CN116270583B - Application of 7, 8-split ring lignans in preparation of medicines for preventing and treating novel coronavirus and acute pneumonia - Google Patents
Application of 7, 8-split ring lignans in preparation of medicines for preventing and treating novel coronavirus and acute pneumonia Download PDFInfo
- Publication number
- CN116270583B CN116270583B CN202310107336.7A CN202310107336A CN116270583B CN 116270583 B CN116270583 B CN 116270583B CN 202310107336 A CN202310107336 A CN 202310107336A CN 116270583 B CN116270583 B CN 116270583B
- Authority
- CN
- China
- Prior art keywords
- compound
- pro
- protease
- preventing
- lignans
- 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.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 206010035664 Pneumonia Diseases 0.000 title claims abstract description 18
- 229930013686 lignan Natural products 0.000 title claims description 11
- 235000009408 lignans Nutrition 0.000 title claims description 11
- 150000005692 lignans Chemical class 0.000 title claims description 9
- 241000711573 Coronaviridae Species 0.000 title abstract description 19
- 229940079593 drug Drugs 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 229940125904 compound 1 Drugs 0.000 claims abstract description 29
- 229940125782 compound 2 Drugs 0.000 claims abstract description 29
- 108091005804 Peptidases Proteins 0.000 claims abstract description 25
- 239000004365 Protease Substances 0.000 claims abstract description 25
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 22
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 210000004072 lung Anatomy 0.000 claims abstract description 12
- 210000002540 macrophage Anatomy 0.000 claims abstract description 11
- XZMJVNBHYBOCGF-PMACEKPBSA-N -secoisolariciresinol Natural products COc1cc(C[C@@H](CO)[C@H](CO)Cc2ccc(C)c(OC)c2)ccc1C XZMJVNBHYBOCGF-PMACEKPBSA-N 0.000 claims abstract description 9
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 8
- 230000028327 secretion Effects 0.000 claims abstract description 3
- 241001678559 COVID-19 virus Species 0.000 claims description 14
- 238000000338 in vitro Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000002255 enzymatic effect Effects 0.000 claims description 3
- 230000028709 inflammatory response Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 28
- 241000700605 Viruses Species 0.000 abstract description 5
- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 230000004054 inflammatory process Effects 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 28
- 238000001514 detection method Methods 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 239000002158 endotoxin Substances 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000007619 statistical method Methods 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 108090001007 Interleukin-8 Proteins 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- -1 lignan compound Chemical class 0.000 description 3
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 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
- 238000011725 BALB/c mouse Methods 0.000 description 2
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 2
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 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
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 2
- 229920002472 Starch Polymers 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
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000000424 bronchial epithelial cell Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 208000017574 dry cough Diseases 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 210000000416 exudates and transudate Anatomy 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- 241000209763 Avena sativa Species 0.000 description 1
- 235000007558 Avena sp Nutrition 0.000 description 1
- 241000008904 Betacoronavirus Species 0.000 description 1
- 235000011299 Brassica oleracea var botrytis Nutrition 0.000 description 1
- 235000017647 Brassica oleracea var italica Nutrition 0.000 description 1
- 240000003259 Brassica oleracea var. botrytis Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 241000711467 Human coronavirus 229E Species 0.000 description 1
- 241001109669 Human coronavirus HKU1 Species 0.000 description 1
- 241000482741 Human coronavirus NL63 Species 0.000 description 1
- 241001428935 Human coronavirus OC43 Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010035737 Pneumonia viral Diseases 0.000 description 1
- 206010035742 Pneumonitis Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 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 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 108091005532 SARS-CoV-2 main proteases Proteins 0.000 description 1
- 241000209056 Secale Species 0.000 description 1
- 235000007238 Secale cereale Nutrition 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 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 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 208000033065 inborn errors of immunity Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 208000027905 limb weakness Diseases 0.000 description 1
- 231100000861 limb weakness Toxicity 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000008807 pathological lesion Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940125675 paxlovid Drugs 0.000 description 1
- 150000002995 phenylpropanoid derivatives Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 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 1
- 238000005070 sampling Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000009421 viral pneumonia Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of 7, 8-secoisolariciresinol diglucoside containing 3CL pro Use of protease viruses and inflammatory drugs. Compound 1 and/or compound 2 are capable of inhibiting 3CL pro The protease activity achieves the effect of inhibiting viruses, and the inflammatory reaction is inhibited by inhibiting the NO secretion of macrophages and the expression of relevant inflammatory factors in the lung. Experimental research results show that the compound 1 and/or the compound 2 can be used for preventing and treating the novel coronavirus diseases and pneumonia.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of 7, 8-split ring lignans in preparation of medicines for preventing and treating novel coronaviruses and acute pneumonia.
Background
Lignans exist in plants, belong to a plant estrogen, and have the effects of scavenging free radicals in bodies and resisting oxidation. The semen Lini and semen Sesami contains high lignans, and cereal foods (such as rye, wheat, oat, barley, etc.), soybean, cruciferous plants (such as broccoli) and fruits (such as strawberry) also contain lignans. The lignan compound is generally polymerized by two molecules of phenylpropanoid derivatives (C6-C3 monomers), is a natural compound, and is mostly free, and only a few glycosides can be combined with sugar. Lignans bind to estrogen receptors and interfere with the carcinotropic effects. Therefore, it is possible to have preventive and therapeutic effects on breast cancer, prostate cancer, colon cancer, etc. Patent CN201410608106 relates to the isolation of novel 7, 8-secoisolariciresinol diglucoside from Saurururaceae medicinal plants, and its preparation method and use, and the results of the study show that the compound has vasodilation effect and can be used for preventing and treating cardiovascular diseases.
Coronaviruses are a type of coronavirus, which is known to have the largest genome among RNA viruses. Since the first isolation of human pathogenic coronaviruses in 1965, 7 coronaviruses have been found to cause disease in humans, among which: coronaviruses HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43 can cause mild respiratory diseases in humans, which clinically account for 10% -30% of respiratory infectious diseases; coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 (novel coronaviruses) are highly pathogenic coronaviruses with mortality rates as high as 10% -30%.
SARS-CoV-2 encodes an essential 3CL pro Proteases, the major proteases that cleave and process RNA in the viral self-code. 3CL has been found in 12 viruses at present pro Protease, and 3CL pro The protease is highly conserved among different coronaviruses, and homologous proteins are not present in human bodies, which means that the protease can be used as a drug target to perform inhibitor design, so that good selectivity and safety expectation can be achieved. 3CL pro High conservation in beta coronavirus, and 3CL screened out pro Inhibitors have broad spectrum anti-coronavirus activity. [1]
The anti-new coronavirus drug PF-07321332/ritonavir tablet (Paxlovid) consists of two antiviral drugs, wherein PF-07321332 is Nemactrevir (Nirmatrevir), which is 3CL of new coronavirus pro Protease inhibitors.
At present, the prevention and treatment of novel coronaviruses are still a weak link, although various types are aimed at 3CL pro The results of protease studies were subsequently published, different 3CL pro Protease inhibitors continue to be presented to humans, but have been very limited in their clinical access. Therefore, the development of new drugs with rapid, safe and effective effects is still urgent for preventing and treating novel coronaviruses.
The infection of the new coronavirus can cause the occurrence of pneumonia, and the symptoms mainly comprise fever, dry cough, limb weakness and the like. Because of obvious hypoimmunity of patients, the symptoms of repeated fever are generated, and thorough treatment cannot be achieved by oral administration of medicines; the lung health condition can be influenced during the onset period, so that the patient can generate frequent dry cough, the symptoms such as stimulating cough and expectoration and the like, part of serious cases can be caused to have different degrees of dyspnea and hypoxia after one week of onset, and serious patients can rapidly progress to acute respiratory distress syndrome and sepsis shock. Some patients infected with the novel coronavirus may develop conjunctivitis symptoms.
The application of 7, 8-secoisolariciresinol diglucoside in preventing and treating the novel coronavirus is not disclosed in the prior art, and the effect of the 7, 8-secoisolariciresinol diglucoside on the infection of the novel coronavirus is not known.
[1]V Mody,Ho J,Wills S,et al.Identification of 3-chymotrypsin like protease(3CLPro)inhibitors as potential anti-SARS-CoV-2agents[J].Communications Biology,2021,4(1):93.
Disclosure of Invention
The present invention aims at solving the problem of medicine development for preventing and curing SARS-CoV-2 virus caused diseases in the prior art, and provides a new medicine for preventing and curing SARS-CoV-2 virus infection and relieving pneumonia symptom.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides a method for preparing and controlling 3 CL-containing 7, 8-split ring lignans pro Use of protease viruses in medicine.
Preferably, the 7, 8-secoisolariciresinol diglucoside is selected from one or two of compound 1 (rel- (1S, 2R) -1- (3, 4-dimethoxyphenyl) -2-methyl-3-oxo-3, 4-dimethoxy benzoate) and compound 2 (rel- (1S, 2S) -1- (3, 4-dimethoxyphenyl) -2-methyl-3-oxo-3, 4-dimethoxy benzoate), and has the following structural formula:
in some embodiments, compound 1 and compound 2 are used alone.
In other embodiments, compound 1 and compound 2 are used in combination.
The compound 1 and/or the compound 2 inhibit 3CL pro Protease in vitro enzyme activity to achieve diseasePreventing and treating effect of toxin.
Preferably, the virus is SARS-CoV-2 virus.
Further, the SARS-CoV-2 virus can be an original strain or a variant strain, including but not limited to: one or more of Delta strain, beta strain, omacron strain, delta strain, epsilon strain, zeta strain, eta strain, theta strain, iota strain, kappa strain, lambda strain.
In particular, the dosage forms of the medicament include, but are not limited to, tablets, liquids, capsules, powders, suppositories or granules.
Specifically, the medicine also comprises other pharmaceutically acceptable auxiliary materials.
Further specifically, the pharmaceutically acceptable excipients include, but are not limited to: starch, hu Jing, sucrose, lactose, microcrystalline cellulose.
In yet another aspect, the invention provides the use of 7, 8-secoisolariciresinol diglucoside in the manufacture of a medicament for the prevention and treatment of inflammation.
Preferably, the 7, 8-split ring lignans are selected from compound 1 and/or compound 2.
Further, the compound 1 and/or compound 2 inhibits macrophage NO secretion and expression of related inflammatory factors in the lung, thereby inhibiting inflammatory response.
Preferably, the inflammation is pneumonia.
Further preferably, the pneumonia is acute pneumonia.
Further preferably, the pneumonia is a pneumonia caused by SARS-CoV-2 virus.
In particular, the dosage forms of the medicament include, but are not limited to, tablets, liquids, capsules, powders, suppositories or granules.
Specifically, the medicine also comprises other pharmaceutically acceptable auxiliary materials.
Further specifically, the pharmaceutically acceptable excipients include, but are not limited to: starch, hu Jing, sucrose, lactose, microcrystalline cellulose.
The invention has the technical effects that:
the invention inhibits 3CL by compound 1 and compound 2 pro Protease in vitro enzyme Activity experiments find that active Compound 1 and Compound 2 vs. 3CL pro The protease has better inhibition activity, and the inhibition rate at 8 mu M is 55.13 +/-2.45% and 52.78 +/-1.39% respectively. Through the measurement of inhibiting the RAW264.7 macrophage from generating NO by the compound 1 and the compound 2, the compound 1 and the compound 2 can be found to obviously inhibit the generation of NO at the concentration of 50 mu M. In subsequent mouse experiments, it is proved that the compound 1 and the compound 2 can obviously reduce the expression of IL-6, TNF-alpha, IL-8 and IL-1 beta in alveolar lavage fluid, thereby reducing lung inflammation. The lung histopathological pictures of mice also show that compound 1 and compound 2 (20 mg/kg) can significantly reduce inflammatory exudates between bronchoalveoli, significantly reduce inflammatory cell infiltration, and maintain the integrity of bronchial epithelial cells. The test results show that the compound 1 and the compound 2 not only can inhibit SARS-CoV-2, but also can relieve symptoms of pneumonia diseases, thereby laying a foundation for the prevention and treatment of viral pneumonia by the compound 1 and the compound 2.
Drawings
FIG. 1 shows that the compounds GC376, 1,2 vs. 3CL at a concentration of 8. Mu.M pro Inhibition of protease activity.
FIG. 2 is Compound 1 and 2 vs. 3CL pro IC for inhibiting protease 50 Fitting a curve.
FIG. 3 shows the effect of compounds 1 and 2 on macrophage proliferation activity at a concentration of 50. Mu.M.
FIG. 4 is a graph showing the results of compounds 1 and 2 inhibiting LPS-induced RAW264.7 macrophage production of NO.
FIG. 5 shows the results of compounds 1 and 2 inhibiting IL-6, TNF- α, IL-8, IL-1β expression in alveolar lavage fluid from LPS-induced acute pneumonitis mice.
Fig. 6 is a diagram of lung tissue pathology.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the present invention, but are merely illustrative of the present invention. The experimental methods used in the following examples are not specifically described, but the experimental methods in which specific conditions are not specified in the examples are generally carried out under conventional conditions, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
Example 1: compound 1,2 vs SARS-CoV-2 3CL pro Protease in vitro enzyme activity inhibition assay
1.1 Experimental drugs and reagents
Monomer compound: compound 1 (rel- (1 s,2 r) -1- (3, 4-dimethoxyphenyl) -2-methyl-3-oxobutyl-3, 4-dimethoxybenzoate), compound 2 (rel- (1 s,2 s) -1- (3, 4-dimethoxyphenyl) -2-methyl-3-oxobutyl-3, 4-dimethoxybenzoate) (all from conventional isolation methods); GC376 (shanghai source leaf biotechnology limited); 3CL pro Proteases (su state offshore protein technologies, inc.); the polypeptide substrate Dabcyl-KTSAVLQSGFRKME-Edans (Jier Biochemical Co., shanghai).
1.2 Main experiment instrument
FlexStation 3 multifunctional enzyme labelling instrument.
1.3 Experimental methods
Evaluation of 2 Compounds against SARS-CoV-2 3CL Using fluorescence resonance energy transfer method pro Inhibition of protease activity.
1.4 Experimental procedure
(1) The reaction system was 102.5. Mu.L, to which 3CL was added pro Protein (12.5. Mu.g/mL), polypeptide substrate Dabcyl-KTSAVLQSGFRKME-Edans (3 mM), test compound (8. Mu.M), GC376 (8. Mu.M) as positive control, buffer TRIS-HCl (20 mM, pH 7.0), 3 replicates per group, incubation at 25℃for 10min.
(2) Fluorescence intensity was measured using a fluorescence microplate reader at 340nm excitation wavelength and 490nm emission wavelength.
The enzyme activity was calculated according to the following formula:
a is the inhibition rate of small molecules to enzymes, df is a dilution factor, deltaOD is the absorbance change rate, C is the final concentration of protein, vs is the total volume of solution, test is the group added with the tested compound, and control is the blank group.
1.5 detection results
As shown in FIG. 1, compounds 1 and 2 vs. 3CL were identified by a preliminary in vitro enzyme activity screen pro The protease has better inhibition activity, and the inhibition rate at 8 mu M is 55.13 +/-2.45% and 52.78 +/-1.39% respectively.
1.6 Compounds 1 and 2 IC inhibiting SARS-CoV-2 3CLpro enzymatic Activity 50 Detection of
1.6.1 Experimental procedure
(1) The reaction system was 102.5. Mu.L, to which 3CL was added pro Protein (12.5. Mu.g/mL), polypeptide substrate Dabcyl-KTSAVLQSGFRKME-Edans (3 mM), test compound were diluted equally to 1. Mu.M, 2. Mu.M, 4. Mu.M, 8. Mu.M, 16. Mu.M, buffer TRIS-HCl (20 mM, pH 7.0) and incubated at 25℃for 10min.
(2) Fluorescence intensity was measured using a fluorescence microplate reader at 340nm excitation wavelength and 490nm emission wavelength. The enzyme activity was calculated according to the following formula:
a is the inhibition rate of small molecules to enzymes, df is a dilution factor, deltaOD is the absorbance change rate, C is the final concentration of protein, vs is the total volume of solution, test is the group added with the tested compound, and control is the blank group. Final mapping and fitting IC 50 。
1.6.2 detection results
As shown in FIG. 2, SARS-CoV-2-3 CL was performed on different concentrations of Compounds 1 and 2 pro Protease in-vitro enzyme activity inhibition activity determination to obtain compounds 1 and 2 for inhibiting 3CL pro IC of protease 50 The values were 4.88.+ -. 0.6. Mu.M, 4.75.+ -. 0.34. Mu.M, respectively, indicating that Compounds 1 and 2 are SARS-CoV-2 3CL pro The protease has better inhibition effect.
Example 2: inhibiting LPS-induced macrophage from secreting NO function
1. Material
Compound (1, 2); mouse RAW264.7 macrophages (purchased from beijing cove medical college cell bank); endotoxin (LPS, 1. Mu.g/mL; sigma Aldrich (Shanghai) trade Co., ltd.); dexamethasone (Dex, 50. Mu.M; shanghai derived leaf Biotechnology Co., ltd.); CCK8 detection kit (bi yun tian); NO detection kit (Biyun Tian).
2. Main instrument
Fluorescent enzyme mark instrument (Tecan Spark)
3. Method of
3.1 determination of macrophage proliferation Rate
(1) Taking RAW264.7 cells in exponential growth phase at 2×10 6 Cell/well density was seeded in 96-well plates, incubated in a 37℃cell incubator for 24h, the supernatant was discarded, 200. Mu.L of Compound 1 or 2 (50 uM) was added for 24h, 3 wells per sample, and 3 experiments were repeated. Cell viability was calculated by measuring absorbance at 540nm using a fluorescence microplate reader according to the CCK8 kit instructions.
(2) Statistical method
Data are expressed as mean ± standard deviation. Statistical analysis was performed using GraphPad Prism 8.0 software and data was analyzed using one-way analysis of variance (ANOVA). Comparison to Control group: # P<0.05， ## P<0.01; comparison with the Model group: * P<0.05， ** P<0.01。
(3) Results
As shown in fig. 3, compounds 1 and 2 did not affect macrophage proliferation activity at 50 μm concentration.
3.2 Compounds 1 and 2 inhibit LPS-induced RAW264.7 macrophage NO production assay
(1) Taking RAW264.7 cells in exponential growth phase at 2×10 6 The density of cells/well is inoculated in a 96-well plate, the 96-well plate is placed in a cell culture box at 37 ℃ for culturing for 5 hours, after the cells are attached, 200 mu L of compound 1 or 2 or Dex is added into the culture medium for incubation for 1 hour, then LPS (final concentration of 1 mu g/mL) is added into the culture medium, the culture is continued for 24 hours, 3 multiple wells are formed in each sample, and 3 experiments are repeated. According to the instruction of NO detection kit (Biyun Tian), the absorbance at 540nm of each well is measured by using a fluorescence microplate reader according to the followingThe concentration of NO in the supernatant per well was calculated by standard curve.
(2) Statistical method
Data are expressed as mean ± standard deviation. Statistical analysis was performed using GraphPad Prism 8.0 software and data was analyzed using one-way analysis of variance (ANOVA). Comparison to Control group: # P<0.05， ## P<0.01; comparison with the Model group: * P<0.05， ** P<0.01。
(3) Results
As shown in fig. 4, compounds 1 and 2 significantly inhibited NO production at 50 μm concentrations (P < 0.05).
Example 3: effects of Compounds 1 and 2 on LPS-induced acute pneumonia
1. Material
Compounds 1, 2; male BALB/c mice (18-22 g, SPF grade) were purchased from Peking Vitrelliw laboratory animal technologies Co., ltd., certification No. SCXK (Beijing) 2021-0006; LPS; dex; IL-6 detection kit (Biolegend); IL-8 detection kit (Shenzhen Xinbo biotechnology Co., ltd.); IL-1 detection kit (Thermo Fisher Scientific); TNF-assay kit (Biolegend).
2. Method of
2.1 animals and groups
Male BALB/c mice were randomly divided into 7 groups: normal control, model control, dex (10 mg/kg), compound 1 (10 mg/kg) low dose, compound 1 (20 mg/kg) high dose, compound 2 (10 mg/kg) low dose, compound 2 (20 mg/kg) high dose, 12 per group.
2.2 model creation and administration
The mice in each group were given 3mg/kg LPS by nasal drops except for normal control group experimental animals. Meanwhile, 10mg/kg Dex, 10mg/kg Compound 1, 20mg/kg Compound 1, 10mg/kg Compound 2, 20mg/kg Compound 2 were respectively administered by gavage, and the blank control group and the model control group were given the same dose of 0.5% CMC-Na by gavage.
2.3 sampling and detection
After 8h of administration, the eyeballs are taken for blood collection and sacrifice, lung tissues are rapidly taken, part of the lung tissues are instilled with 0.6mL of precooled PBS solution through an air pipe for lavage three times, the lavage liquid is centrifuged for 10min at 400 Xg (4 ℃), and the supernatant is collected for detecting inflammatory factors. The other part of the lung was fixed in 4% paraformaldehyde for 72h and embedded with an automatic paraffin embedding machine to prepare 4-6 μm sections. The slices are dewaxed by xylene I and xylene II for 5min respectively, then treated by absolute ethanol, 95% ethanol, 80% ethanol and 70% ethanol for 5min in sequence, and finally washed by distilled water to finish the dewaxing-to-water process. Hematoxylin dye solution is used for dyeing for 5min, and tap water is used for washing for 10min. Differentiation liquid is differentiated for 30s, soaked in distilled water for 15min, placed in eosin dye solution for 10s, washed with distilled water for 2min, and each of xylene I and xylene II is devitrified for 2min, and then sealed with neutral gum. The pathological changes of the lung tissue are observed under a microscope and photographed.
2.4 statistical methods
Data are expressed as mean ± standard deviation. Statistical analysis was performed using GraphPad Prism 8.0 software and data was analyzed using one-way analysis of variance (ANOVA). Comparison to Control group: # P<0.05， ## P<0.01; comparison with the Model group: * P<0.05， ** P<0.01。
2.5 results
The invention examines the influence of the compounds 1 and 2 on the lung inflammation of the mice with acute pneumonia by detecting the expression of IL-6, TNF-, IL-8 and IL-1 in the alveolar lavage fluid of each group of mice by using the corresponding kit. As a result, see FIG. 5, compounds 1 and 2 (20 mg/kg) significantly reduced the expression of IL-6, TNF-, IL-8, IL-1 (P < 0.05) in alveolar lavage fluid.
The results of observation of the lung tissue structure of the mice by HE staining are shown in FIG. 6. Consistent with the detection results of inflammatory factors, compounds 1 and 2 (20 mg/kg) can significantly reduce inflammatory exudates between bronchoalveoli, significantly reduce inflammatory cell infiltration, and maintain the integrity of bronchial epithelial cells. It is demonstrated that compounds 1 and 2 significantly improve the pathological lesions caused by inflammatory reactions in the lung. And compared with the hormone medicine Dex, the compounds 1 and 2 are derived from natural products, so that side effects caused by the hormone medicine can be avoided.
Claims (6)
1.7,8-secoisolariciresinol diglucoside for preparing and controlling 3CL pro Use of a protease SARS-CoV-2 virus in the manufacture of a medicament, wherein the 7, 8-split ring lignans are selected from compound 1 and/or compound 2:
。
2. the use according to claim 1, wherein compound 1 and/or compound 2 inhibits 3CL pro Protease in vitro enzymatic activity.
3. The use according to claim 1, wherein the SARS-CoV-2 virus is an original strain or a variant strain.
The application of 4.7,8-secoisolariciresinol diglucoside in preparing a medicament for preventing and treating pneumonia caused by SARS-CoV-2 virus, characterized in that the 7, 8-secoisolariciresinol diglucoside is selected from compound 1 and/or compound 2:
。
5. the use according to claim 4, wherein compound 1 and/or compound 2 inhibits 3CL pro Protease in vitro enzymatic activity.
6. The use according to claim 4, wherein compound 1 and/or compound 2 inhibits macrophage NO secretion and expression of an associated inflammatory factor in the lung, thereby inhibiting an inflammatory response.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310107336.7A CN116270583B (en) | 2023-01-19 | 2023-01-19 | Application of 7, 8-split ring lignans in preparation of medicines for preventing and treating novel coronavirus and acute pneumonia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310107336.7A CN116270583B (en) | 2023-01-19 | 2023-01-19 | Application of 7, 8-split ring lignans in preparation of medicines for preventing and treating novel coronavirus and acute pneumonia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116270583A CN116270583A (en) | 2023-06-23 |
| CN116270583B true CN116270583B (en) | 2024-03-15 |
Family
ID=86829655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310107336.7A Active CN116270583B (en) | 2023-01-19 | 2023-01-19 | Application of 7, 8-split ring lignans in preparation of medicines for preventing and treating novel coronavirus and acute pneumonia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116270583B (en) |
-
2023
- 2023-01-19 CN CN202310107336.7A patent/CN116270583B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Anti-inflammatory butanolides and lignanoids from the root of Machilus zuihoensis var. mushaensis;Shuen-Shin Yang等;Bioorganic Chemistry;第129卷;第8页右栏3.2项，图5，表4 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116270583A (en) | 2023-06-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111544442A (en) | New use of rutin as coronavirus broad-spectrum inhibitor | |
| Xiao et al. | Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis | |
| CN113244211A (en) | Application of baicalein and baicalin as main components of radix Scutellariae and their composition in resisting coronavirus | |
| Valipour | Different aspects of emetine’s capabilities as a highly potent SARS-CoV-2 inhibitor against COVID-19 | |
| CN112457281B (en) | Small molecule inhibitor for blocking combination of COVID-19 spinous protein and human angiotensin converting enzyme 2 and application thereof | |
| CN111067908A (en) | Substance with function of improving immunity and preparation and application thereof | |
| CN112750496A (en) | Screening method of small molecule inhibitor of COVID-19 spinous process protein, active molecule screened by same and application | |
| CN113813269B (en) | Application of Perifosine in preparation of anti-Hantaan virus medicine | |
| CN113197981B (en) | Use of dredging particles | |
| CN116270583B (en) | Application of 7, 8-split ring lignans in preparation of medicines for preventing and treating novel coronavirus and acute pneumonia | |
| CN115260148B (en) | Compound extracted and separated from long pepper and application of compound in preparation of anti-inflammatory drugs | |
| CN104983729B (en) | Catechin compounds and gallic acid combination are preparing the new application in treating antihyperuricemic disease drug | |
| CN103908447B (en) | The application of shrubby sophora extract and Vexibinol in anti-EV71 virus infection | |
| CN109223801B (en) | Novel gastric cancer tumor stem cell killing agent and application thereof | |
| TW202207909A (en) | Use of disulfiram for treating infection of sars-cov-2 | |
| CN108392530B (en) | Application of scutellaria decoction and equivalent component group thereof in enhancing sensitivity of colon cancer to irinotecan chemotherapy | |
| CN114917222B (en) | Application of Ganetespib in preparation of medicine for resisting adenovirus infection | |
| CN109602737B (en) | Application of hydroxysafflor yellow B in preparation of medicine for treating gastric cancer and medicine | |
| CN115006395B (en) | Application of XL888 in preparation of medicine for resisting adenovirus infection | |
| CN115400122B (en) | Application of TAK-632 in preparing medicine for resisting adenovirus infection | |
| CN114452291B (en) | Application of clavulanoside A in preparation of medicines for inhibiting hepatic fibrosis | |
| CN115400121B (en) | Application of SNX-2112 in preparation of medicines for resisting adenovirus infection | |
| CN108853082B (en) | Application of hematoxylin in preparation of medicine for treating immune glomerulonephritis | |
| CN116983289A (en) | Application of shikonin or shikonin derivative in preparation of medicines for treating coronavirus infection | |
| CN115400120A (en) | Application of Alvespimycin in preparation of medicine for resisting adenovirus infection |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |