CN116322665A - 用于治疗SARS-CoV-2的方法和组合物 - Google Patents
用于治疗SARS-CoV-2的方法和组合物 Download PDFInfo
- Publication number
- CN116322665A CN116322665A CN202180047286.7A CN202180047286A CN116322665A CN 116322665 A CN116322665 A CN 116322665A CN 202180047286 A CN202180047286 A CN 202180047286A CN 116322665 A CN116322665 A CN 116322665A
- Authority
- CN
- China
- Prior art keywords
- cells
- cov
- sars
- compound
- hela
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 241001678559 COVID-19 virus Species 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 32
- 239000000203 mixture Substances 0.000 title description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 208000015181 infectious disease Diseases 0.000 claims abstract description 36
- 229960005475 antiinfective agent Drugs 0.000 claims abstract description 13
- 239000004599 antimicrobial Substances 0.000 claims abstract description 13
- 244000052769 pathogen Species 0.000 claims abstract description 12
- 230000001717 pathogenic effect Effects 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims description 41
- 229940079593 drug Drugs 0.000 claims description 35
- 229960001997 adefovir Drugs 0.000 claims description 30
- 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 30
- -1 flunaridine Chemical compound 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 239000003443 antiviral agent Substances 0.000 claims description 10
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 10
- 229960004171 hydroxychloroquine Drugs 0.000 claims description 10
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 9
- 241000711573 Coronaviridae Species 0.000 claims description 7
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 4
- 229960003957 dexamethasone Drugs 0.000 claims description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 4
- 102000053642 Catalytic RNA Human genes 0.000 claims description 3
- 108090000994 Catalytic RNA Proteins 0.000 claims description 3
- 102100034343 Integrase Human genes 0.000 claims description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 3
- 230000000692 anti-sense effect Effects 0.000 claims description 3
- 108091092562 ribozyme Proteins 0.000 claims description 3
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical group C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 claims description 2
- 229960001444 amodiaquine Drugs 0.000 claims description 2
- 229960004099 azithromycin Drugs 0.000 claims description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 9
- 230000005540 biological transmission Effects 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 105
- 238000003556 assay Methods 0.000 description 41
- 230000000694 effects Effects 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 26
- 238000012216 screening Methods 0.000 description 25
- 238000011282 treatment Methods 0.000 description 23
- 229950002889 apilimod Drugs 0.000 description 22
- HSKAZIJJKRAJAV-KOEQRZSOSA-N n-[(e)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine Chemical compound CC1=CC=CC(\C=N\NC=2N=C(OCCC=3N=CC=CC=3)N=C(C=2)N2CCOCC2)=C1 HSKAZIJJKRAJAV-KOEQRZSOSA-N 0.000 description 22
- 230000000840 anti-viral effect Effects 0.000 description 17
- 210000004072 lung Anatomy 0.000 description 17
- HTNPEHXGEKVIHG-QCNRFFRDSA-N molnupiravir Chemical compound C(OC(=O)C(C)C)[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C(=O)N=C(NO)C=C1 HTNPEHXGEKVIHG-QCNRFFRDSA-N 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 16
- 241000700605 Viruses Species 0.000 description 14
- 201000010099 disease Diseases 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 229950010131 puromycin Drugs 0.000 description 13
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 208000025721 COVID-19 Diseases 0.000 description 11
- 229910002091 carbon monoxide Inorganic materials 0.000 description 11
- 241000699800 Cricetinae Species 0.000 description 10
- 231100000673 dose–response relationship Toxicity 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 230000007502 viral entry Effects 0.000 description 10
- 230000003612 virological effect Effects 0.000 description 10
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 229960000884 nelfinavir Drugs 0.000 description 9
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 230000003389 potentiating effect Effects 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 231100000135 cytotoxicity Toxicity 0.000 description 7
- 230000003013 cytotoxicity Effects 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- 241000699673 Mesocricetus auratus Species 0.000 description 6
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 6
- 102100031989 Transmembrane protease serine 2 Human genes 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 230000000174 oncolytic effect Effects 0.000 description 6
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 230000002195 synergetic effect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 5
- 208000037847 SARS-CoV-2-infection Diseases 0.000 description 5
- SRXKIZXIRHMPFW-UHFFFAOYSA-N [4-[6-[amino(azaniumylidene)methyl]naphthalen-2-yl]oxycarbonylphenyl]-(diaminomethylidene)azanium;methanesulfonate Chemical compound CS([O-])(=O)=O.CS([O-])(=O)=O.C1=CC(N=C([NH3+])N)=CC=C1C(=O)OC1=CC=C(C=C(C=C2)C([NH3+])=N)C2=C1 SRXKIZXIRHMPFW-UHFFFAOYSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 229960005260 amiodarone Drugs 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 239000003086 colorant Substances 0.000 description 5
- 238000002648 combination therapy Methods 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229950009865 nafamostat Drugs 0.000 description 5
- 230000008520 organization Effects 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 230000029812 viral genome replication Effects 0.000 description 5
- 230000009385 viral infection Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 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 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108090000862 Ion Channels Proteins 0.000 description 4
- 102000004310 Ion Channels Human genes 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000012911 assay medium Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000007859 condensation product Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- 238000007424 high content screening assay Methods 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 229960003963 manidipine Drugs 0.000 description 4
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 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 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- 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 description 4
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 3
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 3
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 3
- 102000005600 Cathepsins Human genes 0.000 description 3
- 108010084457 Cathepsins Proteins 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 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 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- 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 description 3
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229960001830 amprenavir Drugs 0.000 description 3
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 3
- 239000000164 antipsychotic agent Substances 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 239000002585 base Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000010432 diamond Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 210000001163 endosome Anatomy 0.000 description 3
- 229960005102 foscarnet Drugs 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 229960001627 lamivudine Drugs 0.000 description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 229960004525 lopinavir Drugs 0.000 description 3
- 210000003712 lysosome Anatomy 0.000 description 3
- 230000001868 lysosomic effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- SHZKQBHERIJWAO-AATRIKPKSA-N ozagrel Chemical compound C1=CC(/C=C/C(=O)O)=CC=C1CN1C=NC=C1 SHZKQBHERIJWAO-AATRIKPKSA-N 0.000 description 3
- 229950003837 ozagrel Drugs 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000012913 prioritisation Methods 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- 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 description 3
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 3
- 229960000311 ritonavir Drugs 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- LGFLRHWJJKLPCC-ZDUSSCGKSA-N (2s)-2-[[4-[2-(2,4-diaminopteridin-6-yl)ethyl]benzoyl]amino]pentanedioic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 LGFLRHWJJKLPCC-ZDUSSCGKSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- ZIAOVIPSKUPPQW-UHFFFAOYSA-N 3-chloro-5-[1-[(4-methyl-5-oxo-1h-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)pyridin-3-yl]oxybenzonitrile Chemical compound N1C(=O)N(C)C(CN2C(C(OC=3C=C(C=C(Cl)C=3)C#N)=C(C=C2)C(F)(F)F)=O)=N1 ZIAOVIPSKUPPQW-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- 229940022962 COVID-19 vaccine Drugs 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 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 description 2
- 208000001528 Coronaviridae Infections Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102100040018 Interferon alpha-2 Human genes 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000713666 Lentivirus Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 description 2
- KJHOZAZQWVKILO-UHFFFAOYSA-N N-(diaminomethylidene)-4-morpholinecarboximidamide Chemical compound NC(N)=NC(=N)N1CCOCC1 KJHOZAZQWVKILO-UHFFFAOYSA-N 0.000 description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 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 description 2
- 241000286209 Phasianidae Species 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 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 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 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 description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 2
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 2
- 229960003805 amantadine Drugs 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000002141 anti-parasite Effects 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 229940005529 antipsychotics Drugs 0.000 description 2
- 239000013584 assay control Substances 0.000 description 2
- 229960003277 atazanavir Drugs 0.000 description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 210000000424 bronchial epithelial cell Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 238000004422 calculation algorithm Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229960000724 cidofovir Drugs 0.000 description 2
- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 description 2
- 229960002402 cobicistat Drugs 0.000 description 2
- FKRSSPOQAMALKA-CUPIEXAXSA-N daclatasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)=CN1 FKRSSPOQAMALKA-CUPIEXAXSA-N 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound 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 description 2
- 230000003831 deregulation Effects 0.000 description 2
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 2
- 229960000735 docosanol Drugs 0.000 description 2
- 229950003141 doravirine Drugs 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 229960000366 emtricitabine Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 229960004396 famciclovir Drugs 0.000 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 description 2
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960002963 ganciclovir Drugs 0.000 description 2
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000007438 host cellular process Effects 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 229960002751 imiquimod Drugs 0.000 description 2
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 229960001936 indinavir Drugs 0.000 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 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 230000004322 lipid homeostasis Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960004710 maraviroc Drugs 0.000 description 2
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 229960005389 moroxydine Drugs 0.000 description 2
- NQHXCOAXSHGTIA-SKXNDZRYSA-N nelfinavir mesylate Chemical compound CS(O)(=O)=O.CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 NQHXCOAXSHGTIA-SKXNDZRYSA-N 0.000 description 2
- 229960005230 nelfinavir mesylate Drugs 0.000 description 2
- 229960002480 nitazoxanide Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 229940127073 nucleoside analogue Drugs 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000003068 pathway analysis Methods 0.000 description 2
- 229960001179 penciclovir Drugs 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 2
- 229960001084 peramivir Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 229960004742 raltegravir Drugs 0.000 description 2
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 2
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229960002814 rilpivirine Drugs 0.000 description 2
- 229960000888 rimantadine Drugs 0.000 description 2
- 229960001852 saquinavir Drugs 0.000 description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound 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 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 229960001203 stavudine Drugs 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000009044 synergistic interaction Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229960005311 telbivudine Drugs 0.000 description 2
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 2
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 2
- 229960004946 tenofovir alafenamide Drugs 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 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
- 238000010361 transduction Methods 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 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 2
- 229940093257 valacyclovir Drugs 0.000 description 2
- 229960002149 valganciclovir Drugs 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229960003636 vidarabine Drugs 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- ZZMYWYZPNZRYPX-SANMLTNESA-N (2r)-2-amino-2-[5-[4-[2-(4-phenylphenyl)ethoxy]-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]propan-1-ol Chemical compound N1C([C@@](N)(CO)C)=NC=C1C(C=C1C(F)(F)F)=CC=C1OCCC1=CC=C(C=2C=CC=CC=2)C=C1 ZZMYWYZPNZRYPX-SANMLTNESA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VXDAVYUFYPFGDX-SNPRPXQTSA-N (2s,4r)-1-acetyl-n-[(2s)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-hydroxypyrrolidine-2-carboxamide Chemical compound CC(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(=O)C1=NC2=CC=CC=C2S1 VXDAVYUFYPFGDX-SNPRPXQTSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- YFVKHKCZBSGZPE-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-(propylamino)propan-1-one Chemical compound CCCNC(C)C(=O)C1=CC=C2OCOC2=C1 YFVKHKCZBSGZPE-UHFFFAOYSA-N 0.000 description 1
- HGVJHAMFCVPSRK-UHFFFAOYSA-N 1-hydroxy-2h-naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(O)(S(O)(=O)=O)CC=CC2=C1 HGVJHAMFCVPSRK-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- 102100038028 1-phosphatidylinositol 3-phosphate 5-kinase Human genes 0.000 description 1
- 101710145421 1-phosphatidylinositol 3-phosphate 5-kinase Proteins 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SGBQUMZTGSQNAO-UHFFFAOYSA-N 2-hydroxynaphthalene-1-sulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(O)=CC=C21 SGBQUMZTGSQNAO-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FOHHNHSLJDZUGQ-UHFFFAOYSA-N 3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol Chemical compound FC(F)(F)C1=CC=C2C(C(O)CCN(CCCC)CCCC)=CC3=C(Cl)C=C(Cl)C=C3C2=C1 FOHHNHSLJDZUGQ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- RZMZJYAMZGWBLB-UHFFFAOYSA-N 3-hydroxynaphthalene-1-sulfonic acid Chemical compound C1=CC=CC2=CC(O)=CC(S(O)(=O)=O)=C21 RZMZJYAMZGWBLB-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
- YLDCUKJMEKGGFI-QCSRICIXSA-N 4-acetamidobenzoic acid;9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one;1-(dimethylamino)propan-2-ol Chemical compound CC(O)CN(C)C.CC(O)CN(C)C.CC(O)CN(C)C.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC=NC2=O)=C2N=C1 YLDCUKJMEKGGFI-QCSRICIXSA-N 0.000 description 1
- WFJIVOKAWHGMBH-UHFFFAOYSA-N 4-hexylbenzene-1,3-diol Chemical compound CCCCCCC1=CC=C(O)C=C1O WFJIVOKAWHGMBH-UHFFFAOYSA-N 0.000 description 1
- VERUFXOALATMPS-UHFFFAOYSA-N 5,5-diamino-2-(2-phenylethenyl)cyclohex-3-ene-1,1-disulfonic acid Chemical compound C1=CC(N)(N)CC(S(O)(=O)=O)(S(O)(=O)=O)C1C=CC1=CC=CC=C1 VERUFXOALATMPS-UHFFFAOYSA-N 0.000 description 1
- USVMJSALORZVDV-UHFFFAOYSA-N 6-(gamma,gamma-dimethylallylamino)purine riboside Natural products C1=NC=2C(NCC=C(C)C)=NC=NC=2N1C1OC(CO)C(O)C1O USVMJSALORZVDV-UHFFFAOYSA-N 0.000 description 1
- OSHIQPFXKULOPB-UHFFFAOYSA-N 6-(hydroxyamino)-1h-pyrimidin-2-one Chemical compound ONC1=CC=NC(=O)N1 OSHIQPFXKULOPB-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 240000000662 Anethum graveolens Species 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 101100272788 Arabidopsis thaliana BSL3 gene Proteins 0.000 description 1
- 101100248253 Arabidopsis thaliana RH40 gene Proteins 0.000 description 1
- 229940080328 Arginase inhibitor Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108700000434 Cannabis sativa edestin Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 102000004171 Cathepsin K Human genes 0.000 description 1
- 108090000625 Cathepsin K Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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-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
- 238000000116 DAPI staining Methods 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000929928 Homo sapiens Angiotensin-converting enzyme 2 Proteins 0.000 description 1
- 101000975003 Homo sapiens Kallistatin Proteins 0.000 description 1
- 101001077723 Homo sapiens Serine protease inhibitor Kazal-type 6 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 108010014726 Interferon Type I Proteins 0.000 description 1
- 102000002227 Interferon Type I Human genes 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 229940122920 Kallikrein inhibitor Drugs 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
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- ITATYELQCJRCCK-UHFFFAOYSA-N Mandelic Acid, Methyl Ester Chemical compound COC(=O)C(O)C1=CC=CC=C1 ITATYELQCJRCCK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- USVMJSALORZVDV-SDBHATRESA-N N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O USVMJSALORZVDV-SDBHATRESA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000283903 Ovis aries Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 230000007022 RNA scission Effects 0.000 description 1
- 101710118046 RNA-directed RNA polymerase Proteins 0.000 description 1
- 238000003559 RNA-seq method Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108091005774 SARS-CoV-2 proteins Proteins 0.000 description 1
- 102100025421 Serine protease inhibitor Kazal-type 6 Human genes 0.000 description 1
- 101000629318 Severe acute respiratory syndrome coronavirus 2 Spike glycoprotein Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 101100537773 Solanum lycopersicum TPM-1 gene Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000031650 Surgical Wound Infection Diseases 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 206010058874 Viraemia Diseases 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- 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 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 210000004504 adult stem cell Anatomy 0.000 description 1
- 210000005058 airway cell Anatomy 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229950003153 amsonate Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- RZVPBGBYGMDSBG-GGAORHGYSA-N baloxavir marboxil Chemical compound COC(=O)OCOc1c2C(=O)N3CCOC[C@H]3N([C@H]3c4ccc(F)c(F)c4CSc4ccccc34)n2ccc1=O RZVPBGBYGMDSBG-GGAORHGYSA-N 0.000 description 1
- 229940008411 baloxavir marboxil Drugs 0.000 description 1
- 229960000817 bazedoxifene Drugs 0.000 description 1
- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 238000007621 cluster analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229940014461 combivir Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000003235 crystal violet staining Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 239000003145 cytotoxic factor Substances 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960005449 daclatasvir Drugs 0.000 description 1
- 229940089180 daklinza Drugs 0.000 description 1
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 1
- 229960002677 darifenacin Drugs 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 229940125371 direct-acting antiviral drugs Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960002542 dolutegravir Drugs 0.000 description 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 229960002030 edoxudine Drugs 0.000 description 1
- XACKNLSZYYIACO-DJLDLDEBSA-N edoxudine Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XACKNLSZYYIACO-DJLDLDEBSA-N 0.000 description 1
- 229940084014 edurant Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229960003586 elvitegravir Drugs 0.000 description 1
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000002121 endocytic effect Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- AWNIEFSZNNQBRL-ZCNUETMSSA-N ethyl (2r,3r)-3-[[4-methyl-1-oxo-1-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]pentan-2-yl]carbamoyl]oxirane-2-carboxylate;sulfuric acid Chemical compound OS(O)(=O)=O.CCOC(=O)[C@@H]1O[C@H]1C(=O)NC(CC(C)C)C(=O)N1CCN(CC=2C(=C(OC)C(OC)=CC=2)OC)CC1.CCOC(=O)[C@@H]1O[C@H]1C(=O)NC(CC(C)C)C(=O)N1CCN(CC=2C(=C(OC)C(OC)=CC=2)OC)CC1 AWNIEFSZNNQBRL-ZCNUETMSSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 229960001447 fomivirsen Drugs 0.000 description 1
- XCWFZHPEARLXJI-UHFFFAOYSA-N fomivirsen Chemical compound C1C(N2C3=C(C(NC(N)=N3)=O)N=C2)OC(CO)C1OP(O)(=S)OCC1OC(N(C)C(=O)\N=C(\N)C=C)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(N=C(N)C=C2)=O)CC1OP(O)(=S)OCC(C(C1)OP(S)(=O)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)OC1N1C=C(C)C(=O)NC1=O XCWFZHPEARLXJI-UHFFFAOYSA-N 0.000 description 1
- 229960003142 fosamprenavir Drugs 0.000 description 1
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229960003242 halofantrine Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 229960003258 hexylresorcinol Drugs 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 102000048657 human ACE2 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 229960000374 ibacitabine Drugs 0.000 description 1
- WEVJJMPVVFNAHZ-RRKCRQDMSA-N ibacitabine Chemical compound C1=C(I)C(N)=NC(=O)N1[C@@H]1O[C@H](CO)[C@@H](O)C1 WEVJJMPVVFNAHZ-RRKCRQDMSA-N 0.000 description 1
- 229950010245 ibalizumab Drugs 0.000 description 1
- 150000008160 idosides Chemical class 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 108010018844 interferon type III Proteins 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- FWYSMLBETOMXAG-QHCPKHFHSA-N letermovir Chemical compound COC1=CC=CC(N2CCN(CC2)C=2N([C@@H](CC(O)=O)C3=CC=CC(F)=C3N=2)C=2C(=CC=C(C=2)C(F)(F)F)OC)=C1 FWYSMLBETOMXAG-QHCPKHFHSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 238000010872 live dead assay kit Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 231100001225 mammalian toxicity Toxicity 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QUFIXTQDTDCCLJ-UHFFFAOYSA-N methyl naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)OC)=CC=CC2=C1 QUFIXTQDTDCCLJ-UHFFFAOYSA-N 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 208000037971 neglected tropical disease Diseases 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229940101771 nexavir Drugs 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 229940072250 norvir Drugs 0.000 description 1
- 238000012758 nuclear staining Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 210000002220 organoid Anatomy 0.000 description 1
- 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 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000020978 protein processing Effects 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013515 script Methods 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000026425 severe pneumonia Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- 229940095064 tartrate Drugs 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ZSDSQXJSNMTJDA-UHFFFAOYSA-N trifluralin Chemical compound CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O ZSDSQXJSNMTJDA-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229940111527 trizivir Drugs 0.000 description 1
- 229960000832 tromantadine Drugs 0.000 description 1
- UXQDWARBDDDTKG-UHFFFAOYSA-N tromantadine Chemical compound C1C(C2)CC3CC2CC1(NC(=O)COCCN(C)C)C3 UXQDWARBDDDTKG-UHFFFAOYSA-N 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229940108442 valtrex Drugs 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 229940086210 victrelis Drugs 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
-
- 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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/407—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 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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 or sparfloxacin
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
本文公开了可用于治疗患有病原体感染例如严重急性呼吸综合征冠状病毒2(SARS‑CoV‑2)的对象、降低对象被病原体感染的可能性以及用于减少病原体从对象向他者的传播的方法。所述方法利用本文表1或表4中公开的化合物,其任选地与另外的药剂例如抗感染剂组合。
Description
本申请要求2020年5月5日提交的美国临时专利申请号62/704,340、2020年6月19日提交的美国临时专利申请号62/705,288和2020年10月30日提交的美国临时专利申请号63/107,893的优先权权益,这些申请的公开内容如同在本文中完整阐述那样并入本公开内容中。
背景技术
冠状病毒感染可导致大量的发病和死亡。虽然针对一些病毒感染,疫苗接种通常可以是有效的,但疫苗针对某些病毒并不总是完全有效的。目前已知的针对严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)的疫苗的长期有效性尚未确定,特别是考虑到可减弱疫苗的整体影响的SARS-CoV-2毒株的出现。因此,治疗这种病毒并防止其向他者的传播在一些年轻人、老年人或免疫低下的群体中变得特别重要。
发明内容
因此,在一个实施方案中,本公开内容提供了用于治疗患有病原体感染的对象的方法。该方法包括将治疗有效量的选自本文所述的表1或表4的至少一种化合物施用于对象,所述化合物不包括阿吡莫德(apilimod)、瑞德西韦(remdesivir)和羟氯喹(hydroxychloroquine)。
在多个实施方案中,该病原体是冠状病毒。例如,在一个实施方案中,冠状病毒是严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。
在一些实施方案中,该方法还包括向对象施用抗感染剂。在多个实施方案中,抗感染剂是抗病毒剂,例如选自以下的一种:抑制进入的药物、抑制脱壳的药物、抑制逆转录酶的药物、反义药物、核酶药物、蛋白酶抑制剂、抑制装配的药物和抑制释放的药物。在一些实施方案中,抗病毒剂包括瑞德西韦。
本公开内容的另一个实施方案是根据式RFM-011-200-5的化合物或其可药用盐:
本公开内容的又一个实施方案是根据式RFM-007-454-4的化合物或其可药用盐:
在另一些实施方案中,本公开内容提供了药物组合物,其包含治疗有效量的选自本文所述的表1或表4的至少一种化合物、治疗有效量的本文所述的抗感染剂、和可药用载体。
附图说明
图1:基于原代细胞的HCI测定确定了针对SARS-CoV-2感染有活性的化合物。A)简化的测定工作流。B)来自经二甲基亚砜(dimethyl sulfoxide,DMSO)处理、经瑞德西韦处理或经阿吡莫德处理的孔的代表性图像。显示每种处理的每孔的整个成像区域(使用10×物镜拍摄并合在一起的4个视野),以及以白框标定的8倍放大部分。DNA信号[4’,6-二脒基-2-苯基吲哚(DAPI)]呈绿色,以及用免疫荧光可视化的病毒呈洋红色。指示了感染的(箭)和未感染的(箭头)细胞;合成图像和放大图像中分别显示500μM和50μM比例尺。显示了根据图像计算的原始值和经归一化的(Norm.)值。C)从独立生物学实验中获得的SARS-CoV-2测定对照EC50的箱线图,其中用条指示平均值并显示所有数据点。线(whisker)指示最小值和最大值。D)来自1.9μM ReFRAME筛选板的经归一化数据的热图。根据比例尺指示了感染细胞百分比和总细胞数目的经归一化的活性值,以及显示了化合物和对照孔的密度图。经DMSO处理的孔位于第24列,以及经阳性对照处理的孔(含2.5μM瑞德西韦、2.5μM阿吡莫德或9.6μM嘌呤霉素的孔的组(block))位于第23列。表示与每种孔类型相关的值的频率的密度图显示在右侧。E)化合物和对照孔的1.9μM ReFRAME筛选数据的分布。F)筛选命中物选择(hitselection)阈值。
图2.在ReFRAME文库中确定出具有抗SARS-CoV-2活性的有效且具有选择性的化合物。A)关于开发的临床阶段和疾病适应证的ReFRAME改用文库的组成。B)剂量响应再确认结果,其中每种化合物的SARS-CoV-2EC50相对于其宿主细胞毒性CC50(如在未感染的HeLa-ACE2细胞中评估的)作图。虚线表示在受试化合物(40μM)和对照阿吡莫德和瑞德西韦(10μM)的剂量响应研究中测试的最大浓度。显示了对照(黑色菱形)和受试化合物(粉色菱形)的活性。也指示了作为此命中再确认的一部分而筛选出的嘌呤霉素的ReFRAME文库拷贝的活性(红色菱形)。C)瑞德西韦、阿吡莫德和嘌呤霉素对照化合物的SARS-CoV-2EC50(蓝色)、感染HeLa-ACE2 EC50(橙色)和未感染HeLa-ACE2 CC50剂量响应曲线作为ReFRAME命中再确认的一部分运行。D)根据功能注释对75种有效且具有选择性的化合物以及135种弱活性或无选择性的化合物的分类。E)阿吡莫德加瑞德西韦药物相互作用情况(单次重复)的协同分析的代表性输出,其显示出总体加和效应(-10<δ<10)。F)瑞德西韦和两种固定浓度(协同实验期间约EC30和EC65)的阿吡莫德之间的加和响应。显示了一式三份技术重复的中值+/-sem。
图3。MOI对对照化合物EC50的影响。在MOI范围为1至26的情况下评估了瑞德西韦、阿吡莫德和嘌呤霉素对照在SARS-CoV-2/HeLa-ACE2测定中的活性。显示了在指定MOI下每种化合物的EC50。
具体实施方式
本公开内容部分地涉及治疗患有病原体感染(例如SARS-CoV-2)的对象的方法。2019年12月初,严重急性呼吸综合征冠状病毒2(SARS-CoV-2)被确定为是称为COVID-19的严重肺炎样症状的数目快速增加的原因。从那时起,世界卫生组织(World HealthOrganization,WHO)就理所当然地给予SARS-CoV-2以大流行地位。截至2021年2月10日,SARS-CoV-2已在全世界扩散,在223个不同国家造成超过106,555,200例确诊感染和超过2,333,440例报告死亡(Organization,W.H.Vol.2020(ed World Health Organization)(World Health Organization,2020))。开发数种有效的抗SARS-CoV-2疫苗无疑将有助于控制大流行,但是,使一些疫苗的有效性降低的具有逃逸突变的SARS-CoV-2毒株的出现,以及总体上受到限制的全球COVID-19疫苗供应使得有理由继续致力于鉴定治疗性干预措施。然而,尽管研究群体做出了大量努力,但针对COVID-19的抗病毒治疗选择仍然极为有限。这些选择包括皮质类固醇,例如地塞米松(dexamethasone)(Group,R.C.etal.Dexamethasone in Hospitalized Patients with Covid-N Engl J Med,doi:10.1056/NEJMoa2021436(2020))和静脉内递送的抗病毒瑞德西韦(de Wit,E.etal.Prophylactic and therapeutic remdesivir(GS-5734)treatment in the rhesusmacaque model of MERS-CoV infection.Proc Natl Acad Sci U S A 117,6771-6776,doi:10.1073/pnas.1922083117(2020);Sheahan,T.P et al.Broad-spectrum antiviralGS-5734inhibits both epidemic and zoonotic coronaviruses.Sci Transl Med 9,doi:10.1126/scitranslmed.aal3653(2017);Lo,M.K.et al.GS-5734and its parentnucleoside analog inhibit Filo-,Pneumo-,and Paramyxoviruses.Sci Rep 7,43395,doi:10.1038/srep43395(2017)),以用于治疗患有严重或危重COVID-19的患者。瑞德西韦,一种具有广泛抗病毒活性的RdRp抑制剂和核苷酸类似物前药,在III期适应性COVID-19治疗试验中表现出阳性临床终点(达到恢复的时间的中值从15天缩短至11天;Health,N.I.o.(2020)证明其获得美国食品和药物管理局的紧急使用授权,以用于治疗住院的COVID-19患者(Administration,U.S.D.(ed U.S.Food&Drug Administration)(U.S.Food&DrugAdministration,2020)。然而,最近,在一项大型多中心WHO SOLIDARITY试验中,其与羟氯喹、洛匹那韦(lopinavir)和干扰素方案一起,未能降低住院的COVID-19患者的死亡率(Pan,H.et a1.Repurposed antiviral drugs for COVID-19-interim WHO SOLIDARITYtrial results.medRxiv,2020.2010.2015.20209817,doi:10.1101/2020.10.15.20209817(2020))。本公开内容还部分地涉及在两种不同的基于细胞的SARS-CoV-2感染测定中且以瑞德西韦增强形式筛选大型药物文库(ReFRAME),以及在二次正交测定中分析所鉴定的命中物。这种筛选级联和随后的命中物优先级排序鉴定并验证了有前景的命中物MK-4482作为SARS-CoV-2的有效抑制剂,这些体外发现已转化至SARS-CoV-2感染的体内仓鼠模型。这些研究中鉴定的另一些命中物可用于改用为治疗剂以及用于阐明冠状病毒复制途径的工具。
定义
如本文所使用,并且除非另有相反说明,否则术语“化合物”是包含性的,因为其涵盖化合物或其可药用盐、立体异构体和/或互变异构体。因此,例如,本文所述的化合物包括该化合物的互变异构体的可药用盐。
在本公开内容中,“可药用盐”是本文所述的化合物的药学上可接受的有机或无机酸或碱盐。代表性的可药用盐包括例如,碱金属盐、碱土盐、铵盐、水溶性和水不溶性盐,例如乙酸盐、氨芪磺酸盐(amsonate)(4,4-二氨基二苯乙烯-2,2-二磺酸盐)、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、钙、依地酸钙、樟磺酸盐、碳酸盐、氯化物、柠檬酸盐、克拉维酸盐(clavulariate)、二盐酸盐、依地酸盐、乙二磺酸盐、依托酸盐(estolate)、乙磺酸盐(esylate)、延胡索酸盐(fiunarate)、葡庚糖酸盐、葡糖酸盐(gluconate)、谷氨酸盐、对羟乙酰氨基苯胂酸盐(glycollylarsanilate)、六氟磷酸盐、己基间苯二酚盐、海巴明(hydrabamine)、氢溴酸盐、盐酸盐、羟基萘酸盐、碘化物、异硫氰酸盐(isothionate)、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、黏液酸盐(mucate)、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐、3-羟基-2-萘甲酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(1,1-亚甲基-双-2-羟基-3-萘甲酸盐,恩贝酸盐(einbonate))、泛酸盐、磷酸盐/二磷酸盐、苦味酸盐、多聚半乳糖醛酸盐、丙酸盐、对甲苯磺酸盐、水杨酸盐、硬脂酸盐、次醋酸盐、琥珀酸盐、硫酸盐、磺基水杨酸盐(sulfosaliculate)、苏拉酸盐(suramate)、单宁酸盐、酒石酸盐、茶氯酸盐(teoclate)、甲苯磺酸盐、三乙碘化物(triethiodide)和戊酸盐。可药用盐在其结构中可以具有多于一个带电原子。在这种情况下,可药用盐可以具有多个反离子。因此,可药用盐可以具有一个或更多个带电原子和/或一个或更多个反离子。
术语“治疗”及其变化形式是指改善或根除疾病或与疾病相关的症状。在多个实施方案中,该术语是指因将本文所述的一种或更多种预防性或治疗性化合物施用于患有疾病的患者而导致的这样的疾病的传播或恶化最小化。
术语“预防”及其变化形式是指因施用本文所述的化合物而导致的对患者中疾病的发作、复发或扩散的预防。
术语“有效量”是指足够在疾病的治疗或预防中提供治疗性或预防性益处或使与疾病相关的症状延迟或最小化的如本文所述的化合物或其他活性成分的量。此外,关于本文所述化合物的治疗有效量意指治疗剂的在单独或与其他治疗组合时在疾病的治疗或预防中提供治疗性益处的量。与本文所述的化合物结合使用时,该术语可涵盖改善疾病的整体治疗、减轻或避免疾病的症状或原因、或者增强另外的治疗剂的效力或与另外的治疗剂协同作用的量。
“患者”或“对象”包括动物,例如人、牛、马、绵羊、羔羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或豚鼠。根据一些实施方案,动物是哺乳动物,例如非灵长类和灵长类(例如,猴和人)。在一个实施方案中,患者是人,例如人婴儿、儿童、青少年或成人。在本公开内容中,术语“患者”和“对象”可互换使用。
筛选测定和方法
ReFRAME(改用、聚焦拯救和加速的医学化学(Repurposing,Focused Rescue,andAccelerated Medchem))药物合集是广泛的药物改用文库,其包含近12,000种显示适合直接用于人的小分子药物(5),并提供了丰富的资源以发现新的治疗,所述新的治疗可用作另外的单一治疗或与瑞德西韦联合使用以进一步增强效力和降低潜在的药物抗性。为了鉴定该文库中可以抑制人细胞中SARS-CoV-2的进入或复制的化合物,我们使用表达人SARS-CoV-2受体,即血管紧张素转换酶2或ACE2的HeLa细胞(HeLa-ACE2)开发了高内涵成像(high-content imaging,HCI)384孔形式测定。在该测定中,在目的化合物存在的情况下用SARS-CoV-2病毒感染HeLa-ACE2细胞,并在24小时之后量化病毒感染(图1,小图A)。该测定依赖于使用从暴露于病毒的患者中纯化的血清对SARS-CoV-2蛋白进行的免疫荧光检测,其与宿主细胞核染色一起允许定量每个孔中的感染细胞百分比(图1,小图B)。
我们使用已报道具有针对埃博拉病毒(Ebola)的活性和疑似或先前已验证具有针对SARS-CoV-2的活性的化合物瑞德西韦(GS-5734)(6)(EC50=194±20nM;5次独立实验的平均值±sem)和PIKfyve抑制剂阿吡莫德(EC50=50±11nM,4次独立实验的平均值±sem)验证了该测定(图1,小图B)。浓度升高的瑞德西韦能够几乎完全地清除感染细胞(图1,小图C),以及我们使用浓度为2.5μM的瑞德西韦作为阳性对照,其中数据相对于其和中性DMSO对照孔进行归一化。虽然阿吡莫德比瑞德西韦更有效,但与瑞德西韦相比,其最大效力略较低(在最高有效浓度下,85%至90%未感染细胞)。此外,我们通过定量每孔的总细胞数目评估了感染情况下的化合物毒性,其中细胞毒性蛋白质合成抑制剂嘌呤霉素作为阳性对照(平均EC50=547±27nM,5次独立实验的平均值±sem;HeLa-ACE2 CC50=2.45±0.23μM,5次独立实验的平均值±sem)。值得注意的是,伴随的细胞数目增加与瑞德西韦和阿吡莫德的抗病毒活性一致,这可能是由于感染细胞的增殖降低(图1,小图B至E)。在相同实验中,改变感染复数对对照化合物的效力有适度影响,其中从MOI=1至MOI=26,瑞德西韦的EC50增加2.7倍,以及阿吡莫德的EC50增加3.7倍,但嘌呤霉素的EC50没有增加(图3)。
使用所开发的测定,我们运行了试验性筛选来评估具有针对冠状病毒感染的疑似治疗潜力的148种小分子的活性(7)(RZ’=0.84)。我们基于从未感染HeLa-ACE224小时活/死测定中获得的数据鉴定了19种EC50<9.6μM的化合物,并且这些中的10种是具有选择性的(未感染HeLa-ACE2 CC50/SARS-CoV-2EC50>10或未感染HeLa-ACE2 CC50>40μM)(表1)。这包括在测定中“重新发现”的阿吡莫德(ECs0=184nM,CC50>40μM)和瑞德西韦(EC50=300nMCC50>40μM)的文库/筛选批次。与新鲜制备的对照粉末原料相比,阿吡莫德和瑞德西韦的较高的EC50可能是由于在筛选板(screening deck)中随着时间推移的轻微降解。
表1.ReFRAME文库、抗病毒活性以及与瑞德西韦协同作用的筛选
我们在1.9μM和9.6μM的最终浓度下筛选了具有12,000种化合物的ReFRAME改用文库。如下表2所示,在两个筛选期间均保持了测定质量(RZ’分别为0.87和0.72)。
表2.初级和验证筛选统计
此外,经DMSO载剂处理(中性对照)、经瑞德西韦处理(阳性对照)、经阿吡莫德处理和经嘌呤霉素处理(毒性对照)的孔的活性特征明显不同(图1,小图D和E))。命中物选择基于以下显示结果:每孔感染细胞数目减少>50%(<-50%活性,其相对于中性对照减去抑制剂归一化)和基于每孔总细胞数目的<40%毒性(>-40%活性,其相对于化合物活性归一化,包括10μM嘌呤霉素)(图1,小图E和F),这鉴定了在1.9μM筛选浓度下的61种初级命中物和在9.6μM筛选浓度下的266种初级命中物(命中率分别为0.51%和2.24%),共计311种命中物。
ReFRAME文库的初级筛选的命中率较高(2.51%),但这对于该生物活性小分子集合并不意外,该集合中的许多是经批准的药物或处于临床开发阶段并用于广泛多种的适应证(图2,小图A)。为了再确认和评估初级命中物的效力和选择性,我们以10-点1∶3稀释剂量响应形式(最高浓度为9.6μM)测试了325种可用化合物。其中,233种(71.7%)表现出针对SARS-CoV-2的EC50<9.6μM的活性,以及另外42种(12.9%)表现出弱活性(EC50>9.6μM)。然而,许多初级筛选命中物也具有细胞毒性,具有不可接受的低选择性比率,如在未感染HeLa-ACE2细胞中确定的(未感染CC50/EC50<10)(表3,图2,小图B)。
表3.具有针对SARS-CoV-2的活性和选择性的所选定的再确认命中物
由于病毒依赖宿主机制以进行复制,因此许多具有抗病毒活性的化合物也会影响重要的宿主过程,这并非不可预期。令人感兴趣的是,这种毒性有时在感染的细胞中被掩盖,因为通过化合物例如蛋白质合成抑制剂嘌呤霉素以及甚至羟氯喹的病毒感染降低在感染的情况下对细胞健康提供了益处,但在未感染的细胞中则没有(图2,小图C)。
在小型试验和ReFRAME筛选之间,我们确定了76种(75种独特的,因为确定了两个不同批次的GW-803430)有效(EC50<9.6μM)且具有选择性的(CC50/EC50>10或CC50>39.8μM)化合物,以及135种仅具有弱活性(EC50>9.6μM)或有效但选择性不足(EC50<9.6μM,CC50/EC50<10)的化合物(图2,小图B和D,表1)。前四类有效且具有选择性的化合物是溶瘤化合物、离子通道调节剂、抗精神病剂和受体结合化合物(图2,小图D)。对于弱活性或无选择性的命中物,前四类别同样包括溶瘤化合物、离子通道调节剂、抗精神病剂以及信号转导调节剂。有效且具有选择性的命中物中五分之一可归类为溶瘤药物,这进一步反映了病毒对快速增殖细胞中存在的宿主细胞过程的依赖。属于抗精神病、心血管以及甚至抗寄生虫(被忽视的热带病)剂类别的化合物的鉴定可反映这些分子中的一些的阳离子两亲性质及其在酸性胞内区室(例如晚期核内体/溶酶体)中积累和影响酸性胞内区室(例如晚期核内体/溶酶体)的能力。因而发生的内溶酶体途径和脂质稳态的失调已被认为会损害病毒进入和/或复制(8),并且这种作用模式对于胺碘酮和羟氯喹已被考虑,这两种药物在此在我们的筛选中都被鉴定为针对SARS-CoV-2有效且具有选择性的命中物(表1和3)。我们还鉴定了两种选择性雌激素受体调节剂(巴多昔芬,EC50=3.47μM;和雷洛昔芬,EC50=4.13μM),其是一类先前被发现抑制埃博拉病毒感染的化合物(9)。
用于本文所述的任何方法或组合物的另一些实施方案包括从ReFRAME筛选中进一步再确认的命中物。这些与来自本文所述的SARS-CoV-2/HeLa-ACE2高内涵筛选测定和SARS-CoV-2/Calu-3高内涵筛选测定的相应数据一起列于表4中(参见实施例)。
表4.在Calu-3细胞中从ReFRAME文库的筛选中再确认的命中物(抗病毒活性)
根据多个实施方案,在鉴定的命中物中,存在新鉴定且已批准的经口药物卤泛群HCl、胺碘酮、甲磺酸奈非那韦、西咪匹韦、马尼地平和奥扎莫德,因为他们的暴露相对较高或作为治疗剂的使用历史较长,并因此具有在动物模型中进行进一步的效力审查之后被迅速改用作COVID-19治疗的潜力。例如,病毒蛋白酶抑制剂奈非那韦和西咪匹韦表现出优异的暴露。
在另一个实施方案中,化合物是选择性鞘氨醇-1-磷酸(sphingosine-1-phosphate,S1P1)受体调节剂奥扎莫德。选择性S1P1激动剂已被证明可通过降低感染部位的炎症(降低肺内皮细胞的细胞因子释放和淋巴细胞浸润到肺部)而在小鼠模型中提供针对流感病毒感染的显著保护(10),并且因此奥扎莫德可用作直接作用的抗病毒药物的优异组合伴侣。
根据另一个实施方案,本文所述方法中施用的化合物是经批准的药物胺碘酮,其具有优异的暴露(C最大值为约684μM);或经批准的钙通道阻断剂马尼地平,其具有低暴露但可以改善高血压患者的COVID-19疾病结局。胺碘酮在体外筛选中被进一步鉴定为具有广谱抗病毒活性(11)。
19种另外的处于不同开发阶段的化合物,例如阿吡莫德(测定对照,其可以通过破坏内溶酶体运输来抑制病毒进入,如针对丝状病毒所发现的(12))、蛋白酶抑制剂NCO700(组织蛋白酶B)和杜他卡替(组织蛋白酶K))(其也可以影响病毒进入)由于它们的效力或药代动力学特征,而均可以显示出效力(表3)。除了非常有效的阿吡莫德,这些中的大多数具有适度的EC50>1μM,其不超过瑞德西韦的效力。
在一些实施方案中,本公开内容还提供了用于降低病原体感染在对象中发生的可能性或减少病原体从受感染的对象传播至其他对象的方法。该方法包括将表1或表4中列出的至少一种化合物施用于对象,所述组合物任选地与本文所述的至少一种抗感染剂组合。
组合治疗
在多个实施方案中,本公开内容的方法还包括施用抗感染剂。抗感染剂可以与本文所述的至少一种化合物(表1和表4)伴随施用,例如在同一制剂或剂型中。或者,可以在化合物之前或之后施用抗感染剂。
在一些实施方案中,抗感染剂选自以下:抑制进入的药物(包括恩夫韦地(enfuvirtide))、抑制脱壳的药物(包括金刚烷胺(amantadine)、金刚乙胺(rimantadine)和普利康那利(pleconaril))、抑制逆转录酶的药物(包括阿昔洛韦(acyclovir)、齐多夫定(zidovudine)和拉米夫定(lamivudine)))、反义药物(包括福米韦生(fomivirsen))、核酶药物、蛋白酶抑制剂、抑制装配的药物(包括利福平(rifampicin))以及抑制释放的药物。
在一些实施方案中,另外的药剂选自地塞米松、阿莫地喹、
在一些实施方案中,另外的抗感染剂是抗病毒剂。在一些实施方案中,抗病毒剂选自:阿巴卡韦(Abacavir)、阿昔洛韦(Aciclovir)、阿德福韦(Adefovir)、金刚烷胺、安普利近(Ampligen)、安普那韦(Amprenavir)(Agenerase)、阿比朵尔、阿扎那韦(Atazanavir)、阿曲普拉(Atripla)、巴拉韦(Balavir)、巴洛沙韦玛波西酯(Baloxavir Marboxil)(Xofluza)、必妥维(Biktarvy)、波普瑞韦(Victrelis)、西多福韦(Cidofovir)、可比司他(Cobicistat)(Tybost)、可比韦(Combivir)、达卡他韦(daclatasvir)(Daklinza)、地瑞那韦(Darunavir)、地拉韦啶(Delavirdine)、达可挥(Descovy)、地达诺新(Didanosine)、二十二烷醇(Docosanol)、多替拉韦(Dolutegravir)、多拉韦林(Doravirine)(Pifeltro)、依可列维(Ecoliever)、依度尿苷(Edoxudine)、依法韦仑(Efavirenz)、埃替拉韦(Elvitegravir)、恩曲他滨(Emtricitabine)、恩夫韦地、恩替卡韦(Entecavir)、依曲韦林(Etravirine)(Intelence)、泛昔洛韦(Famciclovir)、洛匹那韦(T-705;6-氟-3-羟基-2-吡嗪甲酰胺)、福米韦生、福沙那韦(Fosamprenavir)、膦甲酸(Foscarnet)、膦乙酸(Fosfonet)、融合抑制剂、更昔洛韦(Ganciclovir)(Cytovene)、伊巴他滨(Ibacitabine)、伊巴利珠单抗(Ibalizumab)(Trogarzo)、碘苷(Idoxuridine)、咪喹莫特(Imiquimod)、伊姆诺韦(Imunovir)、茚地那韦(Indinavir)、肌苷、整合酶抑制剂、I型干扰素、II型干扰素、III型干扰素、干扰素、拉米夫定、莱特莫韦(Letermovir)(Prevymis)、洛匹那韦、洛韦胺(Loviride)、马拉韦罗(Maraviroc)、甲吲噻腙(Methisazone)、吗啉胍(Moroxydine)、奈非那韦、奈韦拉平(Nevirapine)、Nexavir、硝唑尼特(Nitazoxanide)、利托那韦(Norvir)、核苷类似物、奥司他韦(Oseltamivir)(Tamiflu)、聚乙二醇干扰素α-2a、聚乙二醇干扰素α-2b、喷昔洛韦(Penciclovir)、帕拉米韦(Peramivir)(Rapivab)、普利康那利、鬼臼毒素(Podophyllotoxin)、蛋白酶抑制剂(药理学)、普拉嘧啶(Pyramidine)、雷特格韦(Raltegravir)、瑞德西韦、逆转录酶抑制剂、利巴韦林(Ribavirin)、利匹韦林(Rilpivirine)(Edurant)、金刚乙胺、利托那韦(Ritonavir)、沙奎那韦(Saquinavir)、西咪匹韦(Olysio)、索非布韦(Sofosbuvir)、司他夫定(Stavudine)、协同增强剂(抗逆转录病毒)、特拉匹韦(Telaprevir)、替比夫定(Telbivudine)(Tyzeka)、替诺福韦艾拉酚胺(Tenofovir Alafenamide)、替诺福韦酯(Tenofovir Disoproxil)、替诺福韦、替拉那韦(Tipranavir)、曲氟尿苷(Trifluridine)、三协唯(Trizivir)、曲金刚胺(Tromantadine)、特鲁瓦达(Truvada)、伐昔洛韦(Valaciclovir)(Valtrex)、缬更昔洛韦(Valganciclovir)、维维罗克(Vicriviroc)、阿糖腺苷(Vidarabine)、塔利韦林(Viramidine)、扎西他滨(Zalcitabine)、扎那米韦(Zanamivir)(Relenza)和齐多夫定。
静脉内施用的要求和瑞德西韦潜在有限的效力促使进一步研究替代治疗剂或补充治疗剂。因此,根据多个实施方案,本公开内容提供了作为在组合治疗中瑞德西韦的伴侣的如本文所公开的化合物。
本文公开的组合治疗可以提高治疗效力,同时降低任一或两个组合伴侣的药物剂量,并因此防止可能与更高剂量的施用相关的副作用。药物组合也可以减缓药物抗性的获得。药物协同作用(被定义为组合治疗的活性提高超出预期的加和相互作用)是罕见的,并且加和响应本身可改善治疗方案。相反,拮抗作用(整体组合的活性的抑制超出化合物独立作用时所预期的活性)是不期望的特性。
因此,为了鉴定经FDA批准的瑞德西韦和ReFRAME命中物之间的协同、加和和拮抗相互作用,我们在棋盘实验(checkerboard experiment)中进行了协同相互作用研究,将瑞德西韦的全剂量响应与11种具有有吸引力的安全性和药代动力学特征的命中物的剂量响应在10×10矩阵中进行了比较(图2,小图E)。我们使用R中的synergyfinder包(13)使用零相互作用效力(Zero Interaction Potency,ZIP)模型(14)评估受试化合物之间的相互作用,其中δ评分>10指示可能有协同相互作用,δ<-10指示拮抗相互作用,以及δ介于-10和10之间指示加和相互作用。结果表明,数个示例性组合是加和的(图2,小图E和F,表1)。
该筛选还鉴定了核苷类似物利波腺苷(riboprine)(N6-异戊烯基腺苷,其先前作为抗肿瘤药剂被研究过,用于治疗恶心和手术部位感染,以及为CitraNatal 90DHA(一种处方产前/产后复合维生素/矿物质片剂)的一种组分)和叶酸拮抗剂10-去氮杂氨基蝶呤(目前处于II期开发阶段的抗肿瘤化合物)为具有与瑞德西韦的活性协同作用的活性。在特定浓度下观察到两种化合物的协同效应,如3维协同效应评分情况中的峰值所示。
利波腺苷在测试的浓度范围内实现了最大(100%)效力,但添加瑞德西韦的EC2使其EC50从12μM变为3.6μM,并且添加瑞德西韦的EC24将其效力进一步提高至EC50=1.6μM。10-去氮杂氨基蝶呤在测试的浓度范围内仅显示出40%的最大效力,但添加瑞德西韦的EC2可使最大效力从40%提高到近65%(在此预计会改变2%),并且添加瑞德西韦的EC24使组合的最大效力从40%提高到>80%。
药物组合物
本公开内容在多个实施方案中提供了药物组合物,其包含治疗有效量的选自如本文所述的表1或表4的至少一种化合物、治疗有效量的如本文所述的抗感染剂、和可药用载体。在一些实施方案中,根据药物配混的公认实践,组合物还包含一种或更多种另外的可药用赋形剂、稀释剂、佐剂、稳定剂、乳化剂、防腐剂、着色剂、缓冲剂和风味赋予剂。
本公开内容的药物组合物以符合良好医学实践的方式配制、给药和施用。在本上下文中考虑的因素包括正在治疗的具体病症、正在治疗的具体对象、对象的临床状况、病症的原因、药剂的递送部位、施用的方法、施用的时间安排以及医师已知的其他因素。
施用的化合物(包括组合治疗中的所有活性成分)的“治疗有效量”由这样的考虑因素控制,并且是引发抗感染例如抗病毒作用所必需的最小量。这样的量可以低于对正常细胞或整个对象有毒的量。通常来说,施用的本公开内容的化合物的初始治疗有效量在每天约0.01至约200mg/kg患者体重或约0.1至约20mg/kg患者体重的范围内,其中典型的初始范围为约0.3至约15mg/kg/天。经口单位剂型(例如片剂和胶囊剂)可包含约1mg至约1000mg的本公开内容的化合物。在另一个实施方案中,这样的剂型包含约50mg至约500mg的本公开内容的化合物。在又一个实施方案中,这样的剂型包含约25mg至约200mg的本公开内容的化合物。在另一个实施方案中,这样的剂型包含约10mg至约100mg的本公开内容的化合物。在另一个实施方案中,这样的剂型包含约5mg至约50mg的本公开内容的化合物。
组合物可以以剂量单位制剂经口、局部、肠胃外、通过吸入或喷雾剂或经直肠施用。本文所使用的术语肠胃外包括皮下注射、静脉内、肌内、胸骨内注射或输注技术。
根据本公开内容的合适的经口组合物包括但不限于片剂、含片(troche)、锭剂、水性或油性混悬剂、可分散的散剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、糖浆剂或酏剂。
涵盖在本公开内容的范围内的是适用于单一单位剂量的药物组合物,其包含本公开内容的化合物或其可药用的立体异构体、盐或互变异构体、和可药用载体。
根据用于制备药物组合物的本领域已知的任何方法来制备适用于经口使用的组合物。例如,化合物的液体制剂包含选自甜味剂、矫味剂、着色剂和防腐剂中的一种或更多种试剂,以提供精氨酸酶抑制剂的药学上优雅美观且可口的制剂。
对于片剂组合物,本公开内容的化合物与无毒的可药用赋形剂混合用于制备片剂。这样的赋形剂的实例包括但不限于惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒剂和崩解剂,例如玉米淀粉或藻酸;黏合剂,例如淀粉、明胶或阿拉伯胶,和润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者可以通过已知的包衣技术对其进行包衣,以延迟在胃肠道中的崩解和吸收,并从而在期望的时间内提供持续的治疗作用。例如,可以使用例如单硬脂酸甘油酯或二硬脂酸甘油酯的时间延迟物质。
用于经口使用的制剂也可以制成硬明胶胶囊剂,其中活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土混合;或者制成软明胶胶囊剂,其中活性成分与水或油介质,例如花生油、液体石蜡或橄榄油混合。
对于水性混悬剂,将本公开内容的化合物与适用于维持稳定混悬剂的赋形剂混合。这样的赋形剂的实例包括但不限于羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄芪胶和阿拉伯胶。
经口混悬剂还可包含分散剂或润湿剂,例如天然存在的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如,十七碳乙烯氧基十六烷醇,或环氧乙烷与来源于脂肪酸和己糖醇的偏酯的缩合产物,例如聚氧乙烯山梨糖醇一油酸酯,或环氧乙烷与来源于脂肪酸和己糖醇酐的偏酯的缩合产物,例如聚乙烯脱水山梨糖醇一油酸酯。水性混悬剂还可以包含一种或更多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或更多种着色剂,一种或更多种矫味剂,以及一种或更多种甜味剂,例如蔗糖或糖精。
可通过将本公开内容的化合物混悬在植物油(例如花生油、橄榄油、芝麻油或椰子油)或者矿物油(例如液体石蜡)中来配制油性混悬剂。油性混悬剂可包含增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。
可以添加甜味剂例如如上所示的那些和矫味剂以提供适口的经口制剂。这些组合物可通过添加抗氧化剂例如抗坏血酸来保存。
适用于通过添加水来制备水性混悬剂的可分散的散剂和颗粒剂提供了与分散剂或润湿剂、助悬剂和一种或更多种防腐剂混合的本公开内容的化合物。合适的分散剂或润湿剂和助悬剂通过上面已经提及的那些来例示。还可以存在另外的赋形剂,例如甜味剂、矫味剂和着色剂。
本公开内容的药物组合物还可以是水包油乳剂的形式。油相可以是植物油,例如橄榄油或花生油,或者矿物油,例如液体石蜡,或者这些的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯胶或黄芪胶,天然存在的磷脂,例如大豆、卵磷脂,以及来源于脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇一油酸酯,以及所述偏酯与环氧乙烷的缩合饱和产物,例如聚氧乙烯脱水山梨糖醇一油酸酯。乳剂还可以包含甜味剂和矫味剂。
糖浆剂和酏剂可以用甜味剂例如甘油、丙二醇、山梨糖醇或蔗糖配制。这样的制剂还可以包含缓和剂(demulcent)、防腐剂以及矫味剂和着色剂。药物组合物可以是无菌可注射剂、水性混悬剂或油性混悬剂的形式。可以根据已知技术使用上面已经提及的那些合适的分散剂或润湿剂和助悬剂来配制该混悬剂。无菌可注射制剂也可以是无毒的、亲代可接受的稀释剂或溶剂中的无菌可注射溶液剂或混悬剂,例如作为在1,3-丁二醇中的溶液剂。在可用的载剂和溶剂中,可使用水、林格溶液和等张氯化钠溶液。此外,无菌的不挥发油通常用作溶剂或混悬介质。为此目的,可以使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸可用于制备可注射剂。
本公开内容的化合物还可以以栓剂的形式施用,用于化合物的经直肠施用。这些组合物可通过将药物与合适的非刺激性赋形剂混合来制备,该赋形剂在常温下为固体但在直肠温度下为液体并且因此其将在直肠中融化以释放药物。这样的物质是可可脂和聚乙二醇。
用于肠胃外施用的组合物在无菌介质中施用。取决于所使用的载剂和制剂中药物的浓度,肠胃外制剂可以是混悬剂或包含溶解的药物的溶液剂。还可以将辅料例如局部麻醉剂、防腐剂和缓冲剂添加到肠胃外组合物中。
实施例
以下实施例是举例说明性而并非限制本文所述的组合物、方法和制剂的范围。
病毒产生。将Vero E6细胞(ATCC CRL-1586)平板接种在具有完全DMEM(Corning15-013-CV)的T225烧瓶中于37℃、5%CO2下过夜,所述完全DMEM包含10%FBS、1×PenStrep(Coming 20-002-CL)、2mM L-谷氨酰胺(Corning 25-005-CL)。取出烧瓶中的培养基,并将2mL的在完全DMEM中的SARS-CoV-2毒株USA-WA1/2020(BEI Resources NR-52281)以0.5的MOI添加到烧瓶中,并允许在34℃、5%CO2下孵育30分钟。孵育后,将30mL完全DMEM添加到烧瓶中。然后将烧瓶置于34℃培养箱中于5%CO2下培养5天。在感染之后第5天,收获上清液并以1,000×g离心5分钟。将上清液通过0.22μM过滤器进行过滤,并储存在-80℃下。
ReFRAME文库:化合物管理、药物注释和筛选数据访问。ReFRAME文库集合由近12,000种溶解在高质量二甲基亚砜(DMSO)中的高纯度化合物(>95%)组成。当需要时,通过液相色谱-质谱和/或1H-NMR进行化合物质量控制。该文库以2和10mM两种浓度制备,以支持低浓度(2至10μM)和高浓度(10至50μM)筛选形式。Echo合格(Echo-qualified)的384孔低死体积plus微量板(LP-0200-BC;Labcyte Inc.)用作文库源板,以支持使用Echo 555液体处理器(Labcyte Inc.)进行声学转移。将不溶于DMSO的化合物置于水中(129种化合物);在DMSO中缺乏长期可溶性的化合物在刚好进行分散之前悬浮以避免沉淀(71种化合物)。
以下三种广泛使用的商业药物竞争情报数据库支持相关的化合物注释(表1):Clarivate Integrity、GVK Excelra GoStar和Citeline Pharmaprojects。如果可用,则注释数据可包括临床开发状态和实现的最高开发阶段、作用机制、药物适应证和施用途径。
HeLa-ACE2稳定细胞系。通过转导人ACE2慢病毒来产生HeLa-ACE2细胞。通过使用Lipofectamine 2000(Thermo Fisher Scientific,11668019)将HEK293T细胞与pBOB-hACE2构建体和慢病毒包装质粒pMDL、pREV和pVSV-G(Addgene)共转染来产生慢病毒。转染之后48小时收集上清液,然后将其用于转导预接种的HeLa细胞。转导之后12小时,收集稳定的细胞系,将其扩大规模并储存。在37℃、5%CO2下,将细胞维持在具有10%FBS(Gibco,10438026)和1×丙酮酸钠(Gibco,11360070)的DMEM(Gibco,11965-092)中。
SARS-CoV-2/HeLa-ACE2高内涵筛选测定。将化合物声学转移到384孔μclear底板(μclear-bottom plate)(Greiner,Part.No.781090-2B)中。将HeLa-ACE2细胞以每孔1.0×103个细胞的密度接种在具有2%FBS的13μL DMEM中。将平板接种的细胞转运至BSL3设施,在该设施处每孔添加13μL在测定培养基中稀释的SARS-CoV-2,测定感染复数(multiplicity of infection,MOI)=2.2以用于初级筛选,调整为0.65用于能力再确认。将板在34℃、5%CO2下孵育24小时,并随后用终浓度为4%的甲醛在34℃、5%CO2下固定1小时。在固定和随后的一抗和二抗染色之间,用i×PBS0.05%吐温20洗涤板。将在Perm/Wash缓冲液(BD Biosciences 554723)中以1∶500稀释的人多克隆血浆添加到板中,并在室温下孵育2小时。8μg/mL(1∶250稀释)的山羊抗人H+L缀合的Alexa 488(Thermo FisherScientificA 11013)与8μM在SuperBlock T20(PBS)缓冲液(Thermo Fisher Scientific37515)中的防褪色-46-二脒基-2-苯基吲哚(DAPI;Thermo Fisher Scientific D1306)一起添加到板中,并在室温下于黑暗中孵育1小时。使用具有10×物镜的ImageXpress微共聚焦高内涵成像系统(Molecular Devices)对板进行成像,每个孔成像4个视野。使用多波长细胞评分应用模块(MetaXpress)分析图像,其中DAPI染色鉴定宿主细胞核(图像中的细胞总数目)并且SARS-CoV-2免疫荧光信号导致对感染细胞的鉴定。
时间过程(time of addition,TOA)测定。在34℃、5%CO2下,用测定培养基(含2%FBS的DMEM)中的混悬液形式的SARS-CoV-2以1.5的MOI感染HeLa-ACE2细胞1小时,然后按照标准HeLa-ACE2感染测定,将其用PBS充分洗涤并平板接种于用化合物预点样的准备好用于测定的384孔板中。对于时间进程实验,在4、5、6、7、8、10、11、12和24hpi时用终浓度为4%的甲醛固定细胞,并按照标准感染测定进行染色和成像以确定用于TOA测定的最佳时间点。以相同的方式进行TOA测定,其中在10hpi时进行细胞固定。
Calu-3高内涵筛选测定。该测定按照针对HeLa-ACE2测定概述的进行,除了以下例外之外。将由NCATS/NIH的Catherine Chen博士和Scripps Research的Juan Carlos de laTorre博士惠赠的Calu-3细胞(ATCC HTB-55)以5,000个细胞/20μL/孔的密度接种到测定培养基中(含2%FBS的MEM)以及以0.75至1的MOI添加在测定培养基中稀释的SARS-CoV-2,以实现约30至60%的感染细胞。将板在34℃、5%CO2下孵育48小时,并随后用终浓度为4%的甲醛固定。将固定细胞如在HeLa-ACE2测定中一样进行染色和成像。
未感染宿主细胞细胞毒性计数器筛选。对于HeLa-ACE2细胞,将化合物声学转移到1,536孔μclear板(Greiner Part.No.789091)中。按照对于感染测定所描述的那样维持HeLa-ACE2细胞,并以400个细胞/孔接种在准备好用于测定的板中的含有2%FBS的DMEM中,并将板在37℃、5%CO2下孵育24小时。为了评估细胞生存力,根据制造商的说明使用Image-iT DEAD green试剂(Thermo Fisher)。用4%多聚甲醛固定细胞,并用DAPI复染。使用具有10倍物镜的Image Xpress微共聚焦高内涵成像系统(Molecular Devices)对固定的细胞进行成像,并使用Live Dead应用模块(Meta Xpress)在获得的图像中定量每孔的总活细胞。
对于Calu-3细胞,将化合物声学转移到1,536孔板(Coming No.9006BC)中,然后将Calu-3细胞以600个细胞/5μL/孔的密度接种到测定培养基(含2%FBS的MEM)中。将板在37℃、5%CO2下孵育48小时。为了评估细胞生存力,将2μL在水中稀释的50%Cell-Titer Glo(Promega No G7573)添加到细胞,并在EnVision读板器(Perkin Elmer)上测量发光。
将HepG2(ATCC HB-8065)和HEK293T(ATCC CRL-3216)哺乳动物细胞系维持在37℃、5%CO2下湿润组织培养箱中的具有10%热灭活HyClone FBS(GE Healthcare LifeSciences)、100IU青霉素和100mg/mL链霉素(Gibco)的杜氏改良Eagle培养基(DMEM,Gibco)中。为了测定命中物化合物的哺乳动物毒性,将750个HepG2和375个HEK293T细胞/孔分别接种到1536孔的白色、经组织培养物处理的硬底板(Corning,9006BC)中的测定培养基(DMEM,2%FBS、100IU青霉素和100mg/mL链霉素)中,所述硬底板包含从40μM开始经三倍连续稀释的声学转移的化合物。孵育72小时之后,使用Cell Titer-Glo发光细胞生存力测定(Promega No G7573)对Calu-3细胞的细胞生存力进行量化。
SARS-CoV-2初级ALI HBEC模型。使用PneumaCultTM-ALI培养基(StemcellTechnologies),将正常原代人支气管上皮细胞(human bronchial epithelial cell,HBEC)(Lonza)在带有1μM PET过滤器(Sigma)的Millicell-96细胞培养插入板中在气液界面处培养至少4周。简言之,首先使HBEC在细胞培养瓶中扩增,然后每孔接种10,000个细胞,浸没在PneumaCultTM-Ex Plus培养基中。1周后,将细胞转移到PneumaCultTM-ALI培养基中,并从顶端表面去除培养基。维持气液界面,并且每2至3天更换一次培养基,持续至少4周,以允许细胞分化。在感染之前,用DPBS冲洗顶端表面一次,并将化合物添加到基底外侧室。将20,000PFU SARS-CoV-2毒株USA-WA1/2020添加到50μL PBS中的顶端表面,并孵育2小时。然后除去接种物,并用DPBS冲洗细胞一次。更换培养基,并在感染之后24和48小时添加新鲜化合物。通过向顶端表面添加100μL DPBS 15分钟,在感染之后72小时收集顶端清洗物。使用PureLinkTM Pro 96病毒RNA/DNA纯化试剂盒(Thermo Fisher)从顶端清洗物中分离出RNA,并使用SuperScriptTM III PlatinumTM一步qRT-PCR试剂盒(Thermo Fisher)以及2019-nCoV N1CDC引物和探针组(Integrated DNA Technologies)通过RT-qPCR来分析病毒RNA水平。通过从病毒储液的连续稀释液中分离RNA来生成标准曲线,并将该标准曲线用于确定每个样品的PFU当量/mL。然后确定每个实验化合物处理与中性DMSO对照相比的病毒载量减少,并以对数标度绘制。使用细胞毒性检测试剂盒(LDH)(Sigma)按照制造商的说明通过测量基底外侧培养基中的LDH活性来评估细胞毒性。取实验样品的平均值并将其表示为阳性对照嘌呤霉素的百分比。对抗病毒读出和细胞毒性读出二者运行了一式三份技术重复。
金色叙利亚仓鼠(Golden Syrian Hamster)SARS-CoV-2效力模型。八周龄的金色叙利亚仓鼠(Charles River)(每组五只)按照指示进行经口(PO)给药。第一次给药之后4小时,通过对于每只动物鼻内放置在100μL DMEM中的106总PFU来感染仓鼠。仓鼠每天两次(bidaily,BID)用化合物进行给药,并在研究期间称重。感染之后第5天,处死仓鼠,并分离肺组织用于分析。根据斯克利普斯研究IACUC方案#20-0003(Scripps Research IACUCProtocol#20-0003)批准并执行研究方案。
肺病毒滴度确定。使用100μM细胞过滤器(Myriad2825-8367)通过使器官在DMEM2%FCS中均质化来测量SARS-CoV2滴度。将均质化的器官在6个步骤中以1∶10进行滴定,并在Vero细胞上分层。在37℃下孵育1小时之后,添加DMEM覆盖层中的1%甲基纤维素,并将细胞在37℃下孵育3天。用4%PFA固定细胞并通过结晶紫染色来对斑块计数。
药代动力学研究。根据IACUC指南(IACUC协议#09-0004-5),在斯克里普斯研究所的动物模型核心(Animal Models Core)中进行药代动力学研究。八周龄的雄性叙利亚仓鼠(Charles River)(每组三只)按照对于每种化合物和制剂所指示的那样进行经口给药。监测每个测试样品的血浆浓度长达48小时。在10%DMSO/90%玉米油中配制奈非那韦,以及在10%PEG400/2.5%Cremaphor RH40中配制MK-4482,以用于药代动力学研究和效力研究二者。
仓鼠肺RNA分析。使用RNASeq平台分析来自未感染(U,n=2)、经载剂处理(V,n=4)和经MK-4482处理(T,n=4)的样品的仓鼠肺。使用python包scipy.stats.median_absolute_deviation计算所有基因的平均绝对偏差(mean absolute deviation,MAD)。应用StepMiner算法(Sahoo,D.,Dill,D.L.,Tibshirani,R.&Plevritis,S.K.Extractingbinary signals from microarray time-course data.Nucleic Acids Res 35,3705-3712,doi:10.1093/nar/gkm284(2007))来选择高MAD值,这将22,284个基因过滤到14,939个。再次应用StepMiner算法将14,939个基因过滤到8,617个基因。使用python seabornclustermap文库函数对这8,617个基因进行分层凝聚聚类分析(hierarchicalagglomerative clustering analysis)。使用DESeq227进行差异表达分析(经MK-4482处理的样品vs经载剂处理的样品),并应用经调整的p值<0.1和倍数变化的log2|>1来鉴定上调/下调的基因。对差异表达的基因进行反应组通路分析(reactome pathway analysis)(Fabregat,A.et al.The Reactome Pathway Knowledgebase.Nucleic Acids Res 46,D649-D655,doi:10.1093/nar/gkx1132(2018)),以鉴定基因集中富集的高水平生物学过程。用-logl0(fdr)作为x轴的条形图用于确定富集的生物过程的显著性。
RNASeq。完全按照之前25所述,使用Illumina TruSeq Stranded Total RNALibrary Prep Gold和TruSeq Unique Dual Indexes(Illumina,San Diego,CA)来产生RNA测序文库。简言之,除了将RNA剪切时间修改为5分钟之外,按照制造商的说明处理样品。由加州大学圣地亚哥分校(University of California San Diego)的基因组医学研究所(Institute of Genomic Medicine,IGM)使用100碱基对(bp)配对末端(PE100)以达到约25至40百万个读取/样品的深度在Illumina NovaSeq 6000上对所得到的文库进行多重化并测序。使用bcl2fastq v2.20转换软件(Illumina,San Diego,CA)对样品进行去多重化。使用kallisto(版本0.45.0)、Mesocricetus auratus基因组(MesAur1.0)处理RNASeq数据。使用tximport和biomaRt R包计算基因水平TPM值和基因注释。使用定制python脚本来组织数据并使用如果TPM>1则log2(TPM)以及如果TPM<=1则TPM-1进行log换算。对于仓鼠研究,kallisto索引是在Mesocricetus_auratus.MesAur1.0.ncrna.fa.gz+Mesocricetus_auratus MesAur1.0cdna.all.fa.gz上制备的。原始数据和经处理的数据存放在基因表达大棚车(Gene Expression Omnibus)(来自NCBI GEO的待定的GSEID)中。
仓鼠肺组织病理学/浸润量化。ImageJ软件用于量化H&E染色的载片图像(放大20倍)。首先将图像转换为8位(8-bit)(图像>类型>8位),调整它们的阈值(图像>调整>阈值),选择70%至80%的阈值以确保仅检测到深色染色的细胞核。在阈值处理(thresholding)之后,将图像转换为蒙片(mask)(处理>二进制>转化为蒙片)并使用默认设置进行分析(分析>分析颗粒),添加显示结果并显示轮廓,并将输出导出到GraphPadPrism(V9.0.0)中,其中使用非参数、双侧Mann-Whitney统计检验来计算显著性。
数据分析。使用MetaXpress(版本6.5.4.532)进行高内涵图像分析。将初级体外筛选和宿主细胞细胞毒性计数器筛选数据上传到Genedata Screener,版本16.0.3-标准。将HeLa-ACE2数据相对于中性(DMSO)减去抑制剂对照(对于HeLa-ACE2细胞中的抗病毒作用,2.4μM瑞德西韦;以及对于感染的宿主细胞的毒性,10μM嘌呤霉素)归一化。将Calu-3感染测定数据相对于中性(DMSO)减去抑制剂对照(10μM瑞德西韦)归一化,并且对于Calu-3细胞计数读出,将总细胞相对于刺激剂(10μM瑞德西韦)减去中性对照(DMSO)归一化。对于未感染宿主细胞细胞毒性计数器筛选,40μM嘌呤霉素(Sigma)用作HeLa-ACE2、HepG2和HEK293T细胞的阳性(抑制)对照,以及30μM嘌呤霉素(Sigma)用作Calu-3细胞的阳性(抑制)对照。对于剂量响应实验,在不同的测定板上以一式三份技术重复来测试化合物,并且用四-参数Hill方程拟合剂量曲线。使用中值压缩来分析技术重复数据。报告了在多个独立生物实验中获得的化合物活性(EC50和CC50)的几何平均值和几何标准偏差。R中的synergyfinder包(版本3.6.3)用于协同分析(Ianevski,A.,He,L.,Aittokallio,T.&Tang,J.SynergyFinder:aweb application for analyzing drug combination dose-response matrixdata.Bioinformatics 33,2413-241 5,doi:10.1093/bioinformatics/btx1 62(201 7))。通过计算所有值的对数(以10为底)、计算这些对数的平均值并取该平均值的反对数来计算几何平均值。通过取经对数转换的单独值的标准偏差并取该标准偏差的反对数来计算几何标准偏差。几何标准偏差是无单位的比率并报告为×÷而不是+/-。也就是说,对于报告的0.123μM×÷1.276,标准偏差范围为0.096μM至0.157μM(即0.123μM÷1.276至0.123μM×1.276)。
针对SARS-CoV-2的高通量Calu-3表型ReFRAME筛选。为了补充相对快速的24小时HeLa-ACE2测定并对命中物进行优先级排序,我们使用Calu-3细胞开发了更具生理相关性的第二种感染测定,其依赖于相同的抗体检测和类似的测定工作流,在48个SARS-CoV-2感染之后小时(hpi)时读出(同上文)。Calu-3是人肺上皮细胞,内源性表达ACE2受体和宿主丝氨酸蛋白酶TMPRSS2二者,TMPRSS2是SARS-CoV-2刺突蛋白加工和病毒进入宿主细胞所必需的(Hoffmann,M.et al.SARS-CoV-2Cell Entry Depends on ACE2and TMPRSS2 and IsBlocked by aClinically Proven Protease Inhibitor.Cell 181,271-280e278,doi:10.1016/j.cell.2020.02.052(2020)),而缺乏TMPRSS2表达的HeLa-ACE2细胞的稳健感染可能依赖于内体、组织蛋白酶介导的病毒进入途径,该途径已成为公认的冠状病毒机制(Yang,N.&Shen,H.M.Targeting the Endocytic Pathway and Autophagy Process as aNovel Therapeutic Strategy in COVID-19.Int J Biol Sci 16,1724-1731,doi:10.7150/ijbs.45498(2020))。
瑞德西韦在Calu-3细胞中是有活性的(EC50=444nM×÷1.514(n=4)),TMPRSS2抑制剂甲磺酸萘莫司他(nafamostat mesilate)(EC50=24nM×÷1.55(n=3))也是有活性的。与HeLa-ACE2筛选相比,Calu-3测定中的致细胞病变效应更明显(可能是由于使用了更高的MOI和更长的孵育时间)。作为结果,抗病毒化合物还保护细胞免受病毒诱导的细胞死亡,这提供了与化合物抗病毒活性相关的第二度量。值得注意的是,52种HeLa-ACE2ReFRAME命中物中的大多数在基于Calu-3细胞的测定中是无活性的(58%,30/52)或者无选择性的。
HeLa-ACE2和Calu-3细胞中活性的有限重叠促使使用Calu-3细胞重新筛选ReFRAME文库。在2.5μM的最终浓度、RZ’=0.744下进行筛选,并鉴定了235个初级命中物,这些初级命中物显示>50%的感染抑制、<80%的细胞毒性或>40%的感染抑制和>40%细胞计数增加(保护免受病毒诱导的细胞死亡)。其中,145种在以剂量响应形式进行测试时具有中等活性(EC50<10μM),但只有42种还具有选择性(CC50/EC50>10或CC50>30μM)。选择88种推定的命中物化合物作为新鲜粉末原料在Calu-3细胞中进行测试(CC50/EC50>5或CC50>30μM,CC50/EC50<5,但在未感染细胞毒性测定中减少小于50%,并且EC50<1μM的3种额外化合物显示感染细胞计数读出中的保护作用),并且87种被再确认为是有效的,以及41种被再确认为还具有选择性。同样地,在HeLa-ACE2感染测定中重新测试了41种再确认的Calu-3ReFRAME命中物。其中,63%(26/41)在HeLa-ACE2细胞中针对SARS-CoV-2是无活性的,而34%(14/41)是有活性的但具有强细胞毒性,在未感染的HeLa-ACE2细胞中CC50<3μM。鉴定内体组织蛋白酶介导的进入抑制剂。由于在Calu-3测定中HeLa-ACE2 ReFRAME命中物的有限活性的一种可能来源是病毒在每种细胞系中使用的进入机制,因此我们在HeLa-ACE2细胞中建立了时间过程(TOA)测定以在ReFRAME命中物中鉴定组织蛋白酶介导的病毒进入抑制剂,其在TMPRSS2进入的背景下不可能是有活性的。为了首先确定感染的动力学,用SARS-CoV-2感染HeLa-ACE2细胞1小时,然后洗掉未吸附的病毒,并将细胞平板接种在存在DMSO、羟氯喹、阿吡莫德或瑞德西韦(终浓度为10μM)的384孔板中。从4至24hpi按指示固定孔中的细胞,并且定量每个时间点的感染细胞百分比。
在除瑞德西韦之外的所有处理中,病毒感染通过在6hpi时的抗体染色首次显现,并在10至12hpi时达到接近最大水平。当在1hpi时开始处理的情况下阿吡莫德和羟氯喹二者的活性丧失指示这些化合物阻断了病毒进入HeLa-ACE2细胞,而瑞德西韦处理有效地阻断了感染,虽然处理在1hpi时开始,但这与其直接抗病毒作用机制一致。
基于这些结果,我们使用10hpi时间点来限制TOA测定(同上文)中的复制周期,在该测定中我们评估了所有HeLa-ACE2 ReFRAME命中物的剂量响应活性。我们发现在Calu-3细胞中无活性的33%(10/30)化合物是HeLa-ACE2中的进入抑制剂,这是基于他们在TOA测定中的活性降低,即标准24小时和TOA测定之间的EC50比率>10。相比之下,在Calu-3细胞中也有活性的化合物(EC50<10μM)都不能清楚地归类为在所述阈值处的进入抑制剂。奥希替尼和MK-2206各自的比率均>8,这表明他们可参与HeLa-ACE2细胞中的病毒进入,但它们在Calu-3细胞中的抗病毒活性是非特异性的(SI<2)。
ReFRAME命中物的优先级排序和验证。ReFRAME文库是生物活性小分子的集合,其中许多是经批准的药物或处于临床开发阶段并用于广泛多种的适应证。在HeLa-ACE2筛选中再确认为有能力的前五类有效且具有选择性的化合物是溶瘤化合物(9)、离子通道调节剂(7)、抗炎剂(5)、抗病毒剂(5)和信号转导调节剂(5),而在Calu-3筛选中,前五类是信号转导调节剂(14)、溶瘤化合物(11)、蛋白酶抑制剂(7)、抗生素(3)和离子通道调节剂(3)。两个筛选中有效且具有选择性的命中物中的五分之一可归类为溶瘤药物,这反映出病毒对快速增殖细胞中存在的宿主细胞过程的依赖。仅在HeLa-ACE2细胞中鉴定出属于抗精神病和抗寄生虫(被忽视的热带病)类别的化合物可反映这些分子中的一些的阳离子两亲性质及其在酸性胞内区室(例如晚期核内体/溶酶体)中积累和影响酸性胞内区室(例如晚期核内体/溶酶体)的能力。因此而发生的内溶酶体途径和脂质稳态的失调已被认为会损害病毒进入和/或复制(Salata,C.,Calistri,A.,Parolin,C.,Baritussio,A.&Palu,G.Antiviralactivity of cationic amphiphilic drugs.Expert Rev Anti Infect Ther 15,483-492,doi:10.1080/14787210.2017.1305888(2017)),并且这种作用模式被推测用于胺碘酮和羟氯喹,这两者在HeLa-ACE2筛选中都被鉴定为针对SARS-CoV-2有效且具有选择性的命中物。然而,在我们的测定中,只有羟氯喹被鉴定为进入抑制剂。
在我们的初级筛选中被鉴定为命中物的化合物中,受到高度关注的是特征类似于瑞德西韦的特征的化合物,这些化合物在HeLa-ACE2测定和Calu-3测定二者中均是有活性且具有选择性的,并且未被归类为HeLa-ACE2细胞中的进入抑制剂。前药MK-4482的母体N-羟基胞苷符合该特征,尽管MK-4482本身在体外没有活性,这可能是由于缺乏将其转变为活性形式的代谢。
此外,在Calu-3中有活性但在HeLa-ACE2细胞中没有活性的化合物(例如TMPRSS2抑制剂甲磺酸萘莫司他)具有在晚期感染模型中有活性的潜力。相反,HeLa-ACE2细胞中的进入抑制剂(在Calu-3细胞中没有活性)(例如阿吡莫德、羟氯喹、阿奇霉素)优先级排序降低。根据我们的优先级排序,我们在正交气液界面原代人支气管上皮细胞(ALI-HBEC)感染模型中测试了针对SARS-CoV-2的代表性命中物的活性。这些分化的气道细胞表达高水平的ACE2和TMPRSS2二者。正如预期,瑞德西韦和甲磺酸萘莫司他抑制了ALI-HBEC中的病毒复制,而阿吡莫德则没有。此外,甲磺酸萘莫司他、MK-4482及其母体N-羟基胞苷均导致(在72hpi顶端病毒载量降低>1-log。这些结果与我们的命中物优先级排序的模型一致。
总体而言,我们将经批准的经口药物卤泛群HCl、甲磺酸奈非那韦、西咪匹韦和马尼地平鉴定为最受关注的命中物,因为他们在两种测定中均有活性,并且他们的暴露相对较高或作为治疗剂的使用历史较长,并因此具有在动物模型中进行进一步效力审查之后被迅速改用作COVID-19治疗的潜力。已报道了病毒蛋白酶抑制剂奈非那韦和西咪匹韦的良好的血浆暴露,并且根据所描述的他们的作用模式,他们可以直接抑制SARS-CoV-2。经批准的钙通道阻断剂马尼地平血浆暴露较低,但可具有改善患者的COVID-19疾病结局的潜力。处于不同开发阶段的其他九种化合物因为他们在筛选测定中的效力或药代动力学特征(见表格)而也具有显示出效力的高可能性。TO-195和RWJ-56423二者均是胰蛋白酶抑制剂,并且阿伏司他是在Calu-3细胞中具有活性的激肽释放酶抑制剂,其可阻断病毒进入。p38丝裂原活化蛋白激酶(mitogen-activatedprotein kinase,MAPK)抑制剂LY222820/甲磺酸雷美替尼在HeLa-ACE2筛选和Calu-3筛选二者中均有活性,并且先前显示出通过抑制p38MAPK23来抑制其他冠状病毒的复制。因此,p38 MAPK可以是抑制冠状病毒复制的重要宿主靶标。值得注意的是,前药MK-4482(莫诺匹拉韦,EIDD-2801)的亲本N-羟基胞苷在HeLa-ACE2测定和Calu-3测定二者中均是有效且具有选择性的命中物。MK-4482是经口抗病毒核苷类似物,目前正在由Ridgeback Biotherapeutics和Merck在COVID-19患者的治疗中进行评价。
MK-4482经口给药针对SARS-CoV-2感染是完全保护性的。由于奈非那韦和MK-4482/N-羟基胞苷在ALI-HBEC原代细胞模型中表现出体外效力及其充分暴露(对于单次500mg/kg PO给药的奈非那韦,Calu-3SARS-CoV-2EC50的时间为约3小时,以及对于单次500mg/kg PO给药的MK-4482,HeLa-ACE2和Calu-3 EC50的时间≥7小时),我们在SARS-CoV-2感染的金色叙利亚仓鼠动物模型中研究了奈非那韦和MK-4482的效力。奈非那韦以500mg/kg BID(每日两次)PO递送,以及MK-4482以500mg/kg、150mg/kg和50mg/kg BID PO递送,以评价剂量依赖性保护。匹配的仅载剂混悬剂用作对照。第一次处理之后四小时,通过鼻内施用1×106PFU SARS-CoV-2(USA-WA1/2020)对动物进行攻击。每天称重动物作为疾病进展的度量,并在感染的第五天分离肺组织以确定病毒滴度、肺组织学和基因表达谱。奈非那韦未能保护动物免受体重损失和病毒复制,这可能是由于仓鼠血浆暴露不足。然而,MK-4482在500mg/kg时保护动物免受严重的体重损失,体重在感染第5天时平均为起始体重的97%。与在感染第5天的载剂对照85%相比,150mg/kg和50mg/kg组通过体重损失表现出部分保护,分别平均为起始体重的89%和90%。
为了分析与体重损失的相关性,使用基于结晶紫的斑块测定从第5天的肺样品中确定了相对病毒滴度。500mg/kg和150mg/kg剂量在肺中具有检测不到的活病毒滴度,显示出免受病毒复制的完全保护作用。与平均4.5×105PFU/肺的载剂对照组相比,平均4.5×103PFU/肺的50mg/kg组显示出适度良好的效力(99%病毒减少)。
500mg/kg处理组中免于体重损失和病毒血症的保护作用与来自宿主免疫应答的近乎完全的保护作用相关,这是通过对仓鼠肺进行RNA Seq分析,随后进行无监督的分层聚类确定的;经MK-4482处理(500mg/kg)的样品与未感染的样品聚类在一起。DESeq2分析确定,未感染的经载剂处理的肺诱导与报道在COVID-19中上调的途径相关的66种基因(包括干扰素信号传导和干扰素刺激基因)的表达(Tindle,C.et al.Adult Stem Cell-derivedComplete Lung Organoid Models Emulate LungDisease in COVID-19.bioRxiv,doi:10.1101/2020.10.17.344002(2020);Sahoo,D.et al.AI-guided discovery of theinvariant host response to viral pandemics.bioRxiv,doi:10.1101/2020.09.21.305698(2020))。最后,组织学检查确定了来自经MK-4482处理的仓鼠的肺受到保护,并且与未感染动物的组织更相似。与之形成鲜明对比的是,对经载剂处理的对照组中的肺组织的检查显示出肺泡腔的消失和大量免疫细胞浸润。
本公开内容中引用的已编号的参考文献
通过引用并入
本说明书中提及的所有出版物、专利和专利申请均通过引用并入本文,其程度就如同每个单独的出版物、专利或专利申请被具体且单独地指示通过引用并入。
Claims (11)
3.根据权利要求1或2所述的方法,其中所述病原体是冠状病毒。
4.根据权利要求1至3中任一项所述的方法,其中所述病原体是严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。
5.根据权利要求1至4中任一项所述的方法,其还包括施用抗感染剂。
6.根据权利要求5所述的方法,其中所述抗感染剂包括抗病毒剂。
7.根据权利要求6所述的方法,其中所述抗病毒剂选自抑制进入的药物、抑制脱壳的药物、抑制逆转录酶的药物、反义药物、核酶药物、蛋白酶抑制剂、抑制装配的药物和抑制释放的药物。
8.根据权利要求5或6所述的方法,其中所述抗病毒剂选自瑞德西韦、羟氯喹、咯萘啶、阿奇霉素和法匹拉韦。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062704340P | 2020-05-05 | 2020-05-05 | |
US62/704,340 | 2020-05-05 | ||
US202062705288P | 2020-06-19 | 2020-06-19 | |
US62/705,288 | 2020-06-19 | ||
US202063107893P | 2020-10-30 | 2020-10-30 | |
US63/107,893 | 2020-10-30 | ||
PCT/US2021/027535 WO2021225767A1 (en) | 2020-05-05 | 2021-04-15 | Methods and compositions for the treatment of sars-cov-2 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116322665A true CN116322665A (zh) | 2023-06-23 |
Family
ID=75870727
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180047286.7A Pending CN116322665A (zh) | 2020-05-05 | 2021-04-15 | 用于治疗SARS-CoV-2的方法和组合物 |
Country Status (10)
Country | Link |
---|---|
US (1) | US20230346820A1 (zh) |
EP (1) | EP4146192A1 (zh) |
JP (1) | JP2023524290A (zh) |
KR (1) | KR20230008773A (zh) |
CN (1) | CN116322665A (zh) |
AU (1) | AU2021268164A1 (zh) |
CA (1) | CA3182306A1 (zh) |
IL (1) | IL297911A (zh) |
MX (1) | MX2022013749A (zh) |
WO (1) | WO2021225767A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115776886A (zh) * | 2020-05-06 | 2023-03-10 | 东佩制药股份公司 | 用于治疗covid-19的化合物 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220339180A1 (en) * | 2021-04-27 | 2022-10-27 | National Institute Of Immunology | Methods And Compositions For Treating Viral Diseases Using Combination Of Drugs |
EP4148042A1 (en) * | 2021-09-10 | 2023-03-15 | Centre National de la Recherche Scientifique | Phenoxy-acetyl-thioureido-benzenesulfonamide derivatives, and their uses |
WO2023085392A1 (ja) * | 2021-11-12 | 2023-05-19 | 国立大学法人鹿児島大学 | 抗SARS-CoV-2薬 |
CN114588158B (zh) * | 2022-03-14 | 2023-09-05 | 武汉工程大学 | 吲哚哌啶嘧啶类衍生物在制备新型冠状病毒抑制剂中的应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2950135A1 (de) * | 1979-12-13 | 1981-06-19 | Merck Patent Gmbh, 6100 Darmstadt | Basischer aether, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung |
CN101336239A (zh) * | 2005-12-02 | 2008-12-31 | 艾博特股份有限两合公司 | 经取代的羟吲哚衍生物,含有该衍生物的药物及其用途 |
-
2021
- 2021-04-15 MX MX2022013749A patent/MX2022013749A/es unknown
- 2021-04-15 CA CA3182306A patent/CA3182306A1/en active Pending
- 2021-04-15 EP EP21724426.8A patent/EP4146192A1/en active Pending
- 2021-04-15 JP JP2022567078A patent/JP2023524290A/ja active Pending
- 2021-04-15 US US17/923,171 patent/US20230346820A1/en active Pending
- 2021-04-15 WO PCT/US2021/027535 patent/WO2021225767A1/en unknown
- 2021-04-15 AU AU2021268164A patent/AU2021268164A1/en active Pending
- 2021-04-15 CN CN202180047286.7A patent/CN116322665A/zh active Pending
- 2021-04-15 KR KR1020227042375A patent/KR20230008773A/ko active Search and Examination
- 2021-04-15 IL IL297911A patent/IL297911A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115776886A (zh) * | 2020-05-06 | 2023-03-10 | 东佩制药股份公司 | 用于治疗covid-19的化合物 |
Also Published As
Publication number | Publication date |
---|---|
KR20230008773A (ko) | 2023-01-16 |
CA3182306A1 (en) | 2021-11-11 |
AU2021268164A1 (en) | 2022-12-01 |
JP2023524290A (ja) | 2023-06-09 |
EP4146192A1 (en) | 2023-03-15 |
MX2022013749A (es) | 2022-11-16 |
US20230346820A1 (en) | 2023-11-02 |
IL297911A (en) | 2023-01-01 |
WO2021225767A1 (en) | 2021-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN116322665A (zh) | 用于治疗SARS-CoV-2的方法和组合物 | |
Kearney | Chloroquine as a potential treatment and prevention measure for the 2019 novel coronavirus: a review | |
De et al. | Brief review on repurposed drugs and vaccines for possible treatment of COVID-19 | |
US11376232B2 (en) | Vidofludimus for use in the treatment or prevention of viral diseases | |
JP7393797B2 (ja) | 高サイトカイン血症および重篤なインフルエンザの処置または予防のための方法および化合物 | |
CN116635022A (zh) | 用于治疗或预防冠状病毒感染和/或covid-19细胞因子风暴的mek抑制剂 | |
AU2021235304A1 (en) | Treatment of coronavirus infection | |
RU2353357C2 (ru) | Композиции для супрессии экспрессии ccr5 и способы их применения | |
EP4351610A1 (en) | Method and composition for preventing and treating covid-19 and long covid | |
Rommasi et al. | Antiviral drugs proposed for COVID-19: action mechanism and pharmacological data. | |
WO2021211738A1 (en) | Methods and compositions for antiviral treatment | |
WO2021164689A1 (zh) | 奈非那韦在制备防治新冠肺炎药物中的应用 | |
US20230158103A1 (en) | Pld for use in combination in the treatment of coronavirus | |
Burrell et al. | Antiviral chemotherapy | |
EP3795155A1 (en) | Pharmaceutical composition, comprising rhodanine derivative, for prevention or treatment of aids | |
US20230172907A1 (en) | Sars-cov-2 inhibitors | |
US20230218596A1 (en) | Methods involving neutrophil elastase inhibitor alvelestat for treating coronavirus infection | |
Ghauri et al. | Debate on the Effectiveness of Hydroxychloroquine for Treatment of Coronavirus Disease 2019 (COVID-19) | |
Tolulope | Discovery of OJT009 as a Novel Inhibitor of Severe Acute Respiratory Syndrome Coronavirus 2 Infection for Potential Treatment of COVID-19 | |
WO2024042050A1 (en) | Use of mek1/2 inhibitors to synergistically potentiate the antiviral effect of direct-acting anti-coronavirus drugs | |
EP4271477A1 (en) | <sup2/>? <sub2/>?4?dual inhibition of sars-cov-2 virus of leukotriene ltdreceptor antagonist montelukast | |
CN117860820A (zh) | 药物组合物以及包含其的抗冠状病毒药物 | |
WO2023115220A1 (en) | Drug combinations for inhibiting coronavirus replication | |
WO2022195296A1 (en) | Anti viral therapy | |
IT202100011996A1 (it) | Ciclobenzaprina per l’uso nel trattamento di coronavirus |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |