling pathway is a major signaling pathway involved in mycelial morphogenesis and biofilm formation in Candida albicans.
도 7에 나타난 바와 같이, 아리피프라졸에 의해 생물막 및 균사 형성 억제 효과는 cAMP 활성화제인 db-cAMP(dibutyryl-cAMP)로도 회복되지 않았으며, 상기 결과는 아리피프라졸의 생물막 및 균사 형성 억제 효과는 cAMP 경로와 관련이 없음을 시사해준다.As shown in Figure 7, the biofilm and mycelial formation inhibitory effect by aripiprazole was not recovered even with the cAMP activator db-cAMP (dibutyryl-cAMP), and the results indicate that the biofilm and mycelial formation inhibitory effect of aripiprazole is related to the cAMP pathway. suggests that there is no
또한, 도 8에 나타나바와 같이, 카르복시-H2DCFDA 염색을 통해 ROS-유도 세포 사멸을 관찰한 결과, H2O2가 처리된 균주에서만 상산화 반응이 나타났으며, 아리피프라졸 처리군에서는 나타나지 않은 것을 보아, 아리피프라졸은 칸디다 알비칸스(Candida albicans)에서 항산화 반응을 유발하지 않는다는 것을 시사한다.In addition, as shown in Figure 8, as a result of observing ROS-induced apoptosis through carboxy-H2DCFDA staining, the upper oxidation reaction was observed only in the H 2 O 2 treated strain, but not in the aripiprazole treatment group. , suggesting that aripiprazole does not induce an antioxidant response in Candida albicans.
실시예 6. 아리피프라졸이 진균의 세포막에 미치는 영향 평가Example 6. Evaluation of the effect of aripiprazole on fungal cell membranes
아리피프라졸이 병원성 진균의 성장을 억제하는지 확인하기 위해, 칸디다 알비칸스(Candida albicans) 균주에 대한 아리피프라졸의 MIC 농도를 측정하였다.To determine whether aripiprazole inhibits the growth of pathogenic fungi, the MIC concentration of aripiprazole against Candida albicans strains was measured.
필리핀(filipin)은 진균에서 에르고스테롤(ergosterol)을 정략적으로 분석하는 생물학적 마커로 사용되며, 필리핀 염색을 이용하여 칸디다 알비칸스(Candida albicans)의 스테롤 분포 변화를 관찰하였다.Filipin is used as a biological marker for quantitative analysis of ergosterol in fungi, and changes in sterol distribution of Candida albicans were observed using Filipino staining.
도 9 및 10에 나타난 바와 같이, 칸디다 알비칸스(Candida albicans) ATCC 10231 균주는 가성균사(pseudo hyphae)의 끝에 필리핀 형광이 집중되는 것이 관찰되었으나, 아리피프라졸을 처리한 균주에서는 가성균사 형성이 완전히 차단되고, 균주 세포의 80%에서 가성 균사 형성을 위한 스테롤 분극이 관찰되지 않았다.As shown in Figures 9 and 10, Candida albicans
또한, 도 11에 나타난 바와 같이, 아리피프라졸 또는 케토코나졸이 처리된 칸디다 알비칸스(Candida albicans) ATCC 10231 균주는 70% 이상 세포막이 손상된 것을 확인하였다.In addition, as shown in Figure 11, aripiprazole or ketoconazole-treated Candida albicans ( Candida albicans )
상기 결과는 아리피프라졸이 비가역적으로 병원성 진균의 세포막에 스테롤 합성 및 재배치를 억제하고 세포막을 파괴하는 것을 시사한다.These results suggest that aripiprazole irreversibly inhibits sterol synthesis and rearrangement in the cell membrane of pathogenic fungi and destroys the cell membrane.
실시예 7. 아리피프라졸과 진균의 라노스테롤 14-알파 데메틸라아제(lanosterol 14-alpha-demethylase) 사이의 상호작용 분석Example 7. Analysis of the interaction between aripiprazole and fungal lanosterol 14-alpha-demethylase
아졸계 항진균제는 진균의 라노스테롤 14-알파 데메틸라아제(anosterol 14-alpha-demethylase; CYP51) 억제제로 알려져 있다. 따라서 아리피프라졸이 병원성 진균에 대한 항진균 효과가 CYP51 억제와 관련이 있는지를 확인하기 위해 분자 도킹을 이용하여 아리피프라졸과 CYP51의 상호작용을 분석하였다.Azole-based antifungal agents are known as inhibitors of fungal lanosterol 14-alpha-demethylase (CYP51). Therefore, to determine whether aripiprazole's antifungal effect on pathogenic fungi is related to CYP51 inhibition, the interaction between aripiprazole and CYP51 was analyzed using molecular docking.
CYP51는 진균에서 라노스테롤(lanosterol)을 에르고스테롤(ergosterol)로 전환하는 효소이며, 에르고스테롤의 형성이 억제되면, 세포막 형성이 억제되고, 막 손상이 발생된다. CYP51 is an enzyme that converts lanosterol to ergosterol in fungi. When the formation of ergosterol is inhibited, cell membrane formation is inhibited and membrane damage occurs.
도 12에 나타난 바와 같이, 아리피프라졸은 CYP51의 Hem601 그룹과 상호작용하였으며, 다른 아졸계 항진균제와 동일하게 Tyr118와 π-π 면대 모서리 상호작용이 나타났다. 아리피프라졸의 GScore 및 결합 에너지는 -7.4 kcal/moL 및 -73.48 kcal/moL로 측정되었으며, 상기 아리피프라졸은 이트라코나졸 및 케토코나졸과 유사하였다.As shown in FIG. 12 , aripiprazole interacted with the Hem 601 group of CYP51, and π-π face-to-face interaction with Tyr 118 was shown, similarly to other azole antifungal agents. The GScore and binding energy of aripiprazole were measured to be -7.4 kcal/moL and -73.48 kcal/moL, and aripiprazole was similar to itraconazole and ketoconazole.
실시예 8.Example 8. 아리피프라졸이 진균의 유전자 발현에 미치는 영향 평가Evaluation of the effect of aripiprazole on gene expression in fungi
아리피프라졸이 병원성 진균의 스테롤 합성에 대한 유전학적으로 미치는 영향을 확인하기 위해, 진균에서 스테롤 합성과 관련된 유전자 발현 정도를 측정하였다.To determine the genetic effect of aripiprazole on sterol synthesis in pathogenic fungi, the expression level of genes related to sterol synthesis in the fungus was measured.
도 13에 나타난 바와 같이, 에르고스테롤 생합성과 관련된 유전자인 ERG3 및 CYP51를 암호하는 ERG11의 mRNA 발현 정도는 아리피프라졸에 의해 변하지 않았으며, 이는 아리피프라졸이 CYP51의 heme 보결분자단(prosthetic group)에 결합하여 결국 촉매 주기를 차단하는 효소 억제제라는 것을 시사한다.As shown in FIG. 13 , the mRNA expression levels of ERG3 and ERG11, which encode genes related to ergosterol biosynthesis, and CYP51 were not changed by aripiprazole, which resulted in aripiprazole binding to the heme prosthetic group of CYP51 It suggests that it is an enzyme inhibitor that blocks the catalytic cycle.
또한, 아리피프라졸은 HWP1(hyphal development gene; 균사 발달 유전자)의 mRNA 수준을 약 3배 정도 감소하였으며, 이는 아리피프라졸이 병원성 진균의 균사 형성을 억제하는 효과는 유전적 영향에 의한 것임을 시사한다.In addition, aripiprazole decreased the mRNA level of HWP1 (hyphal development gene) by about 3 times, suggesting that the effect of aripiprazole in inhibiting mycelial formation of pathogenic fungi is due to genetic influence.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 즉, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다.As described above in detail a specific part of the content of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.
Claims (12)
상기 병원성 진균은 칸디다 알비칸스(Candida albicans), 칸디다 크루세이(C. krusei), 칸디다 트로피칼리스(C. tropicalis), 칸디다 글라브라타(C. glabrata), 칸디다 파라프실로시스(C. parapsilosis), 칸디다 두블리니엔시스(C. dubliniensis), 및 칸디다 루시타니에(C. lusitaniae)로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는 항진균용 조성물.
[화학식 1]
As an antifungal composition for pathogenic fungi containing aripiprazole represented by the following formula (1) or a salt thereof as an active ingredient,
The pathogenic fungi are Candida albicans ( Candida albicans ), Candida krusei ( C. krusei ), Candida tropicalis ( C. tropicalis ), Candida glabrata ( C. glabrata ), Candida parapsilosis ( C. parapsilosis ) , Candida dubliniensis ( C. dubliniensis ), and Candida lucitaniae ( C. lusitaniae ) Antifungal composition, characterized in that at least one selected from the group consisting of.
[Formula 1]
상기 병원성 진균에 의해 유발되는 질환은 칸디다성 피부염, 칸디다성 육아종, 칸디다성 구내염, 칸디다성 질염, 칸디다성 귀두염, 칸디다성 요도염, 칸디다성 장염, 칸디다성 수막염, 칸디다성 심내막염, 칸디다성 패혈증, 칸디다성 손발톱염 및 신생아 칸디다증으로 이루어진 군으로부터 선택된 것을 특징으로 하는 병원성 진균에 의해 유발되는 질환에 대한 예방 또는 치료용 약학조성물.
[화학식 1]
As a pharmaceutical composition for preventing or treating diseases caused by pathogenic fungi containing aripiprazole represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient,
Diseases caused by the pathogenic fungus include Candida dermatitis, Candida granuloma, Candida stomatitis, Candida vaginitis, Candida balanitis, Candida urethritis, Candida enteritis, Candida meningitis, Candida endocarditis, Candida sepsis, Candida A pharmaceutical composition for preventing or treating diseases caused by pathogenic fungi, characterized in that it is selected from the group consisting of onychoblastitis and neonatal candidiasis.
[Formula 1]
상기 병원성 진균에 의해 유발되는 질환은 칸디다성 피부염, 칸디다성 육아종, 칸디다성 구내염, 칸디다성 질염, 칸디다성 귀두염, 칸디다성 요도염, 칸디다성 장염, 칸디다성 수막염, 칸디다성 심내막염, 칸디다성 패혈증, 칸디다성 손발톱염 및 신생아 칸디다증으로 이루어진 군으로부터 선택된 것을 특징으로 하는 병원성 진균에 의해 유발되는 질환에 대한 예방 또는 개선용 건강기능식품.
[화학식 1]
As a health functional food for preventing or improving diseases caused by pathogenic fungi containing aripiprazole represented by the following formula (1) or a salt thereof as an active ingredient,
Diseases caused by the pathogenic fungus include Candida dermatitis, Candida granuloma, Candida stomatitis, Candida vaginitis, Candida balanitis, Candida urethritis, Candida enteritis, Candida meningitis, Candida endocarditis, Candida sepsis, Candida A health functional food for preventing or improving diseases caused by pathogenic fungi, characterized in that it is selected from the group consisting of onychomycosis and neonatal candidiasis.
[Formula 1]
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020200009139A KR102287829B1 (en) | 2020-01-23 | 2020-01-23 | Antifungal composition comprising aripiprazole |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020200009139A KR102287829B1 (en) | 2020-01-23 | 2020-01-23 | Antifungal composition comprising aripiprazole |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20210095371A KR20210095371A (en) | 2021-08-02 |
KR102287829B1 true KR102287829B1 (en) | 2021-08-09 |
Family
ID=77313414
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020200009139A KR102287829B1 (en) | 2020-01-23 | 2020-01-23 | Antifungal composition comprising aripiprazole |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR102287829B1 (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100810032B1 (en) | 2004-10-28 | 2008-03-05 | 한국생산기술연구원 | Extract of Coptidis rhizma comprising antifungal protein |
-
2020
- 2020-01-23 KR KR1020200009139A patent/KR102287829B1/en active IP Right Grant
Non-Patent Citations (3)
Title |
---|
Antimicrobial Agents and Chemotherapy, 63(12), e00994-19/1-16, 2019.* |
Antimicrobial Agents and Chemotherapy, 63(5), e00054-19, 2019. |
J. Infect. Chemother., 29, 1141-1145, 2013. |
Also Published As
Publication number | Publication date |
---|---|
KR20210095371A (en) | 2021-08-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101374801B (en) | Histone deacetylase inhibitors for enhancing activity of antifungal agents | |
US9896442B2 (en) | Antifungal treatment | |
CN107249584A (en) | Composition and method for suppressing fungal infection | |
JP2014518878A (en) | Synergistic combinations of polyene fungicides and non-ribosomal peptides and related methods of use | |
AU2015251501B2 (en) | Agents and methods of treatment | |
Nagaraj et al. | Potent antifungal agents and use of nanocarriers to improve delivery to the infected site: A systematic review | |
KR20190133561A (en) | Antimicrobial and Antifungal Composition Comprising Eugenol and Gallic Acid as Active Ingredient | |
US9040573B2 (en) | Anti-fungal agent | |
WO2002036203A2 (en) | Azole containing compositions with enhanced antifungal activity | |
KR102287829B1 (en) | Antifungal composition comprising aripiprazole | |
EP3915538A1 (en) | Injection composition containing fab i inhibitor, and preparation method therefor | |
CN106580999B (en) | The purposes of jnk inhibitor in medicine preparation | |
KR101689033B1 (en) | Bacteriophage that kills Propionibacterium acnes | |
Liang et al. | Discovery of evodiamine derivatives as potential lead antifungal agents for the treatment of superficial fungal infections | |
MX2010011678A (en) | Methods of treating fungal infections. | |
JPWO2017038872A1 (en) | Composition having antifungal activity | |
EP4003016A1 (en) | Antimycotic | |
WO2012088100A2 (en) | Triclabendazole and fenbendazole for cell protection | |
WO2017143964A1 (en) | Novel high-efficiency antimalarial drug, quisinostat | |
KR101141938B1 (en) | Novel antibiotic compounds and methods for treating gram positive bacterial infections | |
Nehmatullah et al. | Antimicrobial potential of some plant extracts against Candida species Isolated from infants oral thrush | |
CN108660120A (en) | Anti-fungus peptide and application thereof | |
Kane et al. | Bisphosphonates synergistically enhance the antifungal activity of azoles in dermatophytes and other pathogenic molds | |
Kaur et al. | A Review on Antifungal Efficiency of Plant Extracts Entrenched Polysaccharide-Based Nanohydrogels. Nutrients 2021, 13, 2055 | |
CN1331855C (en) | Antifungal compound and its prepn process and application |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |