WO2021203702A1 - Use of pyroglutamic acid in preparation of drugs for preventing and treating novel coronavirus of novel coronavirus pneumonia - Google Patents
Use of pyroglutamic acid in preparation of drugs for preventing and treating novel coronavirus of novel coronavirus pneumonia Download PDFInfo
- Publication number
- WO2021203702A1 WO2021203702A1 PCT/CN2020/129184 CN2020129184W WO2021203702A1 WO 2021203702 A1 WO2021203702 A1 WO 2021203702A1 CN 2020129184 W CN2020129184 W CN 2020129184W WO 2021203702 A1 WO2021203702 A1 WO 2021203702A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cov
- coronavirus
- pyroglutamic acid
- preparation
- stereoisomers
- Prior art date
Links
- 241000711573 Coronaviridae Species 0.000 title claims abstract description 57
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 title claims abstract description 31
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 title claims abstract description 29
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229940079593 drug Drugs 0.000 title claims abstract description 20
- 206010035664 Pneumonia Diseases 0.000 title abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 229940002612 prodrug Drugs 0.000 claims abstract description 12
- 239000000651 prodrug Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 241000315672 SARS coronavirus Species 0.000 claims abstract description 11
- 150000001408 amides Chemical class 0.000 claims abstract description 10
- 244000309467 Human Coronavirus Species 0.000 claims abstract description 8
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims abstract description 8
- -1 acemonam Chemical compound 0.000 claims description 17
- 241000700605 Viruses Species 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 239000000645 desinfectant Substances 0.000 claims description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 4
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 claims description 4
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- IWKXBHQELWQLHF-CAPFRKAQSA-N (ne)-n-[(2-amino-3-propan-2-ylsulfonylbenzimidazol-5-yl)-phenylmethylidene]hydroxylamine Chemical compound C1=C2N(S(=O)(=O)C(C)C)C(N)=NC2=CC=C1C(=N\O)\C1=CC=CC=C1 IWKXBHQELWQLHF-CAPFRKAQSA-N 0.000 claims description 2
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 2
- LFFGEYHTAJZONR-UHFFFAOYSA-N 1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinoline;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1OCC1=NCCC2=CC=CC=C12 LFFGEYHTAJZONR-UHFFFAOYSA-N 0.000 claims description 2
- FRFMOVPIHHDDPP-UHFFFAOYSA-N 1-ethoxybutan-2-one Chemical compound CCOCC(=O)CC FRFMOVPIHHDDPP-UHFFFAOYSA-N 0.000 claims description 2
- KCURWTAZOZXKSJ-JBMRGDGGSA-N 4-amino-1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one;hydron;chloride Chemical compound Cl.O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 KCURWTAZOZXKSJ-JBMRGDGGSA-N 0.000 claims description 2
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 claims description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 claims description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 2
- 229930182555 Penicillin Natural products 0.000 claims description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 2
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 2
- IRHXGOXEBNJUSN-YOXDLBRISA-N Saquinavir mesylate Chemical compound CS(O)(=O)=O.C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 IRHXGOXEBNJUSN-YOXDLBRISA-N 0.000 claims description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- ZCDDBUOENGJMLV-QRPNPIFTSA-N Valacyclovir hydrochloride Chemical compound Cl.N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 ZCDDBUOENGJMLV-QRPNPIFTSA-N 0.000 claims description 2
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 claims description 2
- UDMBCSSLTHHNCD-UHTZMRCNSA-N [(2r,3s,4s,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O UDMBCSSLTHHNCD-UHTZMRCNSA-N 0.000 claims description 2
- 229960004748 abacavir Drugs 0.000 claims description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 2
- 229960004150 aciclovir Drugs 0.000 claims description 2
- 229940008235 acyclovir sodium Drugs 0.000 claims description 2
- 229960001997 adefovir Drugs 0.000 claims description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 2
- 229950004424 alovudine Drugs 0.000 claims description 2
- 229960003805 amantadine Drugs 0.000 claims description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229960000724 cidofovir Drugs 0.000 claims description 2
- MEPNHSOMXMALDZ-UHFFFAOYSA-N delavirdine mesylate Chemical compound CS(O)(=O)=O.CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 MEPNHSOMXMALDZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000475 delavirdine mesylate Drugs 0.000 claims description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine mesylate Natural products CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 2
- 229960002656 didanosine Drugs 0.000 claims description 2
- 230000006806 disease prevention Effects 0.000 claims description 2
- QGXLVXZRPRRCRP-MMGZGRSYSA-L disodium;[(2r,3s,4s,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@@H]1O QGXLVXZRPRRCRP-MMGZGRSYSA-L 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 229950008161 enviroxime Drugs 0.000 claims description 2
- 229960004396 famciclovir Drugs 0.000 claims description 2
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 2
- 229960002963 ganciclovir Drugs 0.000 claims description 2
- 229960002687 ganciclovir sodium Drugs 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 claims description 2
- 229960001936 indinavir Drugs 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 229960001627 lamivudine Drugs 0.000 claims description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229960004525 lopinavir Drugs 0.000 claims description 2
- CEQFOVLGLXCDCX-WUKNDPDISA-N methyl red Chemical compound C1=CC(N(C)C)=CC=C1\N=N\C1=CC=CC=C1C(O)=O CEQFOVLGLXCDCX-WUKNDPDISA-N 0.000 claims description 2
- 229960000689 nevirapine Drugs 0.000 claims description 2
- 229960003752 oseltamivir Drugs 0.000 claims description 2
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 claims description 2
- 229960001179 penciclovir Drugs 0.000 claims description 2
- 229940049954 penicillin Drugs 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 230000002685 pulmonary effect Effects 0.000 claims description 2
- 229960000329 ribavirin Drugs 0.000 claims description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 2
- 229960000888 rimantadine Drugs 0.000 claims description 2
- 229960000311 ritonavir Drugs 0.000 claims description 2
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 2
- 229960003542 saquinavir mesylate Drugs 0.000 claims description 2
- 229960001203 stavudine Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 claims description 2
- 229960003962 trifluridine Drugs 0.000 claims description 2
- 229960003636 vidarabine Drugs 0.000 claims description 2
- 229960002555 zidovudine Drugs 0.000 claims description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 2
- 241001109669 Human coronavirus HKU1 Species 0.000 claims 1
- 241001428935 Human coronavirus OC43 Species 0.000 claims 1
- 206010057190 Respiratory tract infections Diseases 0.000 claims 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims 1
- 229930182470 glycoside Natural products 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- KNBQMQYQYHZXSX-UHFFFAOYSA-M sodium;2-phosphonoacetate Chemical compound [Na+].OP(O)(=O)CC([O-])=O KNBQMQYQYHZXSX-UHFFFAOYSA-M 0.000 claims 1
- 229960000523 zalcitabine Drugs 0.000 claims 1
- 230000000840 anti-viral effect Effects 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000120 cytopathologic effect Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 3
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 229940096437 Protein S Drugs 0.000 description 2
- 101710198474 Spike protein Proteins 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229940043131 pyroglutamate Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 206010003757 Atypical pneumonia Diseases 0.000 description 1
- 241000112287 Bat coronavirus Species 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000288673 Chiroptera Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 241001573881 Corolla Species 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000028399 Critical Illness Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 241000282412 Homo Species 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
- 102100034349 Integrase Human genes 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 241000008910 Severe acute respiratory syndrome-related coronavirus Species 0.000 description 1
- 101710147732 Small envelope protein Proteins 0.000 description 1
- GCQYYIHYQMVWLT-HQNLTJAPSA-N Sorivudine Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 GCQYYIHYQMVWLT-HQNLTJAPSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- HQEQKPDTKSCKDI-UHFFFAOYSA-M [Na+].P(=O)(=O)CC(=O)[O-] Chemical compound [Na+].P(=O)(=O)CC(=O)[O-] HQEQKPDTKSCKDI-UHFFFAOYSA-M 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000012268 genome sequencing Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000035931 haemagglutination Effects 0.000 description 1
- 108010028403 hemagglutinin esterase Proteins 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 231100000028 nontoxic concentration Toxicity 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- INAAIJLSXJJHOZ-UHFFFAOYSA-N pibenzimol Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(=NC4=CC=3)C=3C=CC(O)=CC=3)C2=C1 INAAIJLSXJJHOZ-UHFFFAOYSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229950009279 sorivudine Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the invention belongs to the field of antiviral drugs, and specifically relates to the application of pyroglutamic acid in the preparation of drugs for the prevention and treatment of new coronaviruses against new coronary pneumonia.
- Coronavirus pneumonia (Corona Virus Disease 2019) is an infectious disease caused by a new coronavirus (SARS-Cov-2) infecting the human body. Its symptoms mainly include fever, fatigue, dry cough, difficulty breathing, and kidney failure. [The Lancet ,2020,395(10223):507-513; The Lancet,2020,395(10223):497-506]. New coronary pneumonia cases were reported in December 2019, followed by cases in many countries around the world, including South Korea, Japan, Thailand, Iran, Singapore, Germany, France and the United States. Coronaviruses belong to the genus Coronavirus in the family Coronaviridae (Coronaviridae).
- the virus of the genus Coronavirus is a positive-stranded single-stranded RNA virus with an envelope, with a diameter of about 80-120nm. Its genetic material is the largest among all RNA viruses, and generally only infects humans, mice, pigs, cats, and dogs. , Poultry vertebrates.
- the coronavirus was first isolated from chickens in 1937. Coronavirus particles are irregular in shape, about 60-220nm in diameter.
- the virus has an envelope structure with three proteins: Spike Protein (S, Spike Protein), Small Envelope Protein (E, Envelope Protein) and Membrane Protein (M, Membrane Protein), and a few types also have hemagglutination.
- Glycoprotein HE protein, Haemaglutinin-esterase
- SARS-Cov-2 virus particles The diameter of SARS-Cov-2 virus particles is between 60nm and 140nm, and there are 9-12nm spikes outside the envelope, resembling a corolla. Genome sequencing showed that SARS-Cov-2 is a single-stranded RNA coronavirus. By comparison with the gene sequences of other virus samples, it is found that SARS-Cov-2 is similar to SARS-CoV (79.5%) [Nature,2020] and bat coronavirus (96%) [bioRxiv,2020,2020.01.22.914952], and speculates The virus may originate from bats [bioRxiv, 2020, 2020.01.24.915157; Nature, 2020].
- the 2019-nCoV virus belongs to ⁇ CoV, which is the seventh member of the HCoV family that is different from SARS-CoV and MERS-CoV [New England Journal of Medicine, 2020].
- the remaining 6 members include HCoV 229E, NL63, OC43, HKU1, SARS -CoV and MERS-CoV.
- the new type of coronavirus pneumonia is caused by a new type of coronavirus. It is the same type of coronavirus as SARS-CoV, which is known to cause atypical pneumonia, but of different types. Although its fatality rate is lower than SARS-CoV, it is far more infectious. In SARS-CoV. Since then, South Korea, Japan, Thailand, Iran, Singapore, Germany, France, and the United States have all seen confirmed cases of the disease, indicating that the new coronavirus pneumonia epidemic may still spread. But so far, there is still no specific medicine that can cure the new type of coronavirus pneumonia. Most of the current treatment methods are symptomatic treatment, especially for some critically ill patients.
- the purpose of the present invention is to provide the application of L-pyroglutamic acid in the preparation of drugs for the prevention or treatment of new coronaviruses against new coronary pneumonia.
- the present invention provides pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of prevention and/or treatment of coronary Application in medicines for diseases caused by viruses.
- pyroglutamic acid is L-pyroglutamic acid, D-pyroglutamic acid or a mixture thereof.
- the coronaviruses are the new coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
- the disease caused by the coronavirus is pneumonia or its complications caused by any virus of SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 or MERS-CoV.
- L-pyroglutamic acid is represented by structural formula (1)
- pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs are used as the sole active ingredient Application in the preparation of medicines for preventing and/or treating diseases caused by coronaviruses.
- pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs and other antiviral The application of the composition prepared by the medicine as an active ingredient in the preparation of a medicine for preventing and/or treating diseases caused by coronavirus.
- antiviral drugs are selected from the group consisting of ganciclovir, acyclovir, amantadine, rimantadine, oseltamivir, abacavir, acemontan, and acyclovir Sodium, adefovir, alovudine, avirsuto, tricyclodecylamine hydrochloride, alanordine, aridone, ateviridine mesylate, afridine, cidofovir, western Panphylline, Emtricitabine, Cytarabine Hydrochloride, Delavirdine Mesylate, Deciclovir, Didanosine, Dioxali, Edouridine, Emivirin, Etrados Citapine, Enviraden, Enviroxime, Hepatin, Famciclovir, Chlorophenhydroisoquine Hydrochloride, Fecitabine, Feauridine, Phosphatide,
- Another aspect of the present invention provides a pharmaceutical composition for the treatment or prevention of diseases caused by coronaviruses, which comprises pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, and stereoisomers. Mixtures, tautomers, esters, amides or prodrugs.
- the pharmaceutical composition also includes pharmaceutically acceptable excipients.
- the dosage form of the pharmaceutical composition is oral preparation, pulmonary inhalation preparation, mucosal administration preparation, ophthalmic preparation or injection.
- the oral preparation is selected from granules, powders, pills, tablets, capsules or oral liquids.
- Another aspect of the present invention provides the use of pyroglutamic acid as a disinfectant against coronaviruses of the coronavirus family.
- Another aspect of the present invention provides a method for treating diseases caused by viruses of the coronavirus family, comprising adding a therapeutically effective amount of pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, stereo A mixture of isomers, tautomers, esters or prodrugs is administered to the subject.
- Another aspect of the present invention provides a method for preventing a subject from being infected with coronaviruses of the coronavirus family, which comprises adding a therapeutically effective amount of pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, Administration of mixtures of stereoisomers, tautomers, esters or prodrugs is administered to the subject prior to infection.
- the present invention proves for the first time that pyroglutamic acid has a high therapeutic index and a low half effective concentration; the pyroglutamic acid can effectively increase the antivirus effect before being infected.
- Pyroglutamate is used as an effective drug in the treatment of new coronavirus infections caused by new coronary pneumonia.
- the African green monkey kidney cells (VeroE6) were inoculated into 96-well plates at 3 ⁇ 10 5 cells/well. ; GibcoInvitrogen), incubate at 37°C, 5% CO 2 and wait until the monolayer grows up. A 100-fold dilution of the clinical isolates of the new coronavirus pneumonia new type coronavirus was inoculated into a 96-well plate full of monolayer cells, and incubated at 37°C and 5% CO 2 for two days (including the normal control group).
- the degree of disease was as high as 75%, placed in a -80°C ultra-low temperature refrigerator, repeated freezing and thawing once, collecting the amplified virus solution, centrifuged at 3000r/min for 30 minutes, removing the sediment, and placing the small tubes in the -80°C ultra-low temperature refrigerator Long-term preservation.
- VeroE6 cells were cultured overnight in a 48-well cell culture dish with a density of 5 ⁇ 10 4 cells/well.
- Virus MOI of 0.05
- MOI MOI of 0.05
- each concentration is set to 4 replicate wells, with the maximum non-toxic concentration as the initial concentration of the drug, incubate for 2 days in a 34°C, 5% CO 2 incubator.
- CPE Cytopathogenic Effect
- L- pyroglutamic new crown anti-pneumonia novel coronavirus efficacy evaluation efficacy evaluation of L- pyroglutamic CCK8 by law the median effective concentration for the new crown pneumonia novel coronavirus (SARS-Cov-2) of (EC 50 ) Is 9.34 ⁇ M, the half effective concentration is low, indicating that the antiviral effect is good.
- Immunofluorescence microscope In order to detect the expression of viral proteins in VeroE6 cells, the cells were fixed with 4% paraformaldehyde and permeabilized with 0.5% TritonX-100. The cells were then blocked with 5% bovine serum albumin (BSA) for 2 hours at room temperature. Incubate the cells with the primary antibody (polyclonal antibody against the nucleocapsid protein of the bat SARS-related coronavirus, anti-NP, at a dilution of 1:1000) for 2 hours, and then incubate the antibody with the secondary antibody (488 AffiniPure Donkey Anti-Rabbit) IgG (H+L). The nucleus is stained with Hoechst33258 dye (Beyotime, China). Observation by fluorescence microscope shows that pyroglutamate can effectively kill the virus in the cell, and has a small effect on the cell, which has a good therapeutic window.
- BSA bovine serum albumin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed are the use of pyroglutamic acid in the preparation of drugs for preventing and treating novel coronavirus of novel coronavirus pneumonia and the use of pyroglutamic acid or pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs thereof in the preparation of drugs for preventing and/or treating diseases caused by coronaviruses. The coronaviruses are the novel coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV. The median effective concentration of pyroglutamic acid for the novel coronavirus of new coronavirus pneumonia is 9.34 μM. The median effective concentration is low, and the antiviral effect is good.
Description
本发明属于抗病毒药物领域，具体涉及焦谷氨酸在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用。The invention belongs to the field of antiviral drugs, and specifically relates to the application of pyroglutamic acid in the preparation of drugs for the prevention and treatment of new coronaviruses against new coronary pneumonia.
新型冠状病毒肺炎(Corona Virus Disease 2019)是由新型冠状病毒(SARS-Cov-2)感染人体而引起的传染性疾病，其症状主要包括发热、乏力、干咳、呼吸困难和肾衰竭等[The Lancet,2020,395(10223):507-513；The Lancet,2020,395(10223):497-506]。新冠肺炎于2019年12月有报道病例，随后全球多个国家也出现病例，包括韩国、日本、泰国、伊朗、新加坡、德国、法国和美国等。冠状病毒在系统分类上属冠状病毒科(Coronaviridae)冠状病毒属(Corona virus)。冠状病毒属的病毒是具外套膜(envelope)的正链单股RNA病毒，直径约80～120nm，其遗传物质是所有RNA病毒中最大的，一般只会感染人、鼠、猪、猫、犬、禽类脊椎动物。冠状病毒于1937年被首次从鸡身上分离出来。冠状病毒粒子形状并不规则，直径约60～220nm。病毒具有包膜结构，上面有三种蛋白：刺突糖蛋白(S，Spike Protein)、小包膜糖蛋白(E，Envelope Protein)和膜糖蛋白(M，Membrane Protein)，少数种类还有血凝素糖蛋白(HE蛋白，Haemaglutinin－esterase)[NederlandsTijdschriftVoorGeneeskunde,2014,158(158):A8119-A8119]。Coronavirus pneumonia (Corona Virus Disease 2019) is an infectious disease caused by a new coronavirus (SARS-Cov-2) infecting the human body. Its symptoms mainly include fever, fatigue, dry cough, difficulty breathing, and kidney failure. [The Lancet ,2020,395(10223):507-513; The Lancet,2020,395(10223):497-506]. New coronary pneumonia cases were reported in December 2019, followed by cases in many countries around the world, including South Korea, Japan, Thailand, Iran, Singapore, Germany, France and the United States. Coronaviruses belong to the genus Coronavirus in the family Coronaviridae (Coronaviridae). The virus of the genus Coronavirus is a positive-stranded single-stranded RNA virus with an envelope, with a diameter of about 80-120nm. Its genetic material is the largest among all RNA viruses, and generally only infects humans, mice, pigs, cats, and dogs. , Poultry vertebrates. The coronavirus was first isolated from chickens in 1937. Coronavirus particles are irregular in shape, about 60-220nm in diameter. The virus has an envelope structure with three proteins: Spike Protein (S, Spike Protein), Small Envelope Protein (E, Envelope Protein) and Membrane Protein (M, Membrane Protein), and a few types also have hemagglutination. Glycoprotein (HE protein, Haemaglutinin-esterase) [Nederlands Tijdschrift Voor Geneeskunde, 2014, 158(158): A8119-A8119].
SARS-Cov-2病毒颗粒直径在60～140nm之间，包膜外有9～12nm的尖刺，形似花冠。基因组测序表明，SARS-Cov-2是一种单链RNA冠状病毒。通过与其 他病毒样品基因序列的比较，发现SARS-Cov-2与SARS-CoV(79.5％)[Nature,2020]和蝙蝠冠状病毒(96％)相似[bioRxiv,2020,2020.01.22.914952]，并推测该病毒可能起源于蝙蝠[bioRxiv,2020,2020.01.24.915157；Nature,2020]。2019-nCoV病毒属于βCoV，是区别于SARS-CoV和MERS-CoV的HCoV家族的第7个成员[New England Journal of Medicine,2020]，其余6个成员包括HCoV 229E、NL63、OC43、HKU1、SARS-CoV和MERS-CoV。The diameter of SARS-Cov-2 virus particles is between 60nm and 140nm, and there are 9-12nm spikes outside the envelope, resembling a corolla. Genome sequencing showed that SARS-Cov-2 is a single-stranded RNA coronavirus. By comparison with the gene sequences of other virus samples, it is found that SARS-Cov-2 is similar to SARS-CoV (79.5%) [Nature,2020] and bat coronavirus (96%) [bioRxiv,2020,2020.01.22.914952], and speculates The virus may originate from bats [bioRxiv, 2020, 2020.01.24.915157; Nature, 2020]. The 2019-nCoV virus belongs to βCoV, which is the seventh member of the HCoV family that is different from SARS-CoV and MERS-CoV [New England Journal of Medicine, 2020]. The remaining 6 members include HCoV 229E, NL63, OC43, HKU1, SARS -CoV and MERS-CoV.
引起新型冠状病毒肺炎的是一种新型冠状病毒，它与人们熟知的引起非典型性肺炎的SARS-CoV同属冠状病毒，但类型不同，其致死率虽低于SARS-CoV但传染性远远高于SARS-CoV。此后，韩国、日本、泰国、伊朗、新加坡、德国、法国和美国等均出现该病确诊病例，表明新型冠状病毒肺炎疫情仍存在扩散的可能。但是到目前为止依旧没有任何特效药物能够治愈新型冠状病毒肺炎。目前的治疗方法大多是对症治疗，特别是对一些重症患者疗效较差。因此，开发有效的冠状病毒肺炎治疗特效药物成为了当下一个迫在眉睫需要解决的课题。在针对新型冠状病毒(SARS-Cov-2)病毒药物研发方面，本发明研究了L-焦谷氨酸抗SARS-Cov-2病毒作用。The new type of coronavirus pneumonia is caused by a new type of coronavirus. It is the same type of coronavirus as SARS-CoV, which is known to cause atypical pneumonia, but of different types. Although its fatality rate is lower than SARS-CoV, it is far more infectious. In SARS-CoV. Since then, South Korea, Japan, Thailand, Iran, Singapore, Germany, France, and the United States have all seen confirmed cases of the disease, indicating that the new coronavirus pneumonia epidemic may still spread. But so far, there is still no specific medicine that can cure the new type of coronavirus pneumonia. Most of the current treatment methods are symptomatic treatment, especially for some critically ill patients. Therefore, the development of effective drugs for the treatment of coronavirus pneumonia has become an urgent issue that needs to be resolved. In the research and development of new coronavirus (SARS-Cov-2) virus drugs, the present invention studies the anti-SARS-Cov-2 virus effect of L-pyroglutamic acid.
发明内容Summary of the invention
本发明的目的在于提供L-焦谷氨酸在制备预防或治疗抗新冠肺炎新型冠状病毒的药物中的应用。The purpose of the present invention is to provide the application of L-pyroglutamic acid in the preparation of drugs for the prevention or treatment of new coronaviruses against new coronary pneumonia.
具体而言，为解决的本发明的技术问题，采用如下技术方案：Specifically, in order to solve the technical problems of the present invention, the following technical solutions are adopted:
本发明提供了焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。The present invention provides pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of prevention and/or treatment of coronary Application in medicines for diseases caused by viruses.
在本发明的技术方案中，焦谷氨酸为L-焦谷氨酸、D-焦谷氨酸或其混合物。In the technical scheme of the present invention, pyroglutamic acid is L-pyroglutamic acid, D-pyroglutamic acid or a mixture thereof.
在本发明的技术方案中，所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。In the technical solution of the present invention, the coronaviruses are the new coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
在本发明的技术方案中，冠状病毒所致疾病为SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1或MERS-CoV任一病毒引起的肺炎或其并发症。In the technical solution of the present invention, the disease caused by the coronavirus is pneumonia or its complications caused by any virus of SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 or MERS-CoV.
在本发明的技术方案中，L-焦谷氨酸如结构式(1)所示的In the technical scheme of the present invention, L-pyroglutamic acid is represented by structural formula (1)
在本发明的技术方案中，焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药作为唯一活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。In the technical scheme of the present invention, pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs are used as the sole active ingredient Application in the preparation of medicines for preventing and/or treating diseases caused by coronaviruses.
在本发明的技术方案中，焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药与其他抗病毒药物制备的组合物作为活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。In the technical scheme of the present invention, pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs and other antiviral The application of the composition prepared by the medicine as an active ingredient in the preparation of a medicine for preventing and/or treating diseases caused by coronavirus.
在本发明的技术方案中，其他抗病毒药物选自更昔洛韦、阿昔洛韦、金刚烷胺、金刚乙胺、奥司他韦、阿巴卡韦、醋孟南、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸三环癸胺、阿拉诺丁、阿立酮、阿替韦啶甲磺酸酯、阿夫立定、西多福韦、西潘茶碱、恩曲他滨、盐酸阿糖胞苷、甲磺酸地拉韦啶、地昔洛韦、去羟肌苷、二噁沙利、依度尿苷、乙米韦林、依曲西他平、恩韦拉登、恩韦肟、贺普丁、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、非阿尿苷、磷利酯、膦甲酸钠、膦乙酸钠、甘西洛维钠、碘苷、茚地那韦、乙氧丁酮醛、拉米夫定、洛布卡韦、洛德腺苷、洛匹那韦、盐酸美莫汀、甲红硫脲、那非那韦、奈韦拉平、喷 昔洛韦、吡罗达韦、利巴韦林、甲磺酸沙奎那韦、利托那韦、盐酸索金刚胺、索立夫定、匍枝青霉菌素、司他夫定、替诺福韦、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、替拉那韦、韦罗肟、扎西他滨、齐多夫定、净韦肟。In the technical scheme of the present invention, other antiviral drugs are selected from the group consisting of ganciclovir, acyclovir, amantadine, rimantadine, oseltamivir, abacavir, acemontan, and acyclovir Sodium, adefovir, alovudine, avirsuto, tricyclodecylamine hydrochloride, alanordine, aridone, ateviridine mesylate, afridine, cidofovir, western Panphylline, Emtricitabine, Cytarabine Hydrochloride, Delavirdine Mesylate, Deciclovir, Didanosine, Dioxali, Edouridine, Emivirin, Etrados Citapine, Enviraden, Enviroxime, Hepatin, Famciclovir, Chlorophenhydroisoquine Hydrochloride, Fecitabine, Feauridine, Phosphatide, Sodium Foscarnet, Sodium Phosphoacetate, Ganciclovir Sodium, iodoside, indinavir, ethoxybutanone, lamivudine, lobukavir, lordadenosine, lopinavir, memotine hydrochloride, methyl red thiourea, narfinavir , Nevirapine, Penciclovir, Pirotavir, Ribavirin, Saquinavir Mesylate, Ritonavir, Somantine Hydrochloride, Sorivudine, Penicillin, Stavudine , Tenofovir, Tirolone Hydrochloride, Trifluridine, Valaciclovir Hydrochloride, Vidarabine, Vidarabine Phosphate, Vidarabine Sodium Phosphate, Tiranavir, Verooxime, Zha Citabine, zidovudine, virgin oxime.
本发明另一个方面提供了一种治疗或预防冠状病毒科病毒所致疾病的药物组合物，其包括焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药。Another aspect of the present invention provides a pharmaceutical composition for the treatment or prevention of diseases caused by coronaviruses, which comprises pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, and stereoisomers. Mixtures, tautomers, esters, amides or prodrugs.
在本发明的技术方案中，药物组合物的还包括药学上可接受的辅料。In the technical scheme of the present invention, the pharmaceutical composition also includes pharmaceutically acceptable excipients.
在本发明的技术方案中，药物组合物的剂型为口服制剂、肺部吸入制剂、粘膜给药制剂、眼用制剂或注射剂。In the technical scheme of the present invention, the dosage form of the pharmaceutical composition is oral preparation, pulmonary inhalation preparation, mucosal administration preparation, ophthalmic preparation or injection.
在本发明的技术方案中，口服制剂选自颗粒剂、粉磨剂、丸剂、片剂、胶囊或口服液。In the technical scheme of the present invention, the oral preparation is selected from granules, powders, pills, tablets, capsules or oral liquids.
本发明另一个方面提供了焦谷氨酸作为抗冠状病毒科病毒的消毒剂的用途。Another aspect of the present invention provides the use of pyroglutamic acid as a disinfectant against coronaviruses of the coronavirus family.
本发明另一个方面提供了一种用于治疗冠状病毒科病毒所致疾病的方法，包括将治疗有效量的焦谷氨酸或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯或前药给药于受试者。Another aspect of the present invention provides a method for treating diseases caused by viruses of the coronavirus family, comprising adding a therapeutically effective amount of pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, stereo A mixture of isomers, tautomers, esters or prodrugs is administered to the subject.
本发明另一个方面提供了一种用于预防受试者感染冠状病毒科病毒的方法，包括将治疗有效量的焦谷氨酸或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯或前药给药在感染前给予受试者。Another aspect of the present invention provides a method for preventing a subject from being infected with coronaviruses of the coronavirus family, which comprises adding a therapeutically effective amount of pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, Administration of mixtures of stereoisomers, tautomers, esters or prodrugs is administered to the subject prior to infection.
本发明首次证实了焦谷氨酸对新冠肺炎新型冠状病毒抑制作用，其治疗指数高，半数有效浓度低；而且在染毒前施用焦谷氨酸可有效增加防病毒的效果。焦 谷氨酸用作治疗抗新冠肺炎新型冠状病毒感染方面的有效药物。The present invention proves for the first time that pyroglutamic acid has a high therapeutic index and a low half effective concentration; the pyroglutamic acid can effectively increase the antivirus effect before being infected. Pyroglutamate is used as an effective drug in the treatment of new coronavirus infections caused by new coronary pneumonia.
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。In order to make the above objectives, features and advantages of the present invention more obvious and understandable, the specific embodiments of the present invention will be described in detail below in conjunction with the accompanying drawings, but they should not be understood as limiting the scope of implementation of the present invention.
实施例1.病毒扩增Example 1. Virus amplification
将非洲绿猴肾细胞(VeroE6)按3×10
5个/孔，接种至96孔板中，在含有10％胎牛血清(FBS；GibcoInvitrogen)的Eagle最低基础培养基(minimum Eagle’smedium,MEM；GibcoInvitrogen)中，置37℃,5％CO
2培养，待长满单层。将新冠肺炎新型冠状病毒临床分离株100倍稀释接种到长满单层细胞的96孔板中，置37℃,5％CO
2培养两天(含正常对照组)。
The African green monkey kidney cells (VeroE6) were inoculated into 96-well plates at 3×10 5 cells/well. ; GibcoInvitrogen), incubate at 37°C, 5% CO 2 and wait until the monolayer grows up. A 100-fold dilution of the clinical isolates of the new coronavirus pneumonia new type coronavirus was inoculated into a 96-well plate full of monolayer cells, and incubated at 37°C and 5% CO 2 for two days (including the normal control group).
两天后病变程度高达75％以上，置于-80℃超低温冰箱，反复冻融一次，收集细胞扩增的病毒液，3000r/min离心30分钟，去沉淀物，分装小管置-80℃超低温冰箱长期保存。Two days later, the degree of disease was as high as 75%, placed in a -80℃ ultra-low temperature refrigerator, repeated freezing and thawing once, collecting the amplified virus solution, centrifuged at 3000r/min for 30 minutes, removing the sediment, and placing the small tubes in the -80℃ ultra-low temperature refrigerator Long-term preservation.
实施例2 L-焦谷氨酸药物毒性评价Example 2 Evaluation of the toxicity of L-pyroglutamic acid
L-焦谷氨酸粉末用DMSO溶解后，加入培养液稀释至20mg/mL，DMSO终浓度为1％,经0.22μm滤膜过滤后置4℃保存；过滤后置4℃保存。按每孔约2.5×10
4细胞接种到96孔板，24～48h后待细胞长成单层后，弃去培养液，加入不同稀释度的药物l00μL/孔，正常细胞对照孔加入l00μL/孔MEM，37℃ 5％CO
2继续培养2～5天，每孔加CCK8溶液(5mg/mL)20μL，置37℃ 5％CO
2保温箱中继续孵育4小时。吸弃培养上清液，每孔加l00μL二甲基亚砜(DMSO)，低速振荡10分钟，使结晶物充分融解。选择490nm波长，在酶联免疫监测仪上 测定各孔光吸收值。通过毒性评价可知药物添加浓度达到400μM时，依然未见明显细胞毒性，说明药物的细胞毒性低，具有良好的治疗窗口。
After dissolving the L-pyroglutamic acid powder in DMSO, add culture broth to dilute it to 20mg/mL, the final concentration of DMSO is 1%, filter through 0.22μm membrane and store at 4℃; after filtration, store at 4℃. Inoculate about 2.5×10 4 cells per well into a 96-well plate. After 24 to 48 hours, when the cells grow into a monolayer, discard the culture medium, add 100μL/well of drugs of different dilutions, and 100μL/well for normal cell control wells. MEM, 37°C and 5% CO 2 continue to incubate for 2 to 5 days, add 20 μL of CCK8 solution (5 mg/mL) to each well, and place in a 37°C 5% CO 2 incubator for further incubation for 4 hours. Aspirate and discard the culture supernatant, add 100 μL dimethyl sulfoxide (DMSO) to each well, and shake at low speed for 10 minutes to fully melt the crystals. Choose the wavelength of 490nm, and measure the light absorption value of each hole on the enzyme-linked immunosorbent monitor. Through the toxicity evaluation, it can be seen that when the concentration of the drug added reaches 400 μM, there is still no obvious cytotoxicity, indicating that the cytotoxicity of the drug is low and it has a good therapeutic window.
实施例3 L-焦谷氨酸抗新冠肺炎新型冠状病毒药效评价Example 3 Evaluation of the efficacy of L-pyroglutamic acid against new coronavirus pneumonia and new coronavirus
为了评估药物的抗病毒效力，将VeroE6细胞在密度为5×10
4细胞/孔的48孔细胞培养皿中培养过夜。添加病毒(MOI为0.05)使其感染2小时。然后加入2倍梯度稀释的药物，每个浓度设置4个复孔，以最大无毒浓度为药物起始浓度，在34℃、5％CO
2培养箱中孵育2天。记录细胞病变(Cytopathogenic Effect,CPE)。细胞出现CPE按6级标准记录。记录CPE后，用CCK8染色，进行OD值测定。L-焦谷氨酸抗新冠肺炎新型冠状病毒药效评价通过CCK8法对L-焦谷氨酸进行药效评价，对新冠肺炎新型冠状病毒(SARS-Cov-2)的半数有效浓度(EC
50)为9.34μM，半数有效浓度低，说明抗病毒效果好。
In order to evaluate the antiviral efficacy of the drug, VeroE6 cells were cultured overnight in a 48-well cell culture dish with a density of 5×10 4 cells/well. Virus (MOI of 0.05) was added to make it infected for 2 hours. Then add 2 times the gradient dilution of the drug, each concentration is set to 4 replicate wells, with the maximum non-toxic concentration as the initial concentration of the drug, incubate for 2 days in a 34°C, 5% CO 2 incubator. Record Cytopathogenic Effect (CPE). The occurrence of CPE in the cells was recorded according to the level 6 standard. After the CPE was recorded, it was stained with CCK8, and the OD value was measured. L- pyroglutamic new crown anti-pneumonia novel coronavirus efficacy evaluation efficacy evaluation of L- pyroglutamic CCK8 by law, the median effective concentration for the new crown pneumonia novel coronavirus (SARS-Cov-2) of (EC 50 ) Is 9.34μM, the half effective concentration is low, indicating that the antiviral effect is good.
实施例4 免疫荧光Example 4 Immunofluorescence
免疫荧光显微镜:为了检测VeroE6细胞中病毒蛋白的表达，将细胞用4％多聚甲醛固定并用0.5％TritonX-100透化。然后在室温下用5％牛血清白蛋白(BSA)封闭细胞2小时。将细胞与一抗(蝙蝠SARS相关冠状病毒的病毒核衣壳蛋白多克隆抗体，anti-NP，以1：1000稀释度)一起孵育2小时，然后与二抗孵育抗体(488 AffiniPure Donkey Anti-Rabbit IgG(H+L)。细胞核用Hoechst33258染料(Beyotime,China)染色。通过荧光显微镜观察可知焦谷氨酸能有效杀灭细胞中的病毒，并且对细胞影响较小，具有良好的治疗窗口。Immunofluorescence microscope: In order to detect the expression of viral proteins in VeroE6 cells, the cells were fixed with 4% paraformaldehyde and permeabilized with 0.5% TritonX-100. The cells were then blocked with 5% bovine serum albumin (BSA) for 2 hours at room temperature. Incubate the cells with the primary antibody (polyclonal antibody against the nucleocapsid protein of the bat SARS-related coronavirus, anti-NP, at a dilution of 1:1000) for 2 hours, and then incubate the antibody with the secondary antibody (488 AffiniPure Donkey Anti-Rabbit) IgG (H+L). The nucleus is stained with Hoechst33258 dye (Beyotime, China). Observation by fluorescence microscope shows that pyroglutamate can effectively kill the virus in the cell, and has a small effect on the cell, which has a good therapeutic window.
Claims (10)
- 焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。Pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs are used in the preparation of prevention and/or treatment of diseases caused by coronavirus The application of drugs.
- 根据权利要求1所述的用途，所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。The use according to claim 1, wherein the coronaviruses are new coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
- 根据权利要求1所述的用途，冠状病毒所致疾病为SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、HCoV-OC43、HKU1或MERS-CoV任一病毒引起的感染性疾病或其并发症；感染性疾病优选为呼吸道感染疾病。The use according to claim 1, the disease caused by the coronavirus is an infectious disease caused by any virus of SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, HCoV-OC43, HKU1, or MERS-CoV or its complications The infectious disease is preferably a respiratory tract infection disease.
- 根据权利要求1所述的用途，焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药作为唯一活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用；或者The use according to claim 1, wherein pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomers, esters, amides or prodrugs thereof are used as the sole active The application of the ingredients in the preparation of drugs for the prevention and/or treatment of diseases caused by coronavirus; or焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药，与其他抗病毒药物的组合物作为活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用；Pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs, in combination with other antiviral drugs as active ingredients Application in the preparation of medicines for the prevention and/or treatment of diseases caused by coronavirus;优选地，其他抗病毒药物选自更昔洛韦、阿昔洛韦、金刚烷胺、金刚乙胺、奥司他韦、阿巴卡韦、醋孟南、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸三环癸胺、阿拉诺丁、阿立酮、阿替韦啶甲磺酸酯、阿夫立定、西多福韦、西潘茶碱、恩曲他滨、盐酸阿糖胞苷、甲磺酸地拉韦啶、地昔洛韦、去羟肌苷、二噁沙利、依度尿苷、乙米韦林、依曲西他平、恩韦拉登、恩韦肟、贺普丁、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、非阿尿苷、磷利酯、焦谷氨酸、膦乙酸钠、甘西洛维钠、碘苷、茚地那韦、乙氧丁酮醛、拉米夫定、洛布卡韦、洛德腺苷、洛匹那韦、盐酸美莫汀、甲红硫脲、那非那韦、奈韦拉平、喷昔洛韦、吡罗达韦、 利巴韦林、甲磺酸沙奎那韦、利托那韦、盐酸索金刚胺、索立夫定、匍枝青霉菌素、司他夫定、替诺福韦、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、替拉那韦、韦罗肟、扎西他滨、齐多夫定、净韦肟。Preferably, the other antiviral drugs are selected from ganciclovir, acyclovir, amantadine, rimantadine, oseltamivir, abacavir, acemonam, acyclovir sodium, adefo Vir, alovudine, avirsuto, tricyclodecylamine hydrochloride, alanordine, aridone, ateviridine mesylate, afridine, cidofovir, sipantheophylline, en Tritabine, Cytarabine Hydrochloride, Delavirdine Mesylate, Deciclovir, Didanosine, Dioxali, Edouridine, Emivirin, Etrexitapine, Enemy Veraden, Enviroxime, Hepudin, Famciclovir, Chlorophenhydroisoquine Hydrochloride, Fecitabine, Feuridine, Phosphatide, Pyroglutamic Acid, Sodium Phosphonoacetate, Ganciclovir Sodium, Iodine Glycoside, indinavir, ethoxybutanone, lamivudine, lobukavir, lordadenosine, lopinavir, memotine hydrochloride, methyl red thiourea, narfinavir, nevirapine, Penciclovir, Pirotavir, Ribavirin, Saquinavir Mesylate, Ritonavir, Somantine Hydrochloride, Solivudine, Penicillin, Stavudine, Tenol Fovir, Tirolone Hydrochloride, Trifluridine, Valaciclovir Hydrochloride, Vidarabine, Vidarabine Phosphate, Vidarabine Sodium Phosphate, Tiranavir, Verooxime, Zalcitabine , Zidovudine, Jingwei oxime.
- 一种治疗或预防冠状病毒所致疾病的药物组合物，所述药物组合物中包含焦谷氨酸或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药。A pharmaceutical composition for treating or preventing diseases caused by coronavirus, the pharmaceutical composition comprising pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, and interconversion Isomer, ester, amide or prodrug.
- 根据权利要求5所述的药物组合物，药物组合物的还包括药学上可接受的辅料。The pharmaceutical composition according to claim 5, further comprising pharmaceutically acceptable excipients.
- 根据权利要求5所述的药物组合物，药物组合物的剂型为口服制剂、肺部吸入制剂、粘膜给药制剂、眼用制剂或注射剂；优选地，口服制剂选自颗粒剂、粉末剂、丸剂、片剂、胶囊或口服液。The pharmaceutical composition according to claim 5, wherein the dosage form of the pharmaceutical composition is an oral preparation, a pulmonary inhalation preparation, a mucosal administration preparation, an ophthalmic preparation or an injection; preferably, the oral preparation is selected from granules, powders, and pills , Tablets, capsules or oral liquid.
- 一种消除冠状病毒科病毒污染的消毒剂，所述消毒剂包括焦谷氨酸。A disinfectant for eliminating the pollution of the coronavirus family virus, the disinfectant includes pyroglutamic acid.
- 一种用于治疗或预防冠状病毒科病毒所致疾病的方法，包括将治疗有效量的焦谷氨酸或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药给药于受试者。A method for the treatment or prevention of diseases caused by coronaviruses in the coronavirus family, which comprises adding a therapeutically effective amount of pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, or mixture of stereoisomers , Tautomers, esters, amides or prodrugs are administered to the subject.
- 根据权利要求5-7任一项所述的药物组合物或权利要求8所述的消毒剂或权利要求9所述的方法，其中冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。The pharmaceutical composition according to any one of claims 5-7 or the disinfectant according to claim 8 or the method according to claim 9, wherein the coronavirus is a new coronavirus SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010266183.7A CN111467338B (en) | 2020-04-07 | 2020-04-07 | Application of pyroglutamic acid in preparation of medicine for preventing and treating novel coronavirus resistant to new coronary pneumonia |
| CN202010266183.7 | 2020-04-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2021203702A1 true WO2021203702A1 (en) | 2021-10-14 |
Family
ID=71750094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2020/129184 WO2021203702A1 (en) | 2020-04-07 | 2020-11-16 | Use of pyroglutamic acid in preparation of drugs for preventing and treating novel coronavirus of novel coronavirus pneumonia |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111467338B (en) |
| WO (1) | WO2021203702A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111467338B (en) * | 2020-04-07 | 2021-04-23 | 中国科学院深圳先进技术研究院 | Application of pyroglutamic acid in preparation of medicine for preventing and treating novel coronavirus resistant to new coronary pneumonia |
| WO2022088037A1 (en) * | 2020-10-30 | 2022-05-05 | 中国科学院深圳先进技术研究院 | Application of sirtinol in preparation of drug for preventing and treating coronavirus |
| WO2022088038A1 (en) * | 2020-10-30 | 2022-05-05 | 中国科学院深圳先进技术研究院 | Application of cay10603 in preparation of drugs for preventing and treating coronavirus-related diseases |
| CN113350482B (en) * | 2021-05-31 | 2022-05-27 | 中国食品药品检定研究院 | Application of phytohemagglutinin PHA-E in preparation of medicine for treating diseases caused by coronavirus |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1411372A (en) * | 1999-10-19 | 2003-04-16 | 宝洁公司 | Antimicrobial compositions comprising pyroglutamic acid and optionally metal salts |
| CN1946428A (en) * | 2004-04-26 | 2007-04-11 | 宝洁公司 | Therapeutic antimicrobial compositions and methods |
| US20090215854A1 (en) * | 2003-06-20 | 2009-08-27 | The Procter & Gamble Company | Antimicrobial compositions, products and methods employing same |
| EP3118211A1 (en) * | 2014-03-12 | 2017-01-18 | Obschestvo S Ogranichennoi Otvetstennostiyu "Pharmenterprises" | Amide compounds and methods for the production and use thereof |
| CN111467338A (en) * | 2020-04-07 | 2020-07-31 | 中国科学院深圳先进技术研究院 | Application of pyroglutamic acid in preparation of medicine for preventing and treating novel coronavirus resistant to new coronary pneumonia |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040234457A1 (en) * | 1999-10-19 | 2004-11-25 | The Procter & Gamble Company | Methods of preventing and treating SARS using low pH respiratory tract compositions |
-
2020
- 2020-04-07 CN CN202010266183.7A patent/CN111467338B/en active Active
- 2020-11-16 WO PCT/CN2020/129184 patent/WO2021203702A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1411372A (en) * | 1999-10-19 | 2003-04-16 | 宝洁公司 | Antimicrobial compositions comprising pyroglutamic acid and optionally metal salts |
| US20090215854A1 (en) * | 2003-06-20 | 2009-08-27 | The Procter & Gamble Company | Antimicrobial compositions, products and methods employing same |
| CN1946428A (en) * | 2004-04-26 | 2007-04-11 | 宝洁公司 | Therapeutic antimicrobial compositions and methods |
| EP3118211A1 (en) * | 2014-03-12 | 2017-01-18 | Obschestvo S Ogranichennoi Otvetstennostiyu "Pharmenterprises" | Amide compounds and methods for the production and use thereof |
| CN111467338A (en) * | 2020-04-07 | 2020-07-31 | 中国科学院深圳先进技术研究院 | Application of pyroglutamic acid in preparation of medicine for preventing and treating novel coronavirus resistant to new coronary pneumonia |
Non-Patent Citations (2)
| Title |
|---|
| JAVIER CARBAJO-LOZOYA; MARCEL A. MLLER; STEPHAN KALLIES; VOLKER THIEL; CHRISTIAN DROSTEN; ALBRECHT VON BRUNN;: "Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506", VIRUS RESEARCH, AMSTERDAM, NL, vol. 165, no. 1, 3 February 2012 (2012-02-03), NL , pages 112 - 117, XP028475624, ISSN: 0168-1702, DOI: 10.1016/j.virusres.2012.02.002 * |
| WU YU-SHAN, LIN WEN-HSING, T.-A.HSU JOHN, HSIEH HSING-PANG: "Antiviral Drug Discovery Against SARS-CoV", CURRENT MEDICINAL CHEMISTRY, BENTHAM, NL, vol. 13, no. 17, 1 July 2006 (2006-07-01), NL , pages 2003 - 2020, XP055857120, ISSN: 0929-8673, DOI: 10.2174/092986706777584988 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111467338A (en) | 2020-07-31 |
| CN111467338B (en) | 2021-04-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021203702A1 (en) | Use of pyroglutamic acid in preparation of drugs for preventing and treating novel coronavirus of novel coronavirus pneumonia | |
| WO2021203701A1 (en) | Application of sofosbuvir in preparation of drug for preventing and treating coronavirus | |
| RU2769317C2 (en) | Influenza treatment methods | |
| WO2021203703A1 (en) | Use of carglumic acid in preparation of drugs for preventing and treating coronaviruses | |
| WO2021203704A1 (en) | Use of bacitracin a in preparation of drugs for preventing and treating coronaviruses | |
| WO2021203706A1 (en) | Use of foscarnet sodium in preparation of medicines for preventing and treating coronaviruses | |
| KR20180124970A (en) | Thiazolide compounds for treating viral infections | |
| WO2021159570A1 (en) | Application of baicalein in preparing drug for preventing and/or treating novel coronovirus infectious disease | |
| CN108434167A (en) | Application of the different corilagin in preparing anti-influenza virus medicament | |
| WO2021175224A1 (en) | Anti-rna virus drug and application thereof | |
| WO2021253338A1 (en) | Use of romidepsin in preventing and treating coronavirus-related diseases | |
| WO2022088037A1 (en) | Application of sirtinol in preparation of drug for preventing and treating coronavirus | |
| WO2022088047A1 (en) | Application of itf2357 in preparation of drug for preventing and treating coronaviruses | |
| CN113274375A (en) | Application of metformin and derivatives or pharmaceutically acceptable salts thereof in preparation of drugs for treating coronavirus infection | |
| WO2008017264A1 (en) | Pharmaceutical composition comprising methyl donors or methyl donor enhancers and anti-viral compounds | |
| CN113813366A (en) | Application of romidepsin in preparation of medicine for preventing and treating novel anti-new-crown-pneumonia coronavirus | |
| WO2022088038A1 (en) | Application of cay10603 in preparation of drugs for preventing and treating coronavirus-related diseases | |
| CN113855688A (en) | Application of Vina-ginsenoside R18 in preparation of anti-dengue virus pharmaceutical preparation | |
| WO2021218154A1 (en) | Drug, food and application of anti-coronavirus infection | |
| CN111568900A (en) | Application of indomethacin in resisting coronavirus infection | |
| TWI803229B (en) | Compound tsyi-zac is used to inhibit dengue virus infection and its medicinal use | |
| CN114432287A (en) | Application of ITF2357 in preparation of medicine for preventing and treating coronavirus | |
| CN112805027B (en) | Medicine for resisting new coronavirus infection and application | |
| CN113908256B (en) | Application of LANCL1 protein in preparing antiviral drug | |
| CN114432283A (en) | Application of SIRTINOL in preparation of medicine for preventing and treating coronavirus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20930099 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20930099 Country of ref document: EP Kind code of ref document: A1 |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20930099 Country of ref document: EP Kind code of ref document: A1 |
|
| 32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 04/07/2023) |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20930099 Country of ref document: EP Kind code of ref document: A1 |