CN1820019A - 抗微生物多肽 - Google Patents
抗微生物多肽 Download PDFInfo
- Publication number
- CN1820019A CN1820019A CNA2004800196613A CN200480019661A CN1820019A CN 1820019 A CN1820019 A CN 1820019A CN A2004800196613 A CNA2004800196613 A CN A2004800196613A CN 200480019661 A CN200480019661 A CN 200480019661A CN 1820019 A CN1820019 A CN 1820019A
- Authority
- CN
- China
- Prior art keywords
- polypeptide
- antimicrobial
- seq
- definition
- lys
- 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.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 256
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 240
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 239
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 129
- 125000003729 nucleotide group Chemical group 0.000 claims abstract description 71
- 239000002773 nucleotide Substances 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 67
- 108091033319 polynucleotide Proteins 0.000 claims abstract description 28
- 239000002157 polynucleotide Substances 0.000 claims abstract description 28
- 102000040430 polynucleotide Human genes 0.000 claims abstract description 28
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 25
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 25
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims description 117
- 235000001014 amino acid Nutrition 0.000 claims description 71
- 150000001413 amino acids Chemical class 0.000 claims description 70
- 108090000623 proteins and genes Proteins 0.000 claims description 70
- 241001465754 Metazoa Species 0.000 claims description 38
- 239000000654 additive Substances 0.000 claims description 31
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 31
- 244000005700 microbiome Species 0.000 claims description 30
- -1 zytase Proteins 0.000 claims description 30
- 229910052740 iodine Inorganic materials 0.000 claims description 27
- 102000004169 proteins and genes Human genes 0.000 claims description 26
- 235000018102 proteins Nutrition 0.000 claims description 25
- 230000012010 growth Effects 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 230000003115 biocidal effect Effects 0.000 claims description 21
- 239000003599 detergent Substances 0.000 claims description 21
- 239000003139 biocide Substances 0.000 claims description 19
- 230000000996 additive effect Effects 0.000 claims description 18
- 229910052720 vanadium Inorganic materials 0.000 claims description 18
- 239000013604 expression vector Substances 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000012634 fragment Substances 0.000 claims description 11
- 235000013311 vegetables Nutrition 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229940088594 vitamin Drugs 0.000 claims description 9
- 229930003231 vitamin Natural products 0.000 claims description 9
- 235000013343 vitamin Nutrition 0.000 claims description 9
- 239000011782 vitamin Substances 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 230000002147 killing effect Effects 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- 238000003259 recombinant expression Methods 0.000 claims description 7
- 230000009261 transgenic effect Effects 0.000 claims description 7
- 229910052721 tungsten Inorganic materials 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- 239000004599 antimicrobial Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 235000010755 mineral Nutrition 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 5
- 230000003449 preventive effect Effects 0.000 claims description 4
- 239000011573 trace mineral Substances 0.000 claims description 4
- 235000013619 trace mineral Nutrition 0.000 claims description 4
- 108010011619 6-Phytase Proteins 0.000 claims description 3
- 101710152845 Arabinogalactan endo-beta-1,4-galactanase Proteins 0.000 claims description 3
- 101710147028 Endo-beta-1,4-galactanase Proteins 0.000 claims description 3
- 229940085127 phytase Drugs 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 101710130006 Beta-glucanase Proteins 0.000 claims description 2
- 238000011203 antimicrobial therapy Methods 0.000 claims description 2
- 239000013598 vector Substances 0.000 abstract description 7
- 210000004027 cell Anatomy 0.000 description 120
- 229940024606 amino acid Drugs 0.000 description 64
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 47
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 46
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 46
- 241000196324 Embryophyta Species 0.000 description 46
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 46
- 241000894006 Bacteria Species 0.000 description 43
- 230000014509 gene expression Effects 0.000 description 35
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 34
- 238000002360 preparation method Methods 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 31
- 229940088598 enzyme Drugs 0.000 description 31
- 102000004190 Enzymes Human genes 0.000 description 30
- 108090000790 Enzymes Proteins 0.000 description 30
- 239000007864 aqueous solution Substances 0.000 description 24
- UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 description 22
- 229930182817 methionine Natural products 0.000 description 21
- 230000002538 fungal effect Effects 0.000 description 20
- 108020004414 DNA Proteins 0.000 description 19
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 19
- 241000233866 Fungi Species 0.000 description 18
- 230000008859 change Effects 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 108010034529 leucyl-lysine Proteins 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 15
- 102000035195 Peptidases Human genes 0.000 description 15
- 108091005804 Peptidases Proteins 0.000 description 15
- 108010076504 Protein Sorting Signals Proteins 0.000 description 15
- 241000193830 Bacillus <bacterium> Species 0.000 description 14
- 108010059892 Cellulase Proteins 0.000 description 14
- 229940106157 cellulase Drugs 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 108090001060 Lipase Proteins 0.000 description 13
- 102000004882 Lipase Human genes 0.000 description 13
- 239000004367 Lipase Substances 0.000 description 13
- 230000000968 intestinal effect Effects 0.000 description 13
- 235000019421 lipase Nutrition 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 13
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 12
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 239000004382 Amylase Substances 0.000 description 11
- 108010065511 Amylases Proteins 0.000 description 11
- 102000013142 Amylases Human genes 0.000 description 11
- 239000004475 Arginine Substances 0.000 description 11
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 11
- 235000019418 amylase Nutrition 0.000 description 11
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 11
- 229960003121 arginine Drugs 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 229960000310 isoleucine Drugs 0.000 description 11
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 11
- 239000013612 plasmid Substances 0.000 description 11
- 108091026890 Coding region Proteins 0.000 description 10
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 10
- 230000004927 fusion Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 235000012054 meals Nutrition 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 240000006439 Aspergillus oryzae Species 0.000 description 9
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 9
- 241000194108 Bacillus licheniformis Species 0.000 description 9
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 9
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 9
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 9
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229960003136 leucine Drugs 0.000 description 9
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 8
- VCSABYLVNWQYQE-SRVKXCTJSA-N Ala-Lys-Lys Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCCN)C(O)=O VCSABYLVNWQYQE-SRVKXCTJSA-N 0.000 description 8
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 description 8
- 241000228245 Aspergillus niger Species 0.000 description 8
- 239000004471 Glycine Substances 0.000 description 8
- 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 8
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 8
- 239000004473 Threonine Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000003550 marker Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000010076 replication Effects 0.000 description 8
- 229960002898 threonine Drugs 0.000 description 8
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 7
- CLICCYPMVFGUOF-IHRRRGAJSA-N Arg-Lys-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O CLICCYPMVFGUOF-IHRRRGAJSA-N 0.000 description 7
- 241000351920 Aspergillus nidulans Species 0.000 description 7
- 241000223218 Fusarium Species 0.000 description 7
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 7
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 240000007594 Oryza sativa Species 0.000 description 7
- 235000007164 Oryza sativa Nutrition 0.000 description 7
- 102000003992 Peroxidases Human genes 0.000 description 7
- 241000282898 Sus scrofa Species 0.000 description 7
- 230000001580 bacterial effect Effects 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 235000013305 food Nutrition 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 239000002502 liposome Substances 0.000 description 7
- 108040007629 peroxidase activity proteins Proteins 0.000 description 7
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 7
- 229960005190 phenylalanine Drugs 0.000 description 7
- 235000009566 rice Nutrition 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 241000228212 Aspergillus Species 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 108010082495 Dietary Plant Proteins Proteins 0.000 description 6
- 241000223221 Fusarium oxysporum Species 0.000 description 6
- TVUWMSBGMVAHSJ-KBPBESRZSA-N Gly-Leu-Phe Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 TVUWMSBGMVAHSJ-KBPBESRZSA-N 0.000 description 6
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 6
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 6
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 6
- XOQMURBBIXRRCR-SRVKXCTJSA-N Lys-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN XOQMURBBIXRRCR-SRVKXCTJSA-N 0.000 description 6
- 241000589516 Pseudomonas Species 0.000 description 6
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 229960002989 glutamic acid Drugs 0.000 description 6
- 108010066198 glycyl-leucyl-phenylalanine Proteins 0.000 description 6
- 230000008676 import Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 230000010354 integration Effects 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 108010000761 leucylarginine Proteins 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 229960001153 serine Drugs 0.000 description 6
- 108010080629 tryptophan-leucine Proteins 0.000 description 6
- 101000757144 Aspergillus niger Glucoamylase Proteins 0.000 description 5
- 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 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 5
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 5
- 108010064851 Plant Proteins Proteins 0.000 description 5
- 108090000787 Subtilisin Proteins 0.000 description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 5
- 239000006035 Tryptophane Substances 0.000 description 5
- AOILQMZPNLUXCM-AVGNSLFASA-N Val-Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN AOILQMZPNLUXCM-AVGNSLFASA-N 0.000 description 5
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000008034 disappearance Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000007943 implant Substances 0.000 description 5
- 108010017391 lysylvaline Proteins 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 230000037039 plant physiology Effects 0.000 description 5
- 235000021118 plant-derived protein Nutrition 0.000 description 5
- 230000008488 polyadenylation Effects 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 210000000582 semen Anatomy 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 238000004659 sterilization and disinfection Methods 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001810 trypsinlike Effects 0.000 description 5
- 229960004799 tryptophan Drugs 0.000 description 5
- AWZKCUCQJNTBAD-SRVKXCTJSA-N Ala-Leu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN AWZKCUCQJNTBAD-SRVKXCTJSA-N 0.000 description 4
- BTJVOUQWFXABOI-IHRRRGAJSA-N Arg-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCNC(N)=N BTJVOUQWFXABOI-IHRRRGAJSA-N 0.000 description 4
- ORJQQZIXTOYGGH-SRVKXCTJSA-N Asn-Lys-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ORJQQZIXTOYGGH-SRVKXCTJSA-N 0.000 description 4
- 244000063299 Bacillus subtilis Species 0.000 description 4
- 235000014469 Bacillus subtilis Nutrition 0.000 description 4
- 235000016068 Berberis vulgaris Nutrition 0.000 description 4
- 241000335053 Beta vulgaris Species 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- UESJMAMHDLEHGM-NHCYSSNCSA-N Gly-Ile-Leu Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O UESJMAMHDLEHGM-NHCYSSNCSA-N 0.000 description 4
- JPAACTMBBBGAAR-HOTGVXAUSA-N Gly-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)CN)CC(C)C)C(O)=O)=CNC2=C1 JPAACTMBBBGAAR-HOTGVXAUSA-N 0.000 description 4
- YHYDTTUSJXGTQK-UWVGGRQHSA-N Gly-Met-Leu Chemical compound CSCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(C)C)C(O)=O YHYDTTUSJXGTQK-UWVGGRQHSA-N 0.000 description 4
- 235000010469 Glycine max Nutrition 0.000 description 4
- 244000068988 Glycine max Species 0.000 description 4
- 241000223198 Humicola Species 0.000 description 4
- 241001480714 Humicola insolens Species 0.000 description 4
- GVNNAHIRSDRIII-AJNGGQMLSA-N Ile-Lys-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N GVNNAHIRSDRIII-AJNGGQMLSA-N 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- JLWZLIQRYCTYBD-IHRRRGAJSA-N Leu-Lys-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JLWZLIQRYCTYBD-IHRRRGAJSA-N 0.000 description 4
- SJNZALDHDUYDBU-IHRRRGAJSA-N Lys-Arg-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(O)=O SJNZALDHDUYDBU-IHRRRGAJSA-N 0.000 description 4
- PLDJDCJLRCYPJB-VOAKCMCISA-N Lys-Lys-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PLDJDCJLRCYPJB-VOAKCMCISA-N 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 108700026244 Open Reading Frames Proteins 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 4
- 244000046052 Phaseolus vulgaris Species 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- 241000235648 Pichia Species 0.000 description 4
- 108700005078 Synthetic Genes Proteins 0.000 description 4
- 241000223258 Thermomyces lanuginosus Species 0.000 description 4
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 4
- AEMPCGRFEZTWIF-IHRRRGAJSA-N Val-Leu-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O AEMPCGRFEZTWIF-IHRRRGAJSA-N 0.000 description 4
- YMTOEGGOCHVGEH-IHRRRGAJSA-N Val-Lys-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O YMTOEGGOCHVGEH-IHRRRGAJSA-N 0.000 description 4
- 108010048241 acetamidase Proteins 0.000 description 4
- SRBFZHDQGSBBOR-QMKXCQHVSA-N alpha-L-arabinopyranose Chemical compound O[C@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-QMKXCQHVSA-N 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 235000013339 cereals Nutrition 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 108010050848 glycylleucine Proteins 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- 229960002885 histidine Drugs 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 244000144977 poultry Species 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- XCIGOVDXZULBBV-DCAQKATOSA-N Ala-Val-Lys Chemical compound CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CCCCN)C(O)=O XCIGOVDXZULBBV-DCAQKATOSA-N 0.000 description 3
- 102100034044 All-trans-retinol dehydrogenase [NAD(+)] ADH1B Human genes 0.000 description 3
- 101710193111 All-trans-retinol dehydrogenase [NAD(+)] ADH4 Proteins 0.000 description 3
- 235000007319 Avena orientalis Nutrition 0.000 description 3
- 241000193422 Bacillus lentus Species 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- 101000898643 Candida albicans Vacuolar aspartic protease Proteins 0.000 description 3
- 101000898783 Candida tropicalis Candidapepsin Proteins 0.000 description 3
- 244000025254 Cannabis sativa Species 0.000 description 3
- 241000871189 Chenopodiaceae Species 0.000 description 3
- 241000606153 Chlamydia trachomatis Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 235000019750 Crude protein Nutrition 0.000 description 3
- 101000898784 Cryphonectria parasitica Endothiapepsin Proteins 0.000 description 3
- 235000019733 Fish meal Nutrition 0.000 description 3
- 241000221779 Fusarium sambucinum Species 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 240000005979 Hordeum vulgare Species 0.000 description 3
- 235000007340 Hordeum vulgare Nutrition 0.000 description 3
- 125000000570 L-alpha-aspartyl group Chemical group [H]OC(=O)C([H])([H])[C@]([H])(N([H])[H])C(*)=O 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 241000209510 Liliopsida Species 0.000 description 3
- 241000219745 Lupinus Species 0.000 description 3
- WBSCNDJQPKSPII-KKUMJFAQSA-N Lys-Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O WBSCNDJQPKSPII-KKUMJFAQSA-N 0.000 description 3
- 241000235395 Mucor Species 0.000 description 3
- 241000233654 Oomycetes Species 0.000 description 3
- PDUVELWDJZOUEI-IHRRRGAJSA-N Phe-Cys-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PDUVELWDJZOUEI-IHRRRGAJSA-N 0.000 description 3
- 241000209504 Poaceae Species 0.000 description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- 241000235403 Rhizomucor miehei Species 0.000 description 3
- 101000933133 Rhizopus niveus Rhizopuspepsin-1 Proteins 0.000 description 3
- 101000910082 Rhizopus niveus Rhizopuspepsin-2 Proteins 0.000 description 3
- 101000910079 Rhizopus niveus Rhizopuspepsin-3 Proteins 0.000 description 3
- 101000910086 Rhizopus niveus Rhizopuspepsin-4 Proteins 0.000 description 3
- 101000910088 Rhizopus niveus Rhizopuspepsin-5 Proteins 0.000 description 3
- 101000898773 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Saccharopepsin Proteins 0.000 description 3
- 244000061456 Solanum tuberosum Species 0.000 description 3
- 235000002595 Solanum tuberosum Nutrition 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 235000021307 Triticum Nutrition 0.000 description 3
- 241000209140 Triticum Species 0.000 description 3
- GVJUTBOZZBTBIG-AVGNSLFASA-N Val-Lys-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N GVJUTBOZZBTBIG-AVGNSLFASA-N 0.000 description 3
- 240000006677 Vicia faba Species 0.000 description 3
- 235000010749 Vicia faba Nutrition 0.000 description 3
- IXKSXJFAGXLQOQ-XISFHERQSA-N WHWLQLKPGQPMY Chemical compound C([C@@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CNC=N1 IXKSXJFAGXLQOQ-XISFHERQSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 230000009435 amidation Effects 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 229960005261 aspartic acid Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229940041011 carbapenems Drugs 0.000 description 3
- 229940038705 chlamydia trachomatis Drugs 0.000 description 3
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 241001233957 eudicotyledons Species 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 150000002191 fatty alcohols Chemical class 0.000 description 3
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229960004452 methionine Drugs 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 235000021048 nutrient requirements Nutrition 0.000 description 3
- 229940049547 paraxin Drugs 0.000 description 3
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 3
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 150000007660 quinolones Chemical class 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000008521 reorganization Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 230000001131 transforming effect Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 201000008827 tuberculosis Diseases 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 2
- 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
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-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
- 229920000936 Agarose Polymers 0.000 description 2
- 241000743339 Agrostis Species 0.000 description 2
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 2
- ZCUFMRIQCPNOHZ-NRPADANISA-N Ala-Val-Gln Chemical compound C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N ZCUFMRIQCPNOHZ-NRPADANISA-N 0.000 description 2
- 102000007698 Alcohol dehydrogenase Human genes 0.000 description 2
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- 101100163849 Arabidopsis thaliana ARS1 gene Proteins 0.000 description 2
- YVTHEZNOKSAWRW-DCAQKATOSA-N Arg-Lys-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O YVTHEZNOKSAWRW-DCAQKATOSA-N 0.000 description 2
- CVXXSWQORBZAAA-SRVKXCTJSA-N Arg-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N CVXXSWQORBZAAA-SRVKXCTJSA-N 0.000 description 2
- BNYNOWJESJJIOI-XUXIUFHCSA-N Arg-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N BNYNOWJESJJIOI-XUXIUFHCSA-N 0.000 description 2
- 241000235349 Ascomycota Species 0.000 description 2
- 241001513093 Aspergillus awamori Species 0.000 description 2
- 241001480052 Aspergillus japonicus Species 0.000 description 2
- 101000690713 Aspergillus niger Alpha-glucosidase Proteins 0.000 description 2
- 101900318521 Aspergillus oryzae Triosephosphate isomerase Proteins 0.000 description 2
- 241000209763 Avena sativa Species 0.000 description 2
- 235000007558 Avena sp Nutrition 0.000 description 2
- 108090000145 Bacillolysin Proteins 0.000 description 2
- 241000193752 Bacillus circulans Species 0.000 description 2
- 241000193749 Bacillus coagulans Species 0.000 description 2
- 241000194107 Bacillus megaterium Species 0.000 description 2
- 241000194103 Bacillus pumilus Species 0.000 description 2
- 241000193388 Bacillus thuringiensis Species 0.000 description 2
- 241000221198 Basidiomycota Species 0.000 description 2
- 241000588779 Bordetella bronchiseptica Species 0.000 description 2
- 241000588780 Bordetella parapertussis Species 0.000 description 2
- 241000588832 Bordetella pertussis Species 0.000 description 2
- 241000589968 Borrelia Species 0.000 description 2
- 241000219193 Brassicaceae Species 0.000 description 2
- 241000193764 Brevibacillus brevis Species 0.000 description 2
- 241000589513 Burkholderia cepacia Species 0.000 description 2
- 241000589875 Campylobacter jejuni Species 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- JFPVXVDWJQMJEE-QMTHXVAHSA-N Cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CC=CO1 JFPVXVDWJQMJEE-QMTHXVAHSA-N 0.000 description 2
- 241001647372 Chlamydia pneumoniae Species 0.000 description 2
- 241001647378 Chlamydia psittaci Species 0.000 description 2
- 241000233652 Chytridiomycota Species 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 241000222511 Coprinus Species 0.000 description 2
- 244000251987 Coprinus macrorhizus Species 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 description 2
- 101150015836 ENO1 gene Proteins 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 241000220485 Fabaceae Species 0.000 description 2
- 241000234642 Festuca Species 0.000 description 2
- 241000567163 Fusarium cerealis Species 0.000 description 2
- 241000223195 Fusarium graminearum Species 0.000 description 2
- 241000567178 Fusarium venenatum Species 0.000 description 2
- 102000048120 Galactokinases Human genes 0.000 description 2
- 108700023157 Galactokinases Proteins 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 108700007698 Genetic Terminator Regions Proteins 0.000 description 2
- 101100369308 Geobacillus stearothermophilus nprS gene Proteins 0.000 description 2
- 101100080316 Geobacillus stearothermophilus nprT gene Proteins 0.000 description 2
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 2
- MHXKHKWHPNETGG-QWRGUYRKSA-N Gly-Lys-Leu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O MHXKHKWHPNETGG-QWRGUYRKSA-N 0.000 description 2
- SFOXOSKVTLDEDM-HOTGVXAUSA-N Gly-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CN)=CNC2=C1 SFOXOSKVTLDEDM-HOTGVXAUSA-N 0.000 description 2
- UMRIXLHPZZIOML-OALUTQOASA-N Gly-Trp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)CN UMRIXLHPZZIOML-OALUTQOASA-N 0.000 description 2
- 206010018612 Gonorrhoea Diseases 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- YGDWPQCLFJNMOL-MNXVOIDGSA-N Ile-Leu-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YGDWPQCLFJNMOL-MNXVOIDGSA-N 0.000 description 2
- HUORUFRRJHELPD-MNXVOIDGSA-N Ile-Leu-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N HUORUFRRJHELPD-MNXVOIDGSA-N 0.000 description 2
- TVYWVSJGSHQWMT-AJNGGQMLSA-N Ile-Leu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N TVYWVSJGSHQWMT-AJNGGQMLSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000235649 Kluyveromyces Species 0.000 description 2
- 241001138401 Kluyveromyces lactis Species 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 2
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 2
- 108010029541 Laccase Proteins 0.000 description 2
- 241001071864 Lethrinus laticaudis Species 0.000 description 2
- 241000209082 Lolium Species 0.000 description 2
- 208000016604 Lyme disease Diseases 0.000 description 2
- UQRZFMQQXXJTTF-AVGNSLFASA-N Lys-Lys-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O UQRZFMQQXXJTTF-AVGNSLFASA-N 0.000 description 2
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- MJVAVZPDRWSRRC-UHFFFAOYSA-N Menadione Chemical compound C1=CC=C2C(=O)C(C)=CC(=O)C2=C1 MJVAVZPDRWSRRC-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 2
- 241000226677 Myceliophthora Species 0.000 description 2
- 241000204048 Mycoplasma hominis Species 0.000 description 2
- 241000202934 Mycoplasma pneumoniae Species 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- 241000588650 Neisseria meningitidis Species 0.000 description 2
- 241000231286 Neottia Species 0.000 description 2
- 241000221960 Neurospora Species 0.000 description 2
- 241000221961 Neurospora crassa Species 0.000 description 2
- 102000035092 Neutral proteases Human genes 0.000 description 2
- 108091005507 Neutral proteases Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- IGFHQQFPSIBGKE-UHFFFAOYSA-N Nonylphenol Natural products CCCCCCCCCC1=CC=C(O)C=C1 IGFHQQFPSIBGKE-UHFFFAOYSA-N 0.000 description 2
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 2
- 241000194109 Paenibacillus lautus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000228143 Penicillium Species 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 240000004713 Pisum sativum Species 0.000 description 2
- 235000010582 Pisum sativum Nutrition 0.000 description 2
- 241000223960 Plasmodium falciparum Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 108010040201 Polymyxins Proteins 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000168225 Pseudomonas alcaligenes Species 0.000 description 2
- 241000589540 Pseudomonas fluorescens Species 0.000 description 2
- 241000589630 Pseudomonas pseudoalcaligenes Species 0.000 description 2
- 241000589614 Pseudomonas stutzeri Species 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 241000190932 Rhodopseudomonas Species 0.000 description 2
- 241000606695 Rickettsia rickettsii Species 0.000 description 2
- 241000282849 Ruminantia Species 0.000 description 2
- 235000003534 Saccharomyces carlsbergensis Nutrition 0.000 description 2
- 235000001006 Saccharomyces cerevisiae var diastaticus Nutrition 0.000 description 2
- 244000206963 Saccharomyces cerevisiae var. diastaticus Species 0.000 description 2
- 241001123227 Saccharomyces pastorianus Species 0.000 description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 2
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 2
- 241000235346 Schizosaccharomyces Species 0.000 description 2
- 101100097319 Schizosaccharomyces pombe (strain 972 / ATCC 24843) ala1 gene Proteins 0.000 description 2
- 241000209056 Secale Species 0.000 description 2
- 235000007238 Secale cereale Nutrition 0.000 description 2
- RIAKPZVSNBBNRE-BJDJZHNGSA-N Ser-Ile-Leu Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O RIAKPZVSNBBNRE-BJDJZHNGSA-N 0.000 description 2
- LRWBCWGEUCKDTN-BJDJZHNGSA-N Ser-Lys-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LRWBCWGEUCKDTN-BJDJZHNGSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000187432 Streptomyces coelicolor Species 0.000 description 2
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 2
- 108010056079 Subtilisins Proteins 0.000 description 2
- 102000005158 Subtilisins Human genes 0.000 description 2
- 241001540751 Talaromyces ruber Species 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 2
- TZJSEJOXAIWOST-RHYQMDGZSA-N Thr-Lys-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N TZJSEJOXAIWOST-RHYQMDGZSA-N 0.000 description 2
- 241000223259 Trichoderma Species 0.000 description 2
- 241000223104 Trypanosoma Species 0.000 description 2
- XXWBHOWRARMUOC-NHCYSSNCSA-N Val-Lys-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)O)N XXWBHOWRARMUOC-NHCYSSNCSA-N 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- 241000607626 Vibrio cholerae Species 0.000 description 2
- 241000607272 Vibrio parahaemolyticus Species 0.000 description 2
- 235000002098 Vicia faba var. major Nutrition 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 241000607734 Yersinia <bacteria> Species 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- 241000607477 Yersinia pseudotuberculosis Species 0.000 description 2
- 241000758405 Zoopagomycotina Species 0.000 description 2
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 2
- 229920006243 acrylic copolymer Polymers 0.000 description 2
- 238000012867 alanine scanning Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000005466 alkylenyl group Chemical group 0.000 description 2
- 229960004050 aminobenzoic acid Drugs 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001166 anti-perspirative effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000003213 antiperspirant Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 2
- 229960003644 aztreonam Drugs 0.000 description 2
- 229940054340 bacillus coagulans Drugs 0.000 description 2
- 229940097012 bacillus thuringiensis Drugs 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 239000007844 bleaching agent Substances 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- RTYJTGSCYUUYAL-YCAHSCEMSA-L carbenicillin disodium Chemical compound [Na+].[Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)C(C([O-])=O)C1=CC=CC=C1 RTYJTGSCYUUYAL-YCAHSCEMSA-L 0.000 description 2
- 108010089934 carbohydrase Proteins 0.000 description 2
- 230000006860 carbon metabolism Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 2
- 229960005361 cefaclor Drugs 0.000 description 2
- 229960001668 cefuroxime Drugs 0.000 description 2
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 2
- 230000036978 cell physiology Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- 229960004884 fluconazole Drugs 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 108010061330 glucan 1,4-alpha-maltohydrolase Proteins 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 108010049041 glutamylalanine Proteins 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000002744 homologous recombination Methods 0.000 description 2
- 230000006801 homologous recombination Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 210000003000 inclusion body Anatomy 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 229960004130 itraconazole Drugs 0.000 description 2
- 238000005304 joining Methods 0.000 description 2
- 229960000433 latamoxef Drugs 0.000 description 2
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical class CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 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
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 229960002509 miconazole Drugs 0.000 description 2
- 230000002906 microbiologic effect Effects 0.000 description 2
- OCXSDHJRMYFTMA-KMFBOIRUSA-M nafcillin sodium monohydrate Chemical compound O.[Na+].C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C([O-])=O)=O)C(OCC)=CC=C21 OCXSDHJRMYFTMA-KMFBOIRUSA-M 0.000 description 2
- SNQQPOLDUKLAAF-UHFFFAOYSA-N nonylphenol Chemical compound CCCCCCCCCC1=CC=CC=C1O SNQQPOLDUKLAAF-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 229960000988 nystatin Drugs 0.000 description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- VDUVBBMAXXHEQP-SLINCCQESA-M oxacillin sodium Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 VDUVBBMAXXHEQP-SLINCCQESA-M 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 229940056360 penicillin g Drugs 0.000 description 2
- 229940056367 penicillin v Drugs 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 229940041153 polymyxins Drugs 0.000 description 2
- 210000001938 protoplast Anatomy 0.000 description 2
- 235000021251 pulses Nutrition 0.000 description 2
- 101150054232 pyrG gene Proteins 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000002453 shampoo Substances 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 229960000268 spectinomycin Drugs 0.000 description 2
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 2
- 108010005652 splenotritin Proteins 0.000 description 2
- 239000003206 sterilizing agent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 229940040944 tetracyclines Drugs 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 2
- 229960001082 trimethoprim Drugs 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- 229960003165 vancomycin Drugs 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 2
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 1
- LUCFELWCCKCPRT-WXNOHFCQSA-N (2S)-2-amino-5-(diaminomethylideneamino)pentanoic acid (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid (2S)-2-amino-4-methylpentanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.N[C@@H](CCCNC(N)=N)C(O)=O.N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O LUCFELWCCKCPRT-WXNOHFCQSA-N 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
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 101150084750 1 gene Proteins 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- NIBFJPXGNVPNHK-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde Chemical group C1=CC(C=O)=C2OC(F)(F)OC2=C1 NIBFJPXGNVPNHK-UHFFFAOYSA-N 0.000 description 1
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 1
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 240000002245 Acer pensylvanicum Species 0.000 description 1
- 235000006760 Acer pensylvanicum Nutrition 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 241001019659 Acremonium <Plectosphaerellaceae> Species 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 241000589155 Agrobacterium tumefaciens Species 0.000 description 1
- IFTVANMRTIHKML-WDSKDSINSA-N Ala-Gln-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O IFTVANMRTIHKML-WDSKDSINSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- AJBVYEYZVYPFCF-CIUDSAMLSA-N Ala-Lys-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O AJBVYEYZVYPFCF-CIUDSAMLSA-N 0.000 description 1
- OQWQTGBOFPJOIF-DLOVCJGASA-N Ala-Lys-His Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N OQWQTGBOFPJOIF-DLOVCJGASA-N 0.000 description 1
- XHNLCGXYBXNRIS-BJDJZHNGSA-N Ala-Lys-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XHNLCGXYBXNRIS-BJDJZHNGSA-N 0.000 description 1
- YCRAFFCYWOUEOF-DLOVCJGASA-N Ala-Phe-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 YCRAFFCYWOUEOF-DLOVCJGASA-N 0.000 description 1
- 241000220433 Albizia Species 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102000004400 Aminopeptidases Human genes 0.000 description 1
- 108090000915 Aminopeptidases Proteins 0.000 description 1
- 241000219195 Arabidopsis thaliana Species 0.000 description 1
- QEKBCDODJBBWHV-GUBZILKMSA-N Arg-Arg-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O QEKBCDODJBBWHV-GUBZILKMSA-N 0.000 description 1
- HJVGMOYJDDXLMI-AVGNSLFASA-N Arg-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N HJVGMOYJDDXLMI-AVGNSLFASA-N 0.000 description 1
- OOIMKQRCPJBGPD-XUXIUFHCSA-N Arg-Ile-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O OOIMKQRCPJBGPD-XUXIUFHCSA-N 0.000 description 1
- RIQBRKVTFBWEDY-RHYQMDGZSA-N Arg-Lys-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RIQBRKVTFBWEDY-RHYQMDGZSA-N 0.000 description 1
- JWKDQOORUCYUIW-ZPFDUUQYSA-N Asn-Lys-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JWKDQOORUCYUIW-ZPFDUUQYSA-N 0.000 description 1
- UKGGPJNBONZZCM-WDSKDSINSA-N Asp-Pro Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O UKGGPJNBONZZCM-WDSKDSINSA-N 0.000 description 1
- 101000961203 Aspergillus awamori Glucoamylase Proteins 0.000 description 1
- 241000892910 Aspergillus foetidus Species 0.000 description 1
- 241000228243 Aspergillus giganteus Species 0.000 description 1
- 101900127796 Aspergillus oryzae Glucoamylase Proteins 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 101000775727 Bacillus amyloliquefaciens Alpha-amylase Proteins 0.000 description 1
- 241001328122 Bacillus clausii Species 0.000 description 1
- 101000695691 Bacillus licheniformis Beta-lactamase Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000219310 Beta vulgaris subsp. vulgaris Species 0.000 description 1
- 102100030981 Beta-alanine-activating enzyme Human genes 0.000 description 1
- 102100032487 Beta-mannosidase Human genes 0.000 description 1
- 241000588807 Bordetella Species 0.000 description 1
- 241000589972 Borrelia sp. Species 0.000 description 1
- 241000589969 Borreliella burgdorferi Species 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
- 235000011293 Brassica napus Nutrition 0.000 description 1
- 235000011299 Brassica oleracea var botrytis Nutrition 0.000 description 1
- 240000003259 Brassica oleracea var. botrytis Species 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- 241000508772 Brucella sp. Species 0.000 description 1
- 206010051548 Burn infection Diseases 0.000 description 1
- 101100520142 Caenorhabditis elegans pin-2 gene Proteins 0.000 description 1
- 101100043656 Caenorhabditis elegans stdh-4 gene Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 241000589994 Campylobacter sp. Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 108010031396 Catechol oxidase Proteins 0.000 description 1
- 102000030523 Catechol oxidase Human genes 0.000 description 1
- 102100037633 Centrin-3 Human genes 0.000 description 1
- 240000006162 Chenopodium quinoa Species 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 108010022172 Chitinases Proteins 0.000 description 1
- 102000012286 Chitinases Human genes 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 241001495184 Chlamydia sp. Species 0.000 description 1
- 241000606069 Chlamydiaceae Species 0.000 description 1
- 241000701248 Chlorella virus Species 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 208000036086 Chromosome Duplication Diseases 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 241000873310 Citrobacter sp. Species 0.000 description 1
- 241000222290 Cladosporium Species 0.000 description 1
- 241000020428 Colea Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 235000001673 Coprinus macrorhizus Nutrition 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000694959 Cryptococcus sp. Species 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- AGPKZVBTJJNPAG-RFZPGFLSSA-N D-Isoleucine Chemical compound CC[C@@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-RFZPGFLSSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229930182845 D-isoleucine Natural products 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 208000001840 Dandruff Diseases 0.000 description 1
- 108010002069 Defensins Proteins 0.000 description 1
- 102000000541 Defensins Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 101100342470 Dictyostelium discoideum pkbA gene Proteins 0.000 description 1
- 241001063191 Elops affinis Species 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 241000224431 Entamoeba Species 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000147019 Enterobacter sp. Species 0.000 description 1
- 235000002756 Erythrina berteroana Nutrition 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101100385973 Escherichia coli (strain K12) cycA gene Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000589601 Francisella Species 0.000 description 1
- 241000145614 Fusarium bactridioides Species 0.000 description 1
- 241000223194 Fusarium culmorum Species 0.000 description 1
- 241000146406 Fusarium heterosporum Species 0.000 description 1
- 241001112697 Fusarium reticulatum Species 0.000 description 1
- 241001014439 Fusarium sarcochroum Species 0.000 description 1
- 241000223192 Fusarium sporotrichioides Species 0.000 description 1
- 241001465753 Fusarium torulosum Species 0.000 description 1
- 101150108358 GLAA gene Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000726221 Gemma Species 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 101100001650 Geobacillus stearothermophilus amyM gene Proteins 0.000 description 1
- WOMUDRVDJMHTCV-DCAQKATOSA-N Glu-Arg-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOMUDRVDJMHTCV-DCAQKATOSA-N 0.000 description 1
- OQXDUSZKISQQSS-GUBZILKMSA-N Glu-Lys-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OQXDUSZKISQQSS-GUBZILKMSA-N 0.000 description 1
- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 description 1
- JHSRJMUJOGLIHK-GUBZILKMSA-N Glu-Met-Glu Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)O)N JHSRJMUJOGLIHK-GUBZILKMSA-N 0.000 description 1
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 description 1
- 102100022624 Glucoamylase Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- MXXXVOYFNVJHMA-IUCAKERBSA-N Gly-Arg-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CN MXXXVOYFNVJHMA-IUCAKERBSA-N 0.000 description 1
- SCWYHUQOOFRVHP-MBLNEYKQSA-N Gly-Ile-Thr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SCWYHUQOOFRVHP-MBLNEYKQSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- PTIIBFKSLCYQBO-NHCYSSNCSA-N Gly-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)CN PTIIBFKSLCYQBO-NHCYSSNCSA-N 0.000 description 1
- VEPBEGNDJYANCF-QWRGUYRKSA-N Gly-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCCN VEPBEGNDJYANCF-QWRGUYRKSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101150009006 HIS3 gene Proteins 0.000 description 1
- 241000606841 Haemophilus sp. Species 0.000 description 1
- 101100295959 Halobacterium salinarum (strain ATCC 700922 / JCM 11081 / NRC-1) arcB gene Proteins 0.000 description 1
- 101100246753 Halobacterium salinarum (strain ATCC 700922 / JCM 11081 / NRC-1) pyrF gene Proteins 0.000 description 1
- 241000590008 Helicobacter sp. Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000773364 Homo sapiens Beta-alanine-activating enzyme Proteins 0.000 description 1
- 101000880522 Homo sapiens Centrin-3 Proteins 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- FFAUOCITXBMRBT-YTFOTSKYSA-N Ile-Lys-Ile Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FFAUOCITXBMRBT-YTFOTSKYSA-N 0.000 description 1
- YSGBJIQXTIVBHZ-AJNGGQMLSA-N Ile-Lys-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O YSGBJIQXTIVBHZ-AJNGGQMLSA-N 0.000 description 1
- HQLSBZFLOUHQJK-STECZYCISA-N Ile-Tyr-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HQLSBZFLOUHQJK-STECZYCISA-N 0.000 description 1
- AUIYHFRUOOKTGX-UKJIMTQDSA-N Ile-Val-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N AUIYHFRUOOKTGX-UKJIMTQDSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588754 Klebsiella sp. Species 0.000 description 1
- HGCNKOLVKRAVHD-UHFFFAOYSA-N L-Met-L-Phe Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 HGCNKOLVKRAVHD-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- 125000001176 L-lysyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 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
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- 241000235087 Lachancea kluyveri Species 0.000 description 1
- 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 1
- 240000008415 Lactuca sativa Species 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 241000589268 Legionella sp. Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 101710094902 Legumin Proteins 0.000 description 1
- 235000007849 Lepidium sativum Nutrition 0.000 description 1
- 244000211187 Lepidium sativum Species 0.000 description 1
- 241000236488 Lepra Species 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 241000880493 Leptailurus serval Species 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 1
- WXUOJXIGOPMDJM-SRVKXCTJSA-N Leu-Lys-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O WXUOJXIGOPMDJM-SRVKXCTJSA-N 0.000 description 1
- KPYAOIVPJKPIOU-KKUMJFAQSA-N Leu-Lys-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O KPYAOIVPJKPIOU-KKUMJFAQSA-N 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- 241001084338 Listeria sp. Species 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- WXJKFRMKJORORD-DCAQKATOSA-N Lys-Arg-Ala Chemical compound NC(=N)NCCC[C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CCCCN WXJKFRMKJORORD-DCAQKATOSA-N 0.000 description 1
- JGAMUXDWYSXYLM-SRVKXCTJSA-N Lys-Arg-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O JGAMUXDWYSXYLM-SRVKXCTJSA-N 0.000 description 1
- ZXFRGTAIIZHNHG-AJNGGQMLSA-N Lys-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CCCCN)N ZXFRGTAIIZHNHG-AJNGGQMLSA-N 0.000 description 1
- RIJCHEVHFWMDKD-SRVKXCTJSA-N Lys-Lys-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RIJCHEVHFWMDKD-SRVKXCTJSA-N 0.000 description 1
- GAHJXEMYXKLZRQ-AJNGGQMLSA-N Lys-Lys-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GAHJXEMYXKLZRQ-AJNGGQMLSA-N 0.000 description 1
- MTBLFIQZECOEBY-IHRRRGAJSA-N Lys-Met-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(O)=O MTBLFIQZECOEBY-IHRRRGAJSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 1
- 101000920534 Lysinibacillus sphaericus Gamma-D-glutamyl-L-diamino acid endopeptidase 1 Proteins 0.000 description 1
- 101150068888 MET3 gene Proteins 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010054377 Mannosidases Proteins 0.000 description 1
- 102000001696 Mannosidases Human genes 0.000 description 1
- DLAFCQWUMFMZSN-GUBZILKMSA-N Met-Arg-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CCCN=C(N)N DLAFCQWUMFMZSN-GUBZILKMSA-N 0.000 description 1
- KMSMNUFBNCHMII-IHRRRGAJSA-N Met-Leu-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN KMSMNUFBNCHMII-IHRRRGAJSA-N 0.000 description 1
- UNPGTBHYKJOCCZ-DCAQKATOSA-N Met-Lys-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O UNPGTBHYKJOCCZ-DCAQKATOSA-N 0.000 description 1
- JCMMNFZUKMMECJ-DCAQKATOSA-N Met-Lys-Asn Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O JCMMNFZUKMMECJ-DCAQKATOSA-N 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 241000588771 Morganella <proteobacterium> Species 0.000 description 1
- 241000711408 Murine respirovirus Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000202944 Mycoplasma sp. Species 0.000 description 1
- DEFJQIDDEAULHB-UHFFFAOYSA-N N-D-alanyl-D-alanine Natural products CC(N)C(=O)NC(C)C(O)=O DEFJQIDDEAULHB-UHFFFAOYSA-N 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 1
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241001440871 Neisseria sp. Species 0.000 description 1
- 101100022915 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cys-11 gene Proteins 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 108090000913 Nitrate Reductases Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000606860 Pasteurella Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 1
- OXKJSGGTHFMGDT-UFYCRDLUSA-N Phe-Phe-Arg Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 OXKJSGGTHFMGDT-UFYCRDLUSA-N 0.000 description 1
- KCIKTPHTEYBXMG-BVSLBCMMSA-N Phe-Trp-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O KCIKTPHTEYBXMG-BVSLBCMMSA-N 0.000 description 1
- VFDRDMOMHBJGKD-UFYCRDLUSA-N Phe-Tyr-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N VFDRDMOMHBJGKD-UFYCRDLUSA-N 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 108010059820 Polygalacturonase Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000334216 Proteus sp. Species 0.000 description 1
- 241000588768 Providencia Species 0.000 description 1
- 241000588774 Providencia sp. Species 0.000 description 1
- 241000589774 Pseudomonas sp. Species 0.000 description 1
- 241000577556 Pseudomonas wisconsinensis Species 0.000 description 1
- 229920001131 Pulp (paper) Polymers 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 241000235527 Rhizopus Species 0.000 description 1
- 101100394989 Rhodopseudomonas palustris (strain ATCC BAA-98 / CGA009) hisI gene Proteins 0.000 description 1
- 241000606714 Rickettsia sp. Species 0.000 description 1
- 241000606726 Rickettsia typhi Species 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- 101900354623 Saccharomyces cerevisiae Galactokinase Proteins 0.000 description 1
- 101001076706 Saccharomyces cerevisiae Invertase 1 Proteins 0.000 description 1
- 101001053411 Saccharomyces cerevisiae Invertase 3 Proteins 0.000 description 1
- 101001053412 Saccharomyces cerevisiae Invertase 4 Proteins 0.000 description 1
- 101001053409 Saccharomyces cerevisiae Invertase 5 Proteins 0.000 description 1
- 101001053400 Saccharomyces cerevisiae Invertase 7 Proteins 0.000 description 1
- 241000204893 Saccharomyces douglasii Species 0.000 description 1
- 241001407717 Saccharomyces norbensis Species 0.000 description 1
- 241000235343 Saccharomycetales Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607149 Salmonella sp. Species 0.000 description 1
- 101100022918 Schizosaccharomyces pombe (strain 972 / ATCC 24843) sua1 gene Proteins 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 241001199840 Senegalia laeta Species 0.000 description 1
- CWHJIJJSDGEHNS-MYLFLSLOSA-N Senegenin Chemical compound C1[C@H](O)[C@H](O)[C@@](C)(C(O)=O)[C@@H]2CC[C@@]3(C)C(CC[C@]4(CCC(C[C@H]44)(C)C)C(O)=O)=C4[C@@H](CCl)C[C@@H]3[C@]21C CWHJIJJSDGEHNS-MYLFLSLOSA-N 0.000 description 1
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 1
- HBTCFCHYALPXME-HTFCKZLJSA-N Ser-Ile-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HBTCFCHYALPXME-HTFCKZLJSA-N 0.000 description 1
- VMLONWHIORGALA-SRVKXCTJSA-N Ser-Leu-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CO VMLONWHIORGALA-SRVKXCTJSA-N 0.000 description 1
- NNFMANHDYSVNIO-DCAQKATOSA-N Ser-Lys-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NNFMANHDYSVNIO-DCAQKATOSA-N 0.000 description 1
- XNXRTQZTFVMJIJ-DCAQKATOSA-N Ser-Met-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O XNXRTQZTFVMJIJ-DCAQKATOSA-N 0.000 description 1
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000607714 Serratia sp. Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 235000009337 Spinacia oleracea Nutrition 0.000 description 1
- 244000300264 Spinacia oleracea Species 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 101100309436 Streptococcus mutans serotype c (strain ATCC 700610 / UA159) ftf gene Proteins 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 101100370749 Streptomyces coelicolor (strain ATCC BAA-471 / A3(2) / M145) trpC1 gene Proteins 0.000 description 1
- 241000187398 Streptomyces lividans Species 0.000 description 1
- 241001468239 Streptomyces murinus Species 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- 235000021536 Sugar beet Nutrition 0.000 description 1
- 102000004523 Sulfate Adenylyltransferase Human genes 0.000 description 1
- 108010022348 Sulfate adenylyltransferase Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- BGRWYDHXPHLNKA-UHFFFAOYSA-N Tetraacetylethylenediamine Chemical compound CC(=O)N(C(C)=O)CCN(C(C)=O)C(C)=O BGRWYDHXPHLNKA-UHFFFAOYSA-N 0.000 description 1
- 244000152045 Themeda triandra Species 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 241000223257 Thermomyces Species 0.000 description 1
- 241001313536 Thermothelomyces thermophila Species 0.000 description 1
- 241001494489 Thielavia Species 0.000 description 1
- 241001495429 Thielavia terrestris Species 0.000 description 1
- HOVLHEKTGVIKAP-WDCWCFNPSA-N Thr-Leu-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O HOVLHEKTGVIKAP-WDCWCFNPSA-N 0.000 description 1
- MEJHFIOYJHTWMK-VOAKCMCISA-N Thr-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)O MEJHFIOYJHTWMK-VOAKCMCISA-N 0.000 description 1
- UUSQVWOVUYMLJA-PPCPHDFISA-N Thr-Lys-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UUSQVWOVUYMLJA-PPCPHDFISA-N 0.000 description 1
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 1
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 1
- PWONLXBUSVIZPH-RHYQMDGZSA-N Thr-Val-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O PWONLXBUSVIZPH-RHYQMDGZSA-N 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 241001149964 Tolypocladium Species 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 108060008539 Transglutaminase Proteins 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- 241000589906 Treponema sp. Species 0.000 description 1
- 241000223260 Trichoderma harzianum Species 0.000 description 1
- 241000378866 Trichoderma koningii Species 0.000 description 1
- 241000223262 Trichoderma longibrachiatum Species 0.000 description 1
- 241000499912 Trichoderma reesei Species 0.000 description 1
- 241000223261 Trichoderma viride Species 0.000 description 1
- 102000005924 Triose-Phosphate Isomerase Human genes 0.000 description 1
- 108700015934 Triose-phosphate isomerases Proteins 0.000 description 1
- 101800003783 Tritrpticin Proteins 0.000 description 1
- GNCPKOZDOCQRAF-BPUTZDHNSA-N Trp-Ser-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N GNCPKOZDOCQRAF-BPUTZDHNSA-N 0.000 description 1
- 241000223105 Trypanosoma brucei Species 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 241001467018 Typhis Species 0.000 description 1
- ZAGPDPNPWYPEIR-SRVKXCTJSA-N Tyr-Cys-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O ZAGPDPNPWYPEIR-SRVKXCTJSA-N 0.000 description 1
- 101150050575 URA3 gene Proteins 0.000 description 1
- OTJMMKPMLUNTQT-AVGNSLFASA-N Val-Leu-Arg Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N OTJMMKPMLUNTQT-AVGNSLFASA-N 0.000 description 1
- LYERIXUFCYVFFX-GVXVVHGQSA-N Val-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LYERIXUFCYVFFX-GVXVVHGQSA-N 0.000 description 1
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 1
- GIAZPLMMQOERPN-YUMQZZPRSA-N Val-Pro Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(O)=O GIAZPLMMQOERPN-YUMQZZPRSA-N 0.000 description 1
- NGXQOQNXSGOYOI-BQFCYCMXSA-N Val-Trp-Gln Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 NGXQOQNXSGOYOI-BQFCYCMXSA-N 0.000 description 1
- IOUPEELXVYPCPG-UHFFFAOYSA-N Valylglycine Chemical compound CC(C)C(N)C(=O)NCC(O)=O IOUPEELXVYPCPG-UHFFFAOYSA-N 0.000 description 1
- 241000607598 Vibrio Species 0.000 description 1
- 241000607284 Vibrio sp. Species 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003756 Vitamin B7 Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- GLLRIXZGBQOFLM-UHFFFAOYSA-N Xanthorin Natural products C1=C(C)C=C2C(=O)C3=C(O)C(OC)=CC(O)=C3C(=O)C2=C1O GLLRIXZGBQOFLM-UHFFFAOYSA-N 0.000 description 1
- 241000235013 Yarrowia Species 0.000 description 1
- 241000235015 Yarrowia lipolytica Species 0.000 description 1
- 241000607447 Yersinia enterocolitica Species 0.000 description 1
- 241000131891 Yersinia sp. Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine group Chemical group [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12 OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 108010030291 alpha-Galactosidase Proteins 0.000 description 1
- 102000005840 alpha-Galactosidase Human genes 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 235000019728 animal nutrition Nutrition 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000433 anti-nutritional effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 101150009206 aprE gene Proteins 0.000 description 1
- 101150008194 argB gene Proteins 0.000 description 1
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 210000004507 artificial chromosome Anatomy 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 238000005844 autocatalytic reaction Methods 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000000721 bacterilogical effect Effects 0.000 description 1
- 101150103518 bar gene Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 108010047754 beta-Glucosidase Proteins 0.000 description 1
- 102000006995 beta-Glucosidase Human genes 0.000 description 1
- 108010055059 beta-Mannosidase Proteins 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- HKPHPIREJKHECO-UHFFFAOYSA-N butachlor Chemical compound CCCCOCN(C(=O)CCl)C1=C(CC)C=CC=C1CC HKPHPIREJKHECO-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000011111 cardboard Substances 0.000 description 1
- POIUWJQBRNEFGX-XAMSXPGMSA-N cathelicidin Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C1=CC=CC=C1 POIUWJQBRNEFGX-XAMSXPGMSA-N 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 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=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 1
- KAFGYXORACVKTE-UEDJBKKJSA-N chembl503567 Chemical compound C([C@H]1C(=O)N[C@H]2CSSC[C@H](NC(=O)[C@H](CC=3C=CC=CC=3)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(N1)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CCCNC(N)=N)CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)C1=CC=C(O)C=C1 KAFGYXORACVKTE-UEDJBKKJSA-N 0.000 description 1
- 210000003763 chloroplast Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000011098 chromatofocusing Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 210000000877 corpus callosum Anatomy 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000019784 crude fat Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 108010005400 cutinase Proteins 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000024835 cytogamy Effects 0.000 description 1
- 101150005799 dagA gene Proteins 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000002478 diastatic effect Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 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
- 238000004851 dishwashing Methods 0.000 description 1
- NEKNNCABDXGBEN-UHFFFAOYSA-L disodium;4-(4-chloro-2-methylphenoxy)butanoate;4-(2,4-dichlorophenoxy)butanoate Chemical compound [Na+].[Na+].CC1=CC(Cl)=CC=C1OCCCC([O-])=O.[O-]C(=O)CCCOC1=CC=C(Cl)C=C1Cl NEKNNCABDXGBEN-UHFFFAOYSA-L 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 108010091371 endoglucanase 1 Proteins 0.000 description 1
- 108010091384 endoglucanase 2 Proteins 0.000 description 1
- 108010092450 endoglucanase Z Proteins 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- AUAHHJJRFHRVPV-BZDVOYDHSA-N ethambutol dihydrochloride Chemical compound [Cl-].[Cl-].CC[C@@H](CO)[NH2+]CC[NH2+][C@@H](CC)CO AUAHHJJRFHRVPV-BZDVOYDHSA-N 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000002979 fabric softener Substances 0.000 description 1
- 235000019387 fatty acid methyl ester Nutrition 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019688 fish Nutrition 0.000 description 1
- 239000004467 fishmeal Substances 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 235000012055 fruits and vegetables Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 102000057593 human F8 Human genes 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009655 industrial fermentation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000010849 ion bombardment Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 235000021374 legumes Nutrition 0.000 description 1
- 108010077158 leucinyl-arginyl-tryptophan Proteins 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000010687 lubricating oil Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 101150039489 lysZ gene Proteins 0.000 description 1
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 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
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000000442 meristematic effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 108010068488 methionylphenylalanine Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 108010020132 microbial serine proteinases Proteins 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 230000004879 molecular function Effects 0.000 description 1
- 230000021332 multicellular organism growth Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 101150095344 niaD gene Proteins 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 101150105920 npr gene Proteins 0.000 description 1
- 101150017837 nprM gene Proteins 0.000 description 1
- 230000031787 nutrient reservoir activity Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 108010073895 ovispirin Proteins 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 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
- 239000000123 paper Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 101150019841 penP gene Proteins 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 108010082527 phosphinothricin N-acetyltransferase Proteins 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920002006 poly(N-vinylimidazole) polymer Polymers 0.000 description 1
- 229920005646 polycarboxylate Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 108010032966 protegrin-1 Proteins 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 101150108007 prs gene Proteins 0.000 description 1
- 101150086435 prs1 gene Proteins 0.000 description 1
- 101150070305 prsA gene Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 229940047431 recombinate Drugs 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940075118 rickettsia rickettsii Drugs 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 101150025220 sacB gene Proteins 0.000 description 1
- 235000012045 salad Nutrition 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 108010071207 serylmethionine Proteins 0.000 description 1
- 238000012807 shake-flask culturing Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical group O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- MWNQXXOSWHCCOZ-UHFFFAOYSA-L sodium;oxido carbonate Chemical compound [Na+].[O-]OC([O-])=O MWNQXXOSWHCCOZ-UHFFFAOYSA-L 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000010563 solid-state fermentation Methods 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.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](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.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](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 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
- 238000005494 tarnishing Methods 0.000 description 1
- 239000009871 tenuigenin Substances 0.000 description 1
- OFVLGDICTFRJMM-WESIUVDSSA-N tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 108010032153 thanatin Proteins 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 102000003601 transglutaminase Human genes 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- FTKYRNHHOBRIOY-HQUBJAAMSA-N tritrptcin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)C(C)C)C1=CC=CC=C1 FTKYRNHHOBRIOY-HQUBJAAMSA-N 0.000 description 1
- 101150016309 trpC gene Proteins 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000001974 tryptic soy broth Substances 0.000 description 1
- 108010050327 trypticase-soy broth Proteins 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000011912 vitamin B7 Nutrition 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 235000012711 vitamin K3 Nutrition 0.000 description 1
- 239000011652 vitamin K3 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 101150052264 xylA gene Proteins 0.000 description 1
- 101150110790 xylB gene Proteins 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/48—Medical, disinfecting agents, disinfecting, antibacterial, germicidal or antimicrobial compositions
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/142—Amino acids; Derivatives thereof
- A23K20/147—Polymeric derivatives, e.g. peptides or proteins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/174—Vitamins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/189—Enzymes
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/195—Antibiotics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/20—Inorganic substances, e.g. oligoelements
- A23K20/30—Oligoelements
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
- A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
-
- 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
-
- 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
- A61P31/04—Antibacterial agents
-
- 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
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/37—Polymers
- C11D3/3703—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
- C11D3/3719—Polyamides or polyimides
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/38—Products with no well-defined composition, e.g. natural products
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/80—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in fisheries management
- Y02A40/81—Aquaculture, e.g. of fish
- Y02A40/818—Alternative feeds for fish, e.g. in aquacultures
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Polymers & Plastics (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Food Science & Technology (AREA)
- Animal Husbandry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Birds (AREA)
- Medicinal Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Marine Sciences & Fisheries (AREA)
- Toxicology (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Dentistry (AREA)
- Environmental Sciences (AREA)
- Insects & Arthropods (AREA)
- Pulmonology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本发明涉及具有抗微生物活性的多肽及具有编码所述多肽的核苷酸序列的多核苷酸。本发明还涉及核酸构建体、载体及包含所述核酸构建体的宿主细胞以及产生和使用所述多肽的方法。
Description
背景
近年来,抗微生物剂的种类大量增加,然而抗性病原性微生物也平行增加。现在认识到抗性针对所有可临床用抗微生物剂。医学界对抗微生物抗性的反应是应用以前没有应用的针对抗性细菌的新的或备选抗生素。此方法需要持续研发新抗生素,作为可抑制或避开细菌抗性机制的现有化合物的修饰或作为化合物组合。
本发明的目的是提供具有改善抗微生物活性的新多肽及编码所述多肽的多核苷酸。
概述
本发明第一方面涉及具有抗微生物活性的多肽,其包含如下氨基酸序列或其具有抗微生物活性的至少18个氨基酸的片段:
G-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-Z;
其中X1=L、I、W或M;X2=L、F、W或V;X3=S、G、K、T、R、I、N、D或E;X4=K、T、F、I、R、M、L或S;X5=L或I;X6=K、G、R、M或E;X7=K、S、I、R、T或M;X8=A、K、T、N、R或E;X9=A、G、S、I、L、T、V、M或W;X10=S、R、K或E;X11=K、M、R、H、I、N或T;X12=A、V、I、L、Y、F或T;X13=L、A、G、C、F、V或W;X14=K、Q、A、S、R或E;X15=H、G、N、R、S、M、I、V或D;X16=V、I、A或F;z=X17或X17-R-W-L;其中X17=F、L、R、A、G、V、Y、C或P;并且其中组成所述多肽的氨基酸独立地选自D或者L型。
另一方面,本发明涉及具有抗微生物活性的多肽,其由18个氨基酸组成和通过氨基酸序列R-W-L延伸的氨基酸序列组成。
本发明第二方面涉及具有编码本发明的多肽的核苷酸序列的多核苷酸。
本发明第三方面涉及包含核苷酸序列的核酸构建体,所述核苷酸序列编码本发明的多肽,所述核苷酸序列有效连接指导在合适宿主中产生所述多肽的一种或多种控制序列有效连接。
本发明第四方面涉及包含本发明的核酸构建体的重组表达载体。
本发明第五方面涉及包含本发明的核酸构建体的重组宿主细胞。
本发明第六方面涉及用于产生本发明的多肽的方法,该方法包含:
(a)在有益于产生所述多肽的条件下培养本发明的重组宿主细胞;和
(b)回收所述多肽。
本发明的其它方面将从以下描述及所附的权利要求书中是显然的。定义
在进一步详细讨论本发明之前,首先对以下术语及惯用语进行定义:
抗微生物活性:术语“抗微生物活性”文中定义为能杀死或抑制微生物细胞生长的活性。在本发明的上下文中,术语“抗微生物”欲表示杀细菌和/或制细菌作用和/或杀真菌和/或制真菌作用和/或杀病毒作用,其中术语“杀细菌”理解为能杀死细菌细胞。术语“制细菌”理解为能抑制细菌生长,即抑制生长的细菌细胞。术语“杀真菌”理解为能杀死真菌细胞。术语“制真菌”理解为能抑制真菌生长,即抑制生长的真菌细胞。术语“杀病毒”理解为能灭活病毒。术语“微生物细胞”表示细菌或真菌细胞(包括酵母)。
在本发明上下文中,术语“抑制微生物细胞生长”欲表示细胞处于非生长状态,即它们不能增殖。
对于本发明,抗微生物活性可根据Lehrer等人,Journal ofImmunological Methods,第137(2)卷,第167-174页(1991)中描述的方法确定。
在具有抗微生物活性多肽的25%(w/w)的水溶液中,优选10%(w/w)的水溶液中;更优选5%(w/w)的水溶液中;甚至更优选1%(w/w)的水溶液中;最优选0.5%(w/w)的水溶液中;且特别是0.1%(w/w)的水溶液中于20℃孵育8小时后(优选4小时后,更优选2小时后,最优选1小时后,且特别是30分钟后,),具有抗微生物活性多肽可能够将大肠杆菌(Escherichia coli)(DSM 1576)活细胞数降低至1/100。
在微生物生长培养基中,加入1000ppm浓度时,优选加入500ppm浓度时,更优选加入250ppm浓度时,甚至更优选加入100ppm浓度时;最优选加入50ppm浓度时,特别是当加入25ppm浓度时,具有抗微生物活性多肽于25℃孵育24小时也能够抑制大肠杆菌(DSM 1576)的生长晕。
在具有抗微生物活性多肽的25%(w/w)的水溶液中,优选10%(w/w)的水溶液中;更优选5%(w/w)的水溶液中;甚至更优选1%(w/w)的水溶液中;最优选0.5%(w/w)的水溶液中;且特别是0.1%(w/w)的水溶液中,于20℃孵育8小时后(优选4小时后,更优选2小时后,最优选1小时后,且特别是30分钟后,),能够将枯草芽孢杆菌(Bacillus subtilis)(ATCC 6633)的活细胞数降低至1/100。
在微生物生长培养基中,加入1000ppm浓度时,优选加入500ppm浓度时,更优选加入250ppm浓度时,甚至更优选加入100ppm浓度时;最优选加入50ppm浓度时,且特别是当加入25ppm浓度时,具有抗微生物活性多肽于25℃孵育24小时也能够抑制枯草芽孢杆菌(ATCC 6633)的生长晕。
本发明的多肽优选具有由SEQ ID NO:1至SEQ ID NO:37中任意一项1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项1至21位氨基酸显示的氨基酸序列组成的多肽的至少20%抗微生物活性。在特别优选的实施方案中,所述多肽具有由SEQ ID NO:1至SEQ ID NO:37中任意一项1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项1至21位氨基酸显示的氨基酸序列组成的多肽的抗微生物活性的至少40%,如至少50%,优选至少60%,如至少70%,更优选至少80%,如至少90%,最优选至少95%,如约或至少100%。
片段:文中应用时,SEQ ID NO:1至SEQ ID NO:46的任意一项所示氨基酸序列的“片段”为所述多肽的子序列,其中一个或多个氨基酸自氨基端和/或羧基端缺失。优选一个或多个氨基酸已经自羧基端缺失。更优选地,所述片段由至少18个氨基酸组成。
等位变体:在本上下文中,术语“等位变体”表示占据相同染色体基因座基因的任意两个或多个备选形式。等位变异通过突变天然发生,且可在群内导致多态性。基因突变可为沉默的(在所编码多肽中无变化)或可编码具有经改变氨基酸序列的多肽。多肽的等位变体为通过基因的等位变体编码的多肽。
基本上纯的多核苷酸:文中应用的术语“基本上纯的多核苷酸”是指多核苷酸制备物,其中多核苷酸自它的天然遗传环境中去除,并因此没有其它外来或不需要的编码序列且为在遗传工程蛋白质产生系统中适合应用的形式。因此,基本上纯的多核苷酸含有占与它天然相关的其它多核苷酸材料按重量计算至多10%(优选其它多核苷酸材料的较低百分比,例如按重量计算至多8%,按重量计算至多6%,按重量计算至多5%,按重量计算至多4%,按重量计算至多3%,按重量计算至多2%,按重量计算至多1%且按重量计算至多1/2%)。然而,基本上纯的多核苷酸可包括天然存在5’及3’非翻译区,如启动子和终止子。优选基本上纯的多核苷酸至少92%纯,即多核苷酸组成至少占制备物中存在总多核苷酸材料的按重量计算92%,且优选较高百分率如至少94%纯,至少95%纯,至少96%纯,至少97%纯,至少98%纯,至少99%纯且至多99.5%纯是优选的。文中公开的多核苷酸优选基本上纯的形式。特别地,文中公开的多核苷酸为“基本上纯的形式”即多核苷酸制备物基本上无与它天然相关的其它多核苷酸材料是优选的。文中,术语“基本上纯的多核苷酸”与术语“经分离多核苷酸”及“经分离形式的多核苷酸”是同义的。
修饰:本发明上下文中术语“修饰”欲表示由SEQ ID NO:1至SEQ IDNO:37中任意一项1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项1至21位氨基酸显示的氨基酸序列组成的多肽的任意化学修饰以及编码所述多肽的DNA的遗传操作。修饰可为氨基酸侧链的取代,在目的氨基酸中或目的氨基酸的替代、缺失和/或插入;或在氨基酸序列中应用具有相似特征的非天然氨基酸。特别地,修饰可为酰胺化,如C端的酰胺化。
cDNA:术语“cDNA”在本上下文中应用时,欲覆盖可通过自来源于真核细胞的成熟的、已剪接mRNA分子通过反转录制备的DNA分子。cDNA缺乏一般在对应基因组DNA中存在的内含子序列。最初的初级RNA转录物为mRNA前体且经过一系列加工作用成为成熟的已剪接mRNA。此类作用包括通过称为剪接的过程去除内含子序列。由于cDNA来自mRNA,因此它缺乏内含子序列。
核酸构建体:文中应用时,术语“核酸构建体”表示分离自天然存在基因或以在自然界不存在的方式进行修饰以含有核酸节段的单链或双链核酸分子。当核酸构建体含有用于表达本发明的编码序列所需控制序列时,术语核酸构建体与术语“表达盒”是同义的。
控制序列:文中定义的术语“控制序列”包括对本发明的多肽的表达是必需的或有益的所有组分。每个控制序列对编码多肽的核苷酸序列可为天然的或外来的。此类控制序列包括但不限于前导序列、多腺苷酸化序列、前肽序列、启动子、信号肽序列及转录终止子。控制序列最少包括启动子、转录及翻译终止信号。控制序列可与接头一起提供用于导入有助于控制序列与编码多肽的核苷酸序列的编码区连接的特异限制性位点。
有效连接:术语“有效连接”文中定义为构造,所述构造中将控制序列适当置于与DNA序列的编码序列相关位置使控制序列指导多肽的表达。
编码序列:文中应用时,术语“编码序列”欲覆盖核苷酸序列,其直接规定它的蛋白质产物的氨基酸序列。编码序列的边界一般通过通常以ATG起始密码子开始的可读框确定。编码序列一般包括DNA、cDNA及重组核苷酸序列。
表达:在本上下文中,术语“表达”包括多肽产生相关的任意步骤,包括但不限于转录、转录后修饰、翻译及翻译后修饰。优选表达也包含多肽的分泌。
表达载体:在本上下文中,术语“表达载体”覆盖线性或环状DNA分子,其包含编码本发明的多肽的节段且所述节段与提供它转录的额外节段有效连接。
宿主细胞:如文中应用的,术语“宿主细胞”包括用核酸构建体易于转化的任意细胞类型。
术语“多核苷酸探针”、“杂交”以及多种严格条件在标题为“具有抗微生物活性多肽”的节中进行定义。
详述
具有抗微生物活性的多肽
第一方面,本发明涉及具有抗微生物活性的多肽且其中所述多肽包含,优选由SEQ ID NO:1:G-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-Z中给出的氨基酸序列组成;其中X1=L、I、W或M;X2=L、F、W或V;X3=S、G、K、T、R、I、N、D或E;X4=K、T、F、I、R、M、L或S;X5=L或I;X6=K、G、R、M或E;X7=K、S、I、R、T或M;X8=A、K、T、N、R或E;X9=A、G、S、I、L、T、V、M或W;X10=S、R、K或E;X11=K、M、R、H、I、N或T;X12=A、V、I、L、Y、F或T;X13=L、A、G、C、F、V或W;X14=K、Q、A、S、R或E;X15=H、G、N、R、S、M、I、V或D;X16=V、I、A或F;Z=X17或X17-R-W-L;其中X17=F、L、R、A、G、V、Y、C或P;或其中所述多肽包含,优选由SEQ ID NO:1至SEQ IDNO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸组成。在一个令人感兴趣的实施方案中,所述氨基酸序列与SEQ ID NO:1至SEQ ID NO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸具有至多五个氨基酸(例如五个氨基酸),如至多四个氨基酸(例如四个氨基酸),例如至多三个氨基酸(例如三个氨基酸),特别是至多两个氨基酸(例如两个氨基酸),如一个氨基酸不同。
术语“SEQ ID NO:1至SEQ ID NO:37中的任意一项”欲表示SEQ IDNO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ IDNO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQID NO:36或SEQ ID NO:37。
术语“SEQ ID NO:38至SEQ ID NO:46中任意一项”欲表示SEQ IDNO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45或SEQ ID NO:46。
优选地,本发明的多肽包含SEQ ID NO:1至SEQ ID NO:46中任意一项的氨基酸序列;或其具有抗微生物活性的片段。在另一优选实施方案中,本发明的多肽包含SEQ ID NO:1至SEQ ID NO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸。在另一优选实施方案中,所述多肽由SEQ ID NO:1至SEQ IDNO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸组成。
组成本发明的多肽的氨基酸可独立地选自D型或L型。
本发明的多肽可为人工变体,与SEQ ID NO:1至SEQ ID NO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸相比,所述人工变体包含,优选由具有至多三个,例如至多两个,如至多一个氨基酸替代、缺失和/或插入的氨基酸序列组成。此类人工变体可通过本领域已知的标准技术构建,如通过定点/随机诱变包含SEQ ID NO:1至SEQ ID NO:37中任意一项的1至18位氨基酸或SEQID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸显示的氨基酸序列的多肽来构建。在本发明的一个实施方案中,氨基酸变化较小,即为不显著影响蛋白质折叠和/或活性的保守性氨基酸替代;一般为一个至约5个氨基酸的小缺失;小氨基或羧基端延伸,如氨基端甲硫氨酸残基;多达约10-25个残基的小连接肽;或通过改变净电荷或另一功能如多组氨酸道(tract)、抗原表位或结合结构域有助于纯化的小延伸。
保守性替代的实例在碱性氨基酸(精氨酸、赖氨酸及组氨酸)、酸性氨基酸(谷氨酸及天冬氨酸)、极性氨基酸(谷氨酰胺及天冬酰胺)、疏水性氨基酸(亮氨酸、异亮氨酸、缬氨酸及甲硫氨酸)、芳香族氨基酸(苯丙氨酸、色氨酸及酪氨酸)及小氨基酸(甘氨酸、丙氨酸、丝氨酸及苏氨酸)中。一般不改变比活的氨基酸替代是本领域已知的且例如通过H.Neurath和R.L.Hill,1979,在The Proteins,Academic Press,纽约一书中描述。最通常发生的交换为Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Tyr/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu及Asp/Gly以及这些颠倒过来。
在本发明的一个令人感兴趣的实施方案中,氨基酸的改变为多肽理化性质改变的性质。例如可进行改善多肽热稳定性、改变底物特异性、改变最适pH等等的氨基酸改变。
另一方面,本发明涉及具有抗微生物活性的多肽,其由18或19个氨基酸组成和通过氨基酸序列R-W-L延伸的氨基酸组成。在一个实施方案中,所述氨基酸序列由18个氨基酸组成。在另一实施方案中,所述氨基酸序列的第一个氨基酸是甘氨酸。
N端延伸
本发明多肽的N端延伸可适宜地由1至50个氨基酸,优选2-20个氨基酸,特别是3-15个氨基酸组成。在一个实施方案中N端肽延伸不含有Arg(R)。在另一实施方案中N端延伸包含如以下进一步定义的kex2或kex2样切割位点。在优选的实施方案中N端延伸为包含至少两个Glu(E)和/或Asp(D)氨基酸残基的肽,如包含以下序列:EAE、EE、DE及DD之一的N端延伸。
Kex 2位点
Kex2位点(参见,例如,D.Goeddel编辑的Methods in Enzymology第185卷,Academic Press Inc.(1990),San Diego,CA,“Gene ExpressionTechnology”一书)及Kex2样位点为一些蛋白质的前肽编码区及成熟区之间发现的双碱性识别位点(即,切割位点)。
在某些情况中显示插入kex2位点或kex2样位点改善在前肽切割位点的正确内肽酶加工,导致蛋白质分泌水平增加。
在本发明上下文中,插入kex2或kex2样位点导致N端延伸中某位置获得切割的可能性,导致与SEQ ID NO:1至SEQ ID NO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸所示的成熟多肽相比延伸的抗微生物多肽。
融合多肽
本发明的多肽也包括融合多肽或可切割融合多肽,所述融合多肽或可切割融合多肽中另一多肽与本发明的多肽或其片段的N端或C端融合。融合多肽通过编码另一多肽的核苷酸序列(或其部分)与本发明的核苷酸序列(或其部分)融合产生。用于产生融合多肽的技术是本领域已知的,且包括连接编码多肽的编码序列以使它们在框内且融合多肽的表达处于相同启动子及终止子的控制下。
多核苷酸及核苷酸序列
本发明还涉及具有编码本发明的多肽的核苷酸序列的多核苷酸。特别地,本发明涉及由编码本发明的多肽核苷酸序列组成的多核苷酸。由于遗传密码的简并性,本领域技术人员易于认识到可以制备编码本发明的每种多肽的一些核苷酸序列。本领域公知哪些核苷酸组成编码本发明的多肽的氨基酸的密码子。
本发明还涉及编码具有抗微生物活性的SEQ ID NO:1至SEQ IDNO:46中任意一项所示氨基酸序列的片段的多核苷酸。多核苷酸的子序列为其中自5’和/或3’端缺失一个或多个核苷酸的核苷酸序列。
核苷酸序列可通过遗传工程中应用的标准克隆方法获得以将核苷酸序列自一个位置至一个不同位点重新定位,所述核苷酸序列在所述不同位点复制。克隆方法可包含切割及分离包含编码所述多肽的核苷酸序列的目的片段,将该片段插入载体分子及将重组载体整合到宿主细胞,在宿主细胞中所述核苷酸序列的多个拷贝或克隆将进行复制。核苷酸序列可为基因组的、半合成、合成来源的或其任意组合。
编码本发明的多肽的核苷酸序列的修饰对于包含氨基酸序列的多肽合成可能是必需的,所述氨基酸序列与SEQ ID NO:1至SEQ ID NO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ ID NO:46中任意一项的1至21位氨基酸相比,具有至少一个替代、缺失和/或插入。这些人工变体与分离自天然来源的多肽在一些工程方法上不同,例如在比活、热稳定性、最适pH等等中不同的变体。
此类修饰可在对分子功能关键的区域外产生且仍然产生活性多肽对本领域技术人员是显然的。本发明的核苷酸序列编码多肽的活性必需并因此优选不进行修饰,如替代的氨基酸残基可根据本领域已知方法如定点诱变或丙氨酸扫描诱变(参见,例如,Cunningham和Wells,1989,Science 244:1081-1085)进行鉴定。在丙氨酸扫描诱变技术中,在分子的每个正电荷残基上导入突变,对产生的突变分子进行抗微生物活性检测以鉴定对分子活性重要的氨基酸残基。如通过技术如核磁共振分析、晶体学或光亲和标记法(参见,例如,de Vos等人,1992,Science 255:306-312;Smith等人,1992,Journal of Molecular Biology 224:899-904;Wlodaver等人,1992,FEBS Letters 309:59-64)确定的三维结构的分析也可确定底物-酶相互作用位点。
此外,编码本发明的多肽的核苷酸序列可通过导入核苷酸替代进行修饰,所述核苷酸替代不产生核苷酸序列编码的多肽的另一氨基酸序列,但与欲用于产生所述酶的宿主生物体的密码子选择对应。
将突变导入核苷酸序列以将核苷酸改变为另一核苷酸可通过定点诱变完成,使用本领域已知方法中的任意一种。特别有用的为利用具有目的插入片段的超螺旋、双链DNA载体及含有目的突变的两种合成引物的方法。每种与载体的相反链互补的寡核苷酸引物通过Pfu DNA聚合酶在温度循环期间延伸。整合引物后,产生含有交错切口的经突变质粒。温度循环后,将产物用对甲基化及半甲基化DNA特异的Dpnl处理以消化亲代DNA模板并选择包含突变的经合成DNA。也可用本领域已知的其它方法。对核苷酸替代的一般性描述,参见例如Ford等人,1991,Protein Expression andPurification 2:95-107一书。
核酸构建体
本发明还涉及包含本发明的核苷酸序列的核酸构建体,所述核苷酸序列有效连接一种或多种控制序列,所述控制序列在合适宿主细胞中在与控制序列相容条件下指导编码序列的表达。
对编码本发明多肽的核苷酸序列可以多种方式进行操作以提供多肽的表达。取决于表达载体,插入载体前对核苷酸序列的操作可以是所希望的或必需的。用重组DNA方法修饰核苷酸序列的技术是本领域公知的。
控制序列可为适当的启动子序列,所述启动子序列为通过宿主细胞识别用于核苷酸序列的表达的核苷酸序列。启动子序列含有介导多肽表达的转录控制序列。启动子可为在选择的宿主细胞中显示转录活性的任意核苷酸序列,包括突变、截短及杂合启动子,且可自与宿主细胞同源或异源的编码细胞外或细胞内多肽的基因获得。
用于指导本发明的核酸构建体转录,特别是在细菌宿主细胞中转录的合适启动子的实例为获自大肠杆菌lac操纵子、天蓝色链霉菌(Streptomyces coelicolor)琼脂糖酶基因(dagA)、枯草芽孢杆菌(Bacillussubtilis)果聚糖蔗糖酶基因(sacB)、地衣芽孢杆菌(Bacillus licheniformis)α淀粉酶基因(amyL)、嗜热脂肪芽孢杆菌麦芽糖淀粉酶基因(amyM)、解淀粉芽孢杆菌α-淀粉酶基因(amyQ)、地衣芽孢杆菌青霉素酶基因(penP)、枯草芽孢杆菌xylA和xylB基因和原核β-内酰胺酶基因(Villa-Kamaroff等人,1978,Proceedings of the National Academy ofSciences USA 75:3727-3731)的启动子,以及tac启动子(DeBoer等人,1983,Proceedings of the National Academy of Sciences USA 80:21-25)的启动子。更多启动子在“Useful proteins from recombinant bacteria”inScientific American,1980,242:74-94一书中以及在Sambrook等人,1989,同上一书中描述。
用于指导在丝状真菌宿主细胞中本发明的核酸构建体的转录的适宜的启动子的实例为得自以下的启动子:米曲霉TAKA淀粉酶、Rhiomucor miehei天冬氨酸蛋白酶、黑曲霉中性α-淀粉酶、黑曲霉酸稳定α-淀粉酶、黑曲霉或泡盛曲霉葡糖淀粉酶(glaA)、Rhiomucor miehei脂肪酶、米曲霉碱性蛋白酶、米曲霉丙糖磷酸异构酶、构巢曲霉乙酰胺酶和尖孢镰孢胰蛋白酶样蛋白酶(WO 96/00787),以及Na2-tpi启动子(来自黑曲霉中性α-淀粉酶和米曲霉丙糖磷酸异构酶基因的启动子的杂合体)和它们的突变体、截短和杂合启动子。
在酵母宿主中,有用启动子得自以下来源的基因:酿酒酵母烯醇化酶(ENO-1)、酿酒酵母半乳糖激酶(GAL1)、酿酒酵母醇脱氢酶/甘油醛-3-磷酸脱氢酶(ADH2/GAP)和酿酒酵母3-磷酸甘油酸激酶。其它酵母宿主细胞的有用启动子如Romanos等人,1992,酵母(Yeast)8:423-488所述。
所述控制序列还可以是一种适宜的转录终止子序列,其为由宿主细胞识别用于终止转录的序列。终止子序列有效连接到编码所述多肽的核苷酸序列的3’末端。任何在所选择的宿主细胞中发挥功能的终止子可以用于本发明。
优选的用于丝状真菌宿主细胞的终止子得自以下来源的基因:米曲霉TAKA淀粉酶、黑曲霉葡糖淀粉酶、构巢曲霉氨基苯甲酸合酶、黑曲霉α-葡糖苷酶和尖孢镰孢胰蛋白酶样蛋白酶。
优选的酵母宿主细胞终止子得自以下来源的基因:酿酒酵母烯醇化酶、酿酒酵母细胞色素C(CYC1)和酿酒酵母甘油醛-3-磷酸脱氢酶。Romanos等人,1992,上文,描述了其它有用的酵母宿主细胞的终止子。
所述控制序列还可以是适宜的先导序列,为对宿主细胞翻译重要的mRNA非翻译区。所述先导序列有效连接到编码多肽的核苷酸序列的5’末端。任何在所选择的宿主细胞内发挥功能的先导序列可以用于本发明。
优选的用于丝状真菌宿主细胞的先导序列得自以下来源的基因:米曲霉TAKA淀粉酶和构巢曲霉丙糖磷酸异构酶。
适宜的酵母宿主细胞先导序列得自以下来源的基因:酿酒酵母烯醇化酶(ENO-1)、酿酒酵母3-磷酸甘油酸激酶、酿酒酵母α-因子和酿酒酵母醇脱氢酶/甘油醛-3-磷酸脱氢酶(ADH2/GAP)。
所述控制序列还可以是聚腺苷酸化序列,该序列有效连接到核苷酸序列的3’末端且在转录时被宿主细胞识别为一种将聚腺苷残基加至被转录的mRNA的信号的序列。任何在所选择的宿主细胞中发挥功能的聚腺苷酸化序列可以用于本发明。
优选的用于丝状真菌宿主细胞的聚腺苷酸化序列得自以下来源的基因:米曲霉TAKA淀粉酶、黑曲霉葡糖淀粉酶、构巢曲霉氨基苯甲酸合酶、尖孢镰孢胰蛋白酶样蛋白酶和黑曲霉α-葡糖苷酶。
酵母宿主细胞的有用的聚腺苷酸化序列如由Guo和Sherman,1995,分子细胞生物学(Molecular Cellular Biology)15:5983-5990所描述。
所述的控制序列还可以是信号肽编码区,其编码连接到多肽的氨基末端的氨基酸序列并指导所编码的多肽进入细胞分泌途径。所述核苷酸序列的编码序列的5’端本身可以包含一个天然连接在具有编码所分泌的多肽的编码区节段的翻译读框上的信号肽编码区。可选择地,所述编码序列的5’端可以包含此编码序列的外源信号肽编码区。当所述的编码序列并不天然包含一个信号肽编码区时,可能需要外源信号肽编码区。可选择地,所述的天然信号肽编码区可用外源信号肽编码区简单替换以促进多肽的分泌。但任何可指导所表达的多肽进入所选择的宿主细胞的分泌途径的信号肽编码区均可用于本发明。
细菌宿主细胞的有效信号肽编码区是得自以下来源的基因的信号肽编码区:芽孢杆菌属NCIB 11837麦芽糖淀粉酶、嗜热脂肪芽孢杆菌α-淀粉酶、地衣芽孢杆菌枯草杆菌蛋白酶、地衣芽孢杆菌β-内酰胺酶、嗜热脂肪芽孢杆菌中性蛋白酶(nprT、nprS、nprM)和枯草芽孢杆菌prsA。其它的信号肽如在以下文献中所述:Simonen和Palva,1993,微生物学评论(Microbiological Reviews)57:109-137。
丝状真菌宿主细胞的有效信号肽编码区是得自以下基因的信号肽编码区:米曲霉TAKA淀粉酶、黑曲霉中性淀粉酶、黑曲霉葡糖淀粉酶、Rhizomucor miehei天冬氨酸蛋白酶、Humicola insolens纤维素酶和Humicola lanuginosa脂肪酶。
酵母宿主细胞的有用信号肽得自以下来源的基因:酿酒酵母α-因子和酿酒酵母转化酶。Romanos等人,1992,上文,描述了其它有用的信号肽编码区。
所述控制序列还可以是编码位于多肽氨基末端的氨基酸序列的前肽编码区。所得的多肽已知是一种酶原或前多肽(或在某些情况下为酶原)。前多肽一般没有活性,并可以通过催化切割或自身催化切割来自前多肽的前肽而转化为成熟的活性多肽。所述的前肽编码区可以得自以下来源的基因:枯草芽孢杆菌碱性蛋白酶(aprE)、枯草芽孢杆菌中性蛋白酶(nprT)、酿酒酵母α-因子、Rhizomucor miehei天冬氨酸蛋白酶和嗜热毁丝霉漆酶(WO 95/33836)。
当在多肽的氨基末端存在信号肽和前肽区两者时,所述的前肽区与多肽的氨基末端相邻,所述的信号肽区与所述前肽区的氨基末端相邻。
加入对与宿主细胞生长相关的多肽的表达进行调节的控制序列也是有利的。那些调控系统的实例是其对化学或物理刺激物(包括存在的调节化合物)的应答可以使得基因的表达被开启或关闭的系统。原核系统中的调控系统包括lac、tac和trp操纵子系统。在酵母中,可以使用ADH2系统或GAL1系统。在丝状真菌中,TAKAα-淀粉酶启动子、黑曲霉葡糖淀粉酶启动子和米曲霉葡糖淀粉酶启动子可以用作控制序列。控制序列的其它实例为允许基因扩增的控制序列。在真核系统中,它们包括在甲氨蝶呤存在下扩增的二氢叶酸还原酶基因和用重金属扩增的金属硫蛋白基因。在这些情况下,编码多肽的核苷酸序列与控制序列有效连接。
表达载体
本发明还涉及包含本发明的核酸构建体的重组表达载体。以上描述的多种核苷酸及控制序列可连在一起以产生重组表达载体,所述重组表达载体可包括一个或多个方便的限制性位点以允许编码所述多肽的核苷酸序列在这些位点的插入或替代。备选地,本发明的核苷酸序列可通过将核苷酸序列或包含该序列的核酸构建体插入到用于表达的适当载体进行表达。在产生表达载体时,将编码序列置于载体中以使编码序列与适当控制序列有效连接用于表达。
重组表达载体可为任意载体(例如,质粒或病毒),所述任意载体可方便进行重组DNA方法且可以引起核苷酸序列的表达。载体的选择一般取决于载体与将导入载体的宿主细胞的相容性。载体可为线性或闭合环状质粒。
载体可为自主复制载体,即作为染色体外实体存在的载体,其复制不依赖于染色体复制,例如,质粒、染色体外元件、微型染色体或人工染色体。
载体可包含用于确保自身复制的任意方式。备选地,载体可为这种载体,当其导入到宿主细胞时,与基因组整合且与其整合的染色体一起复制。此外,可应用一种载体或质粒或一起含有欲导入到宿主细胞基因组中总DNA的两种或多种载体或质粒或转座子。
本发明的载体优选含有一个或多个允许易于选择经转化细胞的选择标记。选择标记为基因,其产物提供杀生物或病毒抗性、重金属抗性、营养缺陷体原养型等等。
细菌选择标记的实例为来自枯草芽孢杆菌或地衣芽孢杆菌的da1基因,或赋予抗生素抗性如氨苄青霉素、卡那霉素、氯霉素或四环素抗性的标记。用于酵母宿主细胞的合适标记为ADE2、HIS3、LEU2、LYS2、MET3、TRP1及URA3。用于在丝状真菌宿主细胞中应用的选择标记包括但不限于amdS(乙酰胺酶)、argB(鸟氨酸氨甲酰转移酶)、bar(膦丝菌素乙酰转移酶)、hygB(潮霉素磷酸转移酶)、niaD(硝酸还原酶)、pyrG(乳清酸核苷-5’-磷酸脱羧酶)、sC(硫酸腺苷酰转移酶)、trpC(邻氨基苯甲酸合酶)以及其等同物。
优选在曲霉细胞中应用的为构巢曲霉或米曲霉的amdS及pyrG基因及吸水链霉菌(Streptomyces hygroscopicus)的bar基因。
本发明的载体优选含有允许将载体稳定整合到宿主细胞基因组中或不依赖于基因组在细胞的载体中自主复制的元件。
对于整合到宿主细胞基因组中,载体可依赖于编码多肽的核苷酸序列或载体任意其它元件用于通过同源或非同源重组将载体稳定整合到基因组中。备选地,载体可含有额外核苷酸序列用于通过同源重组指导整合到宿主细胞基因组中。额外核苷酸能使载体整合到宿主细胞基因组中染色体中的精确位置。为了增加在精确位置整合的可能性,整合元件优选含有足够数量的核苷酸,如100至1,500个碱基对,优选400至1,500个碱基对,且最优选800至1,500个碱基对,所述碱基对与对应的靶序列高度同源以增强同源重组的可能性。整合元件可为与宿主细胞基因组中靶序列同源的任意序列。此外,整合元件可为非编码或编码核苷酸序列。另一方面,载体可通过非同源重组整合到宿主细胞基因组中。
对于自主复制,载体可进一步包含能使载体在所述宿主细胞中自主复制的复制起点。细菌复制起点的实例为允许在大肠杆菌中复制的质粒pBR322、pUC19、pACYC177及pACYC184及允许在芽孢杆菌中复制的pUB110、pE194、pTA1060及pAMβ1的复制起点。用于在酵母宿主细胞中应用的复制起点实例为2微米复制起点、ARS1、ARS4,ARS1与CEN3的组合以及ARS4与CEN6的组合。复制起点可为具有突变的复制起点,所述突变使得所述复制起点宿主细胞中具有功能性温度敏感(参见,例如,Ehrlich,1978,Proceedings of the National Academy of Sciences USA 75:1433)。
可将一个以上拷贝的本发明核苷酸序列插入到宿主细胞以增加基因产物的产生。核苷酸序列拷贝数的增加可通过将至少一个额外拷贝的序列整合到宿主细胞基因组获得,或者通过所述核苷酸序列包括可扩增的选择标记基因,其中细胞含有选择标记基因的经扩增的拷贝,因此通过在存在适当选择试剂时培养细胞以选择核苷酸序列的额外拷贝可以获得核苷酸序列拷贝数的增加。
用于连接以上的描述元件以构建本发明的重组表达载体的方法对本领域技术人员是公知的(参见,例如,Sambrook等人,1989,同上)。
宿主细胞
本发明还涉及包含本发明的核酸构建体的重组宿主细胞,所述核酸构建体有益地在多肽重组产生中应用。将包含本发明的核苷酸序列的载体导入到宿主细胞中使载体作为染色体整合体或作为如以前描述的自身复制染色体外载体保持。
宿主细胞可为单细胞微生物例如,原核细胞或非单细胞微生物,例如真核细胞。
有用的单细胞细胞为细菌细胞如革兰氏阳性细菌,包括但不限于芽孢杆菌细胞,例如,嗜碱芽孢杆菌(Bacillus alkalophilus)、短芽孢杆菌(Bacillus brevis)、环状芽孢杆菌(Bacillus circulans)、克劳氏芽孢杆菌(Bacillus clausii)、凝结芽孢杆菌(Bacillus coagulans)、灿烂芽孢杆菌(Bacillus lautus)、迟缓芽孢杆菌(Bacillus lentus)、地衣芽孢杆菌、巨大芽孢杆菌(Bacillus megaterium)、嗜热脂肪芽孢杆菌、枯草芽孢杆菌及苏云金芽孢杆菌(Bacillus thuringiensis);或链霉菌细胞,例如,变铅青链霉菌(Streptomyces lividans)或鼠灰链霉菌(Streptomyces murinus),或革兰氏阴性细菌如大肠杆菌及假单胞菌种。在优选的实施方案中,细菌宿主细胞为迟缓芽孢杆菌、地衣芽孢杆菌、嗜热脂肪芽孢杆菌或枯草芽孢杆菌细胞。在另一优选的实施方案中,芽孢杆菌细胞为嗜碱芽孢杆菌。
将载体导入细菌宿主细胞中可通过例如,原生质体转化(参见,例如,Chang和Cohen,1979,Molecular General Genetics 168:111-115)、用感受态细胞(参见,例如,Young和Spizizin,1961,Journal of Bacteriology81:823-829,或Dubnau和Davidoff-Abelson,1971,Journal of MolecularBiology 56:209-221)、电穿孔(参见,例如,Shigekawa和Dower,1988,Biotechniques 6:742-751)或接合(参见,例如,Koehler和Thorne,1987,Journal of Bacteriology 169:5771-5278)进行。
宿主细胞可为真核细胞,如哺乳动物、昆虫、植物或真菌细胞。
在优选的实施方案中,宿主细胞为真菌细胞。如文中应用的“真菌”包括子囊菌门(Ascomycota)、担子菌门(Basidiomycota)、壶菌门(Chytridiomycota)及接合菌门(Zygomycota)(如通过Hawksworth等人,在Ainswoffh and Bisby′s Dictionary of The Fungi,第8版,1995,CAB International,University Press,Cambridge,英国一书中定义的)以及卵菌门(Oomycota)(如在Hawksworth等人,1995,同上,第171页一书中引用的)及所有有丝分裂孢子真菌(Hawksworth等人,1995,同上)。
在更优选的实施方案中,真菌宿主细胞是酵母细胞。文中所用“酵母”包括产子囊孢子酵母(内孢霉目)、产担子孢子酵母和属于半知菌的酵母(芽孢纲)。因为酵母的分类在将来可以改变,所以对于本发明,酵母将如Biology and Activities of Yeast(Skinner,F.A.,Passmore,S.M.,和Davenport,R.R.,编者,Soc.App.Bacterio1.Symposium Series No.9,1980)所描述的定义。
在优选实施方案中,酵母宿主细胞是假丝酵母属(Candida)、汉逊酵母属(Hansenula)、克鲁维酵母属(Kluyveromyces)、毕赤酵母属(Pichia)、酵母属(Saccharomyces)、裂殖酵母属(Schizosaccharomyces)或Yarrowia细胞。
在最优选的实施方案中,酵母宿主细胞是卡氏酵母(Saccharomycescarlsbergensis)、酿酒酵母(Saccharomyces cerevisiae)、糖化酵母(Saccharomyces diastaticus)、Saccharomyces douglasii、可鲁弗酵母(Saccharomyces kluyveri)、诺地酵母(Saccharomyces norbensis)或卵形糖酵母(Saccharomyces oviformis)细胞。在另一最优选的实施方案中,酵母宿主细胞是乳酸克鲁维酵母(Kluyveromyces lactis)细胞。在另一最优选的实施方案中,酵母宿主细胞是Yarrowia lipolytica细胞。
在另一优选实施方案中,真菌宿主细胞是丝状真菌细胞。“丝状真菌”包括真菌门和卵菌门亚门的所有丝状形式(如Hawksworth等人,1995,上文定义)。丝状真菌特征是由菌丝体壁,其由壳多糖、纤维素、葡聚糖、壳聚糖、甘露聚糖和其他复杂多糖组成。营养体生长是通过菌丝延长,碳代谢是专性需氧的。相比,酵母,如酿酒酵母的营养体生长是通过单细胞菌体的出芽,碳代谢是发酵的。
在甚至更优选的实施方案中,丝状真菌宿主细胞是但不限于,枝顶孢霉属(Acremonium)、曲霉属(Aspergillus)、镰孢属(Fusarium)、腐质霉属(Humicola)、毛霉(Mucor)、毁丝霉属(Myceliophthora)、链孢霉属(Neurospora)、青霉属(Penicillium)、草根霉菌属(Thielavia)、Tolypocladium或木霉属(Trichoderma)的细胞。
在最优选的实施方案中,丝状真菌宿主细胞是泡盛曲霉(Aspergillusawamori)、臭曲霉(Aspergillus foetidus)、日本曲霉(Aspergillusjaponicus)、构巢曲霉(Aspergillus nidulans)、黑曲霉(Aspergillus niger)或米曲霉(Aspergillus oryzae)细胞。在另一最优选的实施方案中,丝状真菌宿主细胞是杆孢状镰孢(Fusarium bactridioides)、Fusarium cerealis、Fusarium crookwellense、大刀镰孢(Fusarium culmorum)、禾谷镰孢(Fusarium graminearum)、禾赤镰孢(Fusarium graminum)、异孢镰孢(Fusarium heterosporium)、合欢木镰孢(Fusarium negundi)、尖孢镰孢(Fusarium oxysporum)、多枝镰孢(Fusarium reticulatum)、玫瑰色镰孢(Fusarium roseum)、接骨木镰孢(Fusarium sambucinum)、肤色镰孢(Fusarium sarcochroum)、拟分枝孢镰孢(Fusarium sporotrichioides)、硫色镰孢(Fusarium sulphureum)、Fusarium torulosum、Fusariumtrichothecioides或Fusarium venenatum细胞。在甚至最优选的实施方案中,丝状真菌亲本细胞是Fusarium venenatum(Nirenberg sp.nov.)。在另一最优选的实施方案中,丝状真菌宿主细胞是Humicola insolens、Humicolalanuginosa、米赫毛霉(Mucor miehei)、嗜热毁丝霉(Myceliophthorathermophila)、粗糙链孢霉(Neurospora crassa)、产紫青霉(Penicilliumpurpurogenum)、Thielavia terrestris、Trichoderma harzianum、康宁木霉(Trichoderma koningii)、Trichoderma longibrachiatum、Trichodermareesei或绿色木霉(Trichoderma viride)细胞。
通过一种本身已知方法可以转化真菌细胞,所述方法包括原生质体形成、转化原生质体和再生细胞壁。用于转化曲霉属宿主细胞的适宜的方法在EP 238 023和Yelton等人1984,Proceedings of the National Academy ofSciences USA 81:1470-1474中描述。用于转化镰孢属的适宜方法由Malardier等人,1989,Gene 78:147-156和WO 96/00787描述。使用Becker和Guarente,Abelson,J.N.和Simon,M.I.,编者,Guide to YeastGenetics and Molecular Biology,Methods in Enzymology,卷194,182-187页,Academic Press Inc.,New York;Ito等人,1983,Journal ofBacteriology 153:163;和Hinnen等人,1978,Proceedings of the NationalAcademy of Sciences USA 75:1920所描述的方法转化酵母。
产生方法
本发明还涉及用于产生本发明的多肽的方法,所述方法包含(a)在有益于产生所述多肽的条件下培养宿主细胞;及(b)回收所述多肽。
在本发明产生方法中,用本领域已知方法在适合于产生所述多肽的营养培养基中培养所述细胞。例如,可通过摇瓶培养、在实验室或工业发酵罐中小规模互大规模发酵(包括连续、分批、补料分批或固态发酵)在合适培养基中并在允许所述多肽表达和/或分离的条件下培养所述细胞。使用本领域已知方法,在包含碳源、氮源及无机盐的合适营养培养基中进行培养。合适培养基可以获自供应商或可根据已公开的组分(例如,在美国典型培养物保藏中心的目录中)制备。如果多肽分泌到营养培养基中,那么可直接自培养基中回收多肽。如果所述多肽不分泌,那么可自细胞裂解物中回收所述多肽。
可用对所述多肽特异的本领域已知方法检测所述多肽。这些检测方法可包括应用特异抗体、酶产物的形成或酶底物的消失。例如,酶测定法可用于确定如文中描述的多肽的活性。
所得多肽可通过本领域已知方法进行回收。例如,可通过常规方法自营养培养基中回收所述多肽,所述常规方法包括但不限于,离心、过滤、提取、喷雾干燥、蒸发或沉淀。
可通过本领域已知的多种方法纯化本发明的多肽,所述方法包括但不限于层析(例如,离子交换、亲和、疏水、层析聚焦及大小排阻)、电泳方法(例如,制备等电聚焦)、差别溶解性(例如,硫酸铵沉淀)、SDS-PAGE或提取(参见,例如,Protein Purification,J.-C.Janson和Lars Ryden编辑,VCH Publishers,纽约,1989)。
植物
本发明还涉及转基因植物、植物部分或植物细胞,所述转基因植物、植物部分或植物细胞用编码具有本发明的抗微生物活性多肽的核苷酸序列转化以表达及产生可回收量的多肽。可自植物或植物部分回收所述多肽。备选地,含有重组多肽的植物或植物部分可这样使用用于提高食品或饲料品质,例如提高营养价值、适口性、流变学性质或破坏抗营养因子。经回收多肽、植物或植物部分可用于改善或改变动物及家畜中的消化菌群。
转基因植物可为双子叶(双子叶植物)或单子叶(单子叶植物)。单子叶植物的实例为禾本科植物,如牧草(blue grass、Poa),饲料草如羊茅属(Festuca)、黑麦草属(Lolium),温带草如剪股颖属(Agrostis)及谷类,例如小麦、燕麦、黑麦、大麦、稻、高梁及玉米(玉蜀黍)。
双子叶植物的实例为烟草、马铃薯、甜菜,豆类如羽扇豆、豌豆、豆和大豆及十字花科植物(十字花科)如花椰菜、油菜籽及密切相关的模式生物拟南芥(Arabidopsis thaliana)。
植物部分的实例为茎、愈伤组织、叶、根、果实、种子及块茎。特定植物组织如叶绿体、质外体、线粒体、液泡、过氧化物酶体及细胞质也被考虑为植物部分。此外,任意植物细胞无论任意组织来源都被考虑为植物部分。
此类植物、植物部分及植物细胞的子代也包括在本发明范围内。
表达本发明的多肽的转基因植物或植物细胞可根据本领域已知方法进行构建。简而言之,通过将编码本发明的多肽的一个或多个表达构建体整合到植物宿主基因组并将产生的经修饰植物或植物细胞增殖成转基因植物或植物细胞构建植物或植物细胞。
方便地,表达构建体为核酸构建体,所述核酸构建体包含编码本发明多肽的核苷酸序列,其与在所选植物或植物部分中表达所述核苷酸序列所需的适当调节序列有效连接。此外,表达构建体可包含用于鉴定表达构建体已经整合的宿主细胞的选择标记及用于将构建体导入所述植物中必需的DNA序列(所述DNA序列取决于应用的DNA导入方法)。
调节序列如启动子及终止序列及任选的信号或转运序列的选择例如在希望多肽何时、在哪里及怎样进行表达的基础上进行鉴定。例如,编码本发明多肽的基因的表达可为组成型或诱导型,或可为发育、阶段或组织特异的,且基因产物可靶向特定组织或植物部分如种子或叶。例如Tague等人,1988,Plant Physiology 86:506描述了调节序列。
对于组成型表达,可应用35S-CaMV启动子(Franck等人,1980,Cell 21:285-294)。器官特异启动子可为,例如来自储存库(sink)组织如种子、马铃薯块茎及果实(Edwards和Coruzzi,1990,Ann.Rev.Genet.24:275-303)或来自代谢库组织如分生组织(Ito等人,1994,Plant Mol.Biol.24:863-878)的启动子,种子特异启动子如来自稻的谷蛋白、谷醇溶蛋白、球蛋白或白蛋白启动子(Wu等人,1998,Plant and Cell Physiology 39:885-889)、来自蚕豆的豆球蛋白B4及未知种子蛋白质基因的蚕豆(Viciafaba)启动子(Conrad等人,1998,Journal of Plant Physiology 152:708-711)、来自种子油体蛋白质的启动子(Chen等人,1998,Plant and CellPhysiology 39:935-941)、来自欧洲油菜(Brassica napus)储藏蛋白质的napA启动子或本领域已知的任意其它特异启动子,例如在WO91/14772中描述。此外,启动子可为叶特异启动子,如来自稻或番茄的rbcs启动子(Kyozuka等人,1993,Plant Physiology 102:991-1000)、小球藻病毒腺嘌呤甲基转移酶基因启动子(Mitra和Higgins,1994,Plant MolecularBiology 26:85-93)或来自稻的aldP基因启动子(Kagaya等人,1995,Molecular and General Genetics 248:668-674)或创伤诱导型启动子,如马铃薯pin2启动子(Xu等人,1993,Plant Molecular Biology 22:573-588)。
也可应用启动子增强子元件以获得在植物中所述酶的较高表达。例如,启动子增强子元件可为置于启动子和编码本发明多肽的核苷酸序列之间的内含子。例如,Xu等人,1993,同上公开了应用稻肌动蛋白1基因的第一个内含子以增强表达。
选择标记基因及表达构建体的任意其它部分可自本领域可获得的选择标记基因及表达构建体中选择。
根据本领域已知的常规技术,将核酸构建体整合到植物基因组中,所述技术包括农杆菌介导的转化、病毒介导的转化、显微注射、粒子轰击、生物射弹转化及电穿孔(Gasser等人,1990,Science 244:1993;Potrykus,1990,Bio/Technology 8:535;Shimamoto等人,1989,Nature 338:274)。
当前,根癌农杆菌介导的基因转移是用于产生转基因双子叶植物的所选方法(对于综述,参见Hooykas和Schilperoort,1992,Plant MolecularBiology 19:15-38)。然而它也可用于转化单子叶植物,尽管对于这些植物一般优选其它转化方法。当前,用于产生转基因单子叶植物的所选方法为离子轰击(用转化DNA包裹的显微金或钨颗粒)胚胎胼胝体或正发育的胚胎(Christou,1992,Plant Journal 2:275-281;Shimamoto,1994,Current Opinion Biotechnology 5:158-162;Vasil等人,1992,Bio/Technology 10:667-674)。用于转化单子叶植物的备选方法基于如Omirulleh等人,1993,Plant Molecular Biology 21:415-428描述的原生质体转化。
转化后,根据本领域公知方法对其中整合表达构建体的转化体进行选择并再生成完整植物。
本发明还涉及用于产生本发明的多肽的方法,所述方法包含(a)在有益于产生所述多肽的条件下,培养包含编码具有本发明的抗微生物活性的多肽的核苷酸序列的转基因植物或植物细胞;和(b)回收所述多肽。
组合物
在又一方面,本发明涉及包含本发明的抗微生物多肽的组合物,如药物组合物。
组合物可包含本发明的多肽作为主要多肽组分,例如单组分组合物。备选地,组合物可包含多种酶活性,如氨肽酶、淀粉酶、糖酶、羧肽酶、过氧化氢酶、纤维素酶、壳多糖酶、角化酶(cutinase)、环糊精糖基转移酶、脱氧核糖核酸酶、酯酶、α-半乳糖苷酶、β-半乳糖苷酶、葡糖淀粉酶、α-葡糖苷酶、β-葡糖苷酶、卤过氧化物酶(haloperoxidase)、转化酶、漆酶、脂肪酶、甘露糖苷酶、氧化酶、果胶分解酶、肽谷氨酰胺酶、过氧化物酶、植酸酶、多酚氧化酶、蛋白水解酶、核糖核酸酶、转谷氨酰胺酶或木聚糖酶。
所述组合物可还包含另一种药学活性剂,如额外的杀生物剂,如以上定义显示抗微生物活性的另一抗微生物多肽。如本领域已知的,杀生物剂可为抗生素。抗生素类型包括青霉素,例如青霉素G、青霉素V、二甲氧基苯青霉素、苯唑青霉素、羧苄青霉素、乙氧萘青霉素、氨苄青霉素等;青霉素与β-内酰胺酶抑制剂的组合,头孢菌素,例如,头孢克洛、头孢唑啉、头孢氨呋肟、拉氧头孢等;碳青霉烯类(carbapenems);单环内酰胺;氨基糖苷类;四环素类;大环内酯类;林可霉素类;多粘菌素类;磺胺类;喹诺酮类(quinolones);氯霉素;甲硝唑;壮观霉素、甲氧苄啶、万古霉素等。杀生物剂也可为抗真菌剂,包括多烯,例如两性霉素B、制霉菌素;5-flucosyn及吡咯类,例如咪康唑、酮康唑、伊曲康唑及氟康唑。
在一个实施方案中,杀生物剂为非酶化学剂。在另一实施方案中杀生物剂为非多肽化学剂。
在杀生物剂的25%(w/w)水溶液中,优选在10%(w/w)水溶液中;更优选在5%(w/w)水溶液中;甚至更优选在1%(w/w)水溶液中;最优选在0.5%(w/w)水溶液中;且特别是在0.1%(w/w)水溶液中于20℃孵育8小时后(优选4小时后,更优选2小时后,最优选1小时后,且特别是30分钟后),杀生物剂能够降低大肠杆菌(DSM 1576)活细胞数至1/100。
在微生物生长培养基中,当加入1000ppm浓度;优选加入500ppm浓度;更优选加入250ppm浓度;甚至更优选当加入100ppm浓度;最优选加入50ppm浓度;且特别是加入25ppm浓度杀生物剂时,于25℃作用24小时,所述杀生物剂也能够抑制大肠杆菌(DSM 1576)生长晕。
在杀生物剂的25%(w/w)水溶液中,优选在10%(w/w)水溶液中;更优选在5%(w/w)水溶液中;甚至更优选在1%(w/w)水溶液中;最优选在0.5%(w/w)水溶液中;且特别是在0.1%(w/w)水溶液中于20℃孵育8小时后(优选4小时后,更优选2小时后,最优选1小时后,且特别是30分钟后),杀生物剂能够降低枯草芽孢杆菌(ATCC 6633)活细胞数至1/100。
在微生物生长培养基中,当加入1000ppm浓度;优选加入500ppm浓度;更优选加入250ppm浓度;甚至更优选加入100ppm浓度;最优选加入50ppm浓度;且特别是加入25ppm浓度杀生物剂时,于25℃作用24小时,所述杀生物剂也能够抑制枯草芽孢杆菌(ATCC 6633)生长晕。
组合物可包含合适的载体材料。当组合物用作药物时,组合物也可包含能将本发明的抗微生物多肽递送到目的部位的合适递送载体。
组合物可根据本领域已知方法进行制备且可为液态或干燥组合物形式。例如,多肽组合物可为颗粒或微颗粒形式。组合物中包括的多肽可根据本领域已知方法进行稳定。
以下给出了本发明的多肽组合物优选用途的实例。本发明的多肽组合物的剂量及组合物应用的其它条件可基于本领域已知方法确定。
方法及用途
本发明还包含本发明的抗微生物多肽的多种用途。抗微生物多肽一般用于受细菌、真菌、酵母或藻类污染的任意部位。一般地,所述部位为水系统,如冷却水系统、洗衣冲洗水,油系统如切削油、润滑油、油田等等,需要杀死所述部位的微生物或控制它们的生长。然而,本发明也可用于已知抗微生物组合物有用的所有应用中,如木材、乳胶、粘合剂、胶水、纸、纸板、纺织品、皮革、塑料、堵塞材料及饲料的保护。
其它用途包括食品、饮料、化妆品如洗液、面霜、凝胶、油膏、肥皂、洗发剂、调节剂、止汗剂、除臭剂、漱口水、隐形眼镜制品、酶制剂或食品成分的保存。
因此,本发明的抗微生物多肽可作为消毒剂用于例如治疗痤疮、眼或口中的感染、皮肤感染;止汗剂或防臭剂;足浴盐;用于隐形镜片、坚硬表面、牙齿(口腔护理)、创伤、擦伤等等的清洁及消毒。
大体上,可以考虑本发明的抗微生物多肽用于任意坚硬表面的清洁、消毒或抑制微生物生长。可与本发明的抗微生物多肽有益接触的表面的实例为,所用加工设备的表面,所述加工设备为例如乳制品、化学品或药物加工车间、水卫生系统、油加工车间、纸浆加工车间、水处理车间及冷却塔。本发明的抗微生物多肽应以对所述表面清洁、消毒或抑制微生物生长有效的量应用。
此外,设想本发明的抗微生物多肽可有益地在就地清洗(C.I.P.)系统中应用用于清洁任意种类加工设备。
本发明的抗微生物多肽又可用于在食品加工车间清洁表面及烹饪用具以及准备或提供食品的任意区域,如医院、疗养院、饭店,特别是快餐店、熟食店等等。在食品制品中它也可作为抗微生物剂应用且特别用于奶酪、水果及蔬菜以及色拉棒上食品的表面抗微生物剂。
所述多肽也可在基于水的油漆中用作防腐剂或消毒剂。
本发明的抗微生物多肽也用于水位线的微生物控制,和用于水的消毒,特别用于工业水的消毒。
本发明还涉及本发明的抗微生物多肽或组合物作为药物的用途。此外,本发明的抗微生物多肽或组合物也可用于制造药物用于控制或抗击微生物,如真菌生物或细菌,优选革兰氏阳性细菌。
本发明的组合物及抗微生物多肽可用作兽医用或者用于人的抗微生物治疗剂或预防剂。因此,本发明的组合物及抗微生物多肽可用于制备兽医用的或者用于人的治疗剂或预防剂用以治疗微生物感染,如细菌或真菌感染,优选革兰氏阳性细菌感染。特别地微生物感染可与肺病相关,所述肺病包括但不限于肺结核、肺炎及囊性纤维化以及治疗性传播疾病,包括但不限于淋病及衣原体。
本发明的组合物包含有效量的本发明的抗微生物多肽。
术语“有效量”在文中应用时欲表示包含足可抑制所述微生物生长的所述抗微生物多肽或其片段或变体的量,所述多肽包含SEQ ID NO:1至SEQ ID NO:37中任意一项的1至18位氨基酸或SEQ ID NO:38至SEQ IDNO:46中任意一项的1至21位氨基酸显示的氨基酸序列。
本发明还涉及创伤愈合组合物或产物如绷带、医疗器具例如导管,还涉及抗头皮屑产品如洗发剂。
对遭受或易患微生物感染的宿主施用本发明的抗微生物多肽的制剂。取决于特异微生物,施用可为体表(topical)、局部(localized)或全身的,优选局部施用。大体上本发明的抗微生物多肽的剂量足可降低微生物群体到至少约50%,一般至少1/10,且可杀死至1/100或者以下。本发明的化合物以降低微生物群体而将任意副作用降到最小的剂量施用。设想得到并在医师的指导下体内使用所述组合物。本发明的抗微生物多肽特别用于杀死革兰氏阴性细菌,包括绿脓假单胞杆菌(Pseudomonas aeruginosa)和沙眼衣原体(Chlamydia trachomatis);及革兰氏阳性细菌,包括多种葡萄球菌(staphylococci)及链球菌(streptococci)。
本发明的抗微生物多肽也用于体外制剂以杀死微生物,特别是当不希望导入常规抗生素量时。例如,本发明的抗微生物多肽可加入到动物和/或人食物制品中;或它们可作为用于体外细胞培养的添加剂以防止组织培养中微生物的过度生长。
如在实验部分中详细说明的,特定微生物对用本发明的抗微生物多肽杀死的敏感性可通过体外检测确定。一般地微生物的培养物与抗微生物多肽以多种浓度组合作用足可使蛋白质作用一段时间,一般为约一小时到一天。然后对有活力微生物进行计数并确定杀死水平。
目的微生物包括但不限于,革兰氏阴性细菌,例如:柠檬酸细菌属(Citrobacter sp.);肠杆菌属(Enterobacter sp.);埃希杆菌属(Escherichiasp.),例如大肠杆菌;克雷伯杆菌属(Klebsiella sp.);摩根菌属(Morganellasp.);变形菌属(Proteus sp.);普罗威登斯菌属(Providencia sp.);沙门氏菌属(Salmonella sp.),例如伤寒沙门氏菌(S.typhi)、鼠伤寒沙门氏菌(S.typhimurium);沙雷氏菌属(Serratia sp.);志贺菌属(Shigellasp.);假单胞菌属(Pseudomonas sp.),例如铜绿假单胞菌(P.aeruginosa);耶尔森菌属(Yersinia sp.),例如鼠疫耶尔森菌(Y.pestis)、假结核耶尔森菌(Y.pseudotuberculosis)、结肠耶尔森菌(Y.enterocolitica);弗朗西丝菌属(Franciscella sp.);巴斯德氏菌属(Pasturella sp.);弧菌属(Vibrio sp.),例如霍乱弧菌(V.cholera)、副溶血弧菌(V.parahemolyticus);弯曲杆菌属(Campylobacter sp.),例如空肠弯曲菌(C.jejuni);嗜血杆菌属(Haemophilus sp.),例如流感嗜血杆菌(H.influenzae)、杜克雷嗜血杆菌(H.ducreyi);博德特氏菌属(Bordetellasp.),例如,百日咳博德特氏菌(B.pertussis)、支气管炎博德特氏菌(B.bronchiseptica)、副百日咳博德特氏菌(B.parapertussis);布鲁氏菌属(Brucella sp.);奈瑟氏球菌属(Neisseria sp.),例如淋病(gonorrhoeae)、脑膜炎奈瑟氏球菌(N.meningitidis)等。其它目的细菌包括军团杆菌属(Legionella sp.),例如嗜肺性军团杆菌(L.pneumophila);利斯特氏菌属(Listeria sp.),例如产单核细胞利斯特氏菌(L.monocytogenes);支原体属(Mycoplasma sp.),例如人支原体(M.hominis)、肺炎支原体(M.pneumoniae);分支杆菌属(Mycobacteriumsp.),例如结核分支杆菌(M.tuberculosis)、麻风分支杆菌(M.lepra);密螺旋体属(Treponema sp.),例如苍白密螺旋体(T.pallidum);疏螺旋体属(Borrelia sp.),例如伯氏疏螺旋体(B.burgdorferi);细螺旋体属(Leptospirae sp.);立克次体属(Rickettsia sp.),例如立克立克次体(R.rickettsii)、地方性斑疹伤寒立克次体(R.typhi);衣原体属(Chlamydia sp.),例如沙眼衣原体、肺炎衣原体(C.pneumoniae)、鹦鹉热衣原体(C.psittaci);螺旋杆菌属(Helicobacter sp.),例如幽门螺旋杆菌(H.pylori)等。
目的非细菌病原体包括真菌及原生动物病原体,例如疟原虫属(Plasmodia sp.),例如恶性疟原虫(P.falciparum);锥虫属(Trypanosomasp.),例如布氏锥虫(T.brucei);shistosomes;内阿米巴属(Entaemoebasp.);隐球菌属(Cryptococcus sp.);念珠菌属(Candida sp.),例如白色念珠菌(C.albicans);等等。
可应用多种施用方法。多肽制剂可经口、或静脉内注射、皮下注射、腹膜内注射,通过气溶胶、经眼、膀胱内施用、局部施用等。例如,通过吸入施用的方法是本领域公知的。取决于施用的特定抗微生物多肽、疾病性质、施用频率、施用方式、活性剂自宿主的清除等等,治疗制剂的剂量有很大程度变化。初始剂量可较大,接着是较小的维持剂量。剂量可不经常地每周或每两周进行施用,或分为较小剂量并每天、每半周等施用一次或几次以维持有效剂量水平。在许多情况下,经口施用比静脉内施用需要更高剂量。对于经口施用,可对酰胺键以及氨基及羧基端进行修饰以得到更大稳定性。例如,可对羧基端进行酰胺化。
剂型
本发明的化合物可掺入到多种剂型用于治疗性施用。更特别地,本发明的化合物可通过与适当可药用载体或稀释剂组合制成药物组合物,且可制成固体、半固体、液体或气体形式的制剂,如片剂、胶囊剂、粉剂、颗粒剂、软膏剂、乳膏、泡沫剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球、洗剂及气雾剂。如此,化合物的施用可以多种方式完成,包括经口、含服、经直肠、肠胃外、腹膜内、皮内、经皮、气管内等。本发明的抗微生物多肽在施用后可达到全身或可通过应用在植入部位保持活性剂量的植入物或其它剂型局部化。
在一个实施方案中,用于局部应用的剂型包含降低二价阳离子,特别是钙离子及镁离子有效浓度的螯合剂。例如,可包括试剂如柠檬酸盐、EGTA或EDTA,优选柠檬酸盐。柠檬酸盐的浓度一般自约1至10mM。
本发明的化合物可单独施用、互相组合施用,或它们可与其它已知化合物(例如,穿孔蛋白、消炎剂、抗生素等)组合应用。在药物剂型中,化合物可以它们可药用盐的形式施用。以下方法及赋型剂仅仅为示例性的并且绝非限制。
对于经口制剂,化合物可单独应用或与适当添加剂组合以制备片剂、粉剂、颗粒剂或胶囊剂,例如,与常规添加剂如乳糖、甘露醇、玉米淀粉或马铃薯淀粉;与粘合剂如晶体纤维素、纤维素衍生物、阿拉伯胶、玉米淀粉或明胶;与崩解剂如玉米淀粉、马铃薯淀粉或羧甲基纤维素钠;与润滑剂如滑石或硬脂酸镁;且根据需要,与稀释剂、缓冲剂、湿润剂、防腐剂及芳香剂组合应用。
通过将化合物在水性溶剂或非水溶剂如植物油或其它相似油,合成脂族酸甘油酯、高等脂族酸酯或丙二醇中溶解、悬浮或乳化,并且如果需要,使用常规添加剂如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂将所述化合物制成注射用制剂。
化合物可以以气雾剂剂型通过吸入施用进行应用。本发明的化合物可配制到可加压推进剂,如二氯二氟甲烷、丙烷、氮等等中。
化合物可通过与常规添加剂如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂及防腐剂制备作为例如以防止烧伤感染的洗剂应用。
此外,化合物可通过与多种基质如乳化基质或水溶性基质混合制成栓剂。本发明的化合物可通过栓剂经直肠施用。栓剂可包括在体温溶解,但在室温固化的载体如可可脂、碳蜡及聚乙二醇。
可提供用于经口或经直肠施用的单位剂型如糖浆剂、酏剂及混悬剂,其中每种剂量单位,例如一茶匙、一汤匙、片剂或栓剂含有预定量的组合物,其含有本发明的一种或多种化合物。相似地,用于注射或静脉内施用的单位剂型可包含组合物中的本发明化合物,所述组合物作为无菌水、生理盐水或另一可药用载体中的溶液剂。
用于持续释放剂型的植入物是本领域公知的。植入物与可生物降解或不可生物降解聚合物配制成微球体、厚片(slab)等。例如,乳酸和/或乙醇酸的聚合物形成宿主良好耐受的易蚀聚合物。将含有本发明的抗微生物多肽的植入物置于感染位置附近,使活性剂的局部浓度相对于身体的其余部位增加。
如文中应用的术语“单位剂型”是指适合用于人及动物受试者的单一剂量的物理上离散的单位,每个单位含有经计算与可药用稀释剂、载体或运载体(vehicle)联合足可产生目的作用的量的预定量的本发明化合物。用于本发明的单位剂型的说明书取决于应用的具体化合物及欲达到的效果和在宿主中与所述化合物相关的药物动力学。
可药用赋形剂如运载体、佐剂、载体或稀释剂对公众是易于获得的。此外,可药用辅助物质,如pH调节及缓冲剂、张力调节剂、稳定剂、湿润剂等等对公众是易于获得的。
用于全身施用的一般剂量为每次施用0.1pg至100微克/kg受试者体重。一般剂量可为每天服用两至六次,每次一粒片剂或每天服用一次一粒定时释放胶囊剂或一粒片剂且包含较高比例含量的活性成分。定时释放作用可通过在不同pH值溶解的胶囊剂材料、通过渗透压缓慢释放的胶囊剂或通过任意其它控制释放的已知方法获得。
本领域技术人员易于理解剂量水平可随特定化合物、症状的严重度及受试者对副作用的易感性而变化。一些特定化合物比其它化合物更强效。本领域技术人员通过多种方法易于确定给定化合物的优选剂量。优选方法为测定给定化合物的生理效能。
应用脂质体作为递送载体是一个令人感兴趣的方法。脂质体与靶位点的细胞融合并将腔内容物递送到细胞内。使用保持接触的多种方法,如分离、结合剂等等使脂质体保持接触细胞足够时间用于融合。在本发明一方面,将脂质体设计为气溶胶化用于肺部施用。可用介导膜融合的经纯化蛋白质或肽,如仙台病毒或流感病毒等制备脂质体。脂类可为已知形成脂质体的脂类,包括阳离子或两性离子脂类,如磷脂酰胆碱的任意有用组合。剩余脂类通常为中性或酸性脂类,如胆固醇、磷脂酰丝氨酸、磷脂酰甘油等等。
对于脂质体的制备,可应用Kato等人,(1991)J.Biol.Chem.266:3361描述的方法。简而言之,脂类及含有肽的腔组合物在适当水性介质中组合,所述水性介质方便地为盐水介质,其中总固体为约1-10重量百分比。短时间强烈搅拌约5-60秒后,将试管置于约25-40℃的温水浴中并将此循环重复约5-10次。然后将组合物进行超声处理一段方便时间,一般约1-10秒,并可进一步通过涡旋搅拌。然后通过加入水性介质将体积扩大,大体上增加体积约1-2倍,接着进行摇动及冷却。此方法使高分子量分子掺入到腔中。
与其它活性剂的剂型
对于用于主题方法中,本发明的抗微生物多肽可与其它药学活性剂,特别是其他抗微生物剂配制。如本领域已知的,其它目的活性剂包括多种抗生素。抗生素类型包括青霉素,例如,青霉素G、青霉素V、二甲氧基苯青霉素、苯唑青霉素、羧苄青霉素、乙氧萘青霉素、氨苄青霉素等;青霉素与β-内酰胺酶抑制剂的组合,头孢菌素,例如,头孢克洛、头孢唑啉、头孢氨呋肟、拉氧头孢等;碳青霉烯类;单菌霉素;氨基糖苷类;四环素类;大环内酯类;林可霉素类;多粘菌素类;磺胺类;喹诺酮类;氯霉素;甲硝唑;壮观霉素、甲氧苄啶;万古霉素;等。
抗真菌剂也是有用的,包括多烯,例如两性霉素B、制霉菌素;5-flucosyn及吡咯类,例如咪康唑、酮康唑、伊曲康唑及氟康唑。抗结核病药包括异烟肼、乙胺丁醇、链霉素及利福平。细胞因子也可以包括在本发明的抗微生物多肽剂型中,所述细胞因子为例如γ干扰素、肿瘤坏死因子α、白细胞介素12等。
体外合成
用如本领域已知的常规方法,可通过体外合成制备本发明的抗微生物多肽。多种商品化合成装置例如通过Applied BiosystemsInc.,Beckman的自动合成仪等是可获得的。通过用合成仪,可用非天然氨基酸,特别是D-异构体(或D-型)例如,D-丙氨酸及D-异亮氨酸、非对映异构体、具有不同长度或功能性的侧链等等替代天然存在氨基酸。特定序列及制备方式可由方便性、经济、所需纯度等等决定。
可为包含方便官能度的多种肽或蛋白质提供化学连接用于形成键,如氨基用于酰胺或取代胺形成,例如还原性胺化,巯基用于硫醚或二硫化物形成,羧基用于酰胺形成等等。
如果希望,在合成期间或表达期间,可将允许与其它分子或与表面连接的多种基团导入到肽中。因此,可用半胱氨酸制备硫醚、组氨酸用于连接金属离子络合物、羧基用于形成酰胺或酯、氨基用于形成酰胺等等。
也可根据重组合成的常规方法对多肽进行分离及纯化。可制备表达宿主的裂解物且用HPLC、排阻层析、凝胶电泳、亲和层析或其它纯化技术对裂解物进行纯化。对于大部分,相对于与产物制备方法及它的纯化相关的污染物,应用的组分占目的产物至少20%重量,更一般占至少约75%重量,优选至少约95%重量,并且对于治疗目的,一般占至少约99.5%重量。一般地,百分率基于总蛋白质。
动物饲料
本发明还涉及在动物饲料中使用具有抗微生物活性多肽的方法,还涉及包含本发明的抗微生物多肽的饲料组合物及饲料添加剂。
术语动物包括所有动物,包括人。动物的实例为非反刍动物及反刍动物,如牛、绵羊及马。在特定实施方案中,动物为非反刍动物。非反刍动物包括单胃动物,例如猪(包括但不限于小猪、成长猪及母猪);家禽如火鸡及鸡(包括但不限于适于烘烤小鸡、产蛋鸡);小牛;及鱼(包括但不限于鲑鱼)。
术语饲料或饲料组合物表示动物适合或欲用于动物摄取的任意化合物、制备物、混合物或组合物。
在根据本发明的用途中,抗微生物多肽可在膳食之前、之后或同时进行喂食,与膳食同时喂食是优选的。
在特定实施方案中,对加入到饲料中,或包括在饲料添加剂中的形式的抗微生物多肽进行了明确定义。明确定义表示抗微生物多肽制剂为至少50%纯,这可以如通过大小排阻层析(参见WO01/58275实施例12)确定。在另一特定实施方案中,如通过这个方法确定的,抗微生物多肽制剂至少60、70、80、85、88、90、92、94或至少95%纯。
明确定义的抗微生物多肽制剂是有益的。例如,向饲料中正确添加基本上不干扰或污染其它抗微生物多肽的抗微生物多肽是较容易的。术语正确添加特别是指获得一致及恒定结果的目的,和基于预期效果优化剂量的能力。
然后,对于在动物饲料中应用,抗微生物多肽不必那么纯;例如它可包括其它酶,在这种情况下它可称为抗微生物多肽制剂。
抗微生物多肽制剂可(a)直接加入到饲料中(或在植物蛋白质的处理过程中直接应用),或(b)它可在产生一种或多种中间组合物如饲料添加剂或预混物中应用,所述中间组合物随后加入到饲料中(或在处理过程中应用)。无论是根据以上(a)或(b)应用,以上描述的纯度是指初始抗微生物多肽制剂的纯度。
具有这个数量级纯度的抗微生物多肽制剂用重组产生方法是特别易获得的,而通过传统发酵方法产生抗微生物多肽时,它们不易获得且批与批之间差异也较大。
此类抗微生物多肽制剂当然可与其它酶混合。
如文中应用的术语植物蛋白质是指包括来自或起始自植物的至少一种蛋白质的任意化合物、组合物、制剂或混合物,包括经修饰蛋白质及蛋白质衍生物。在特定实施方案中,植物蛋白质的蛋白质含量为至少10、20、30、40、50或60%(w/w)。
植物蛋白质可来自植物蛋白质源,如豆类及谷类,例如来自豆科(Fabaceae(Leguminosae))、十字花科、藜科(Chenopodiaceae)及禾本科(Poaceae)植物的物质,如大豆膳食、羽扇豆膳食及油菜籽膳食。
在特定实施方案中,植物蛋白质源为来自豆科的一种或多种植物的材料,例如大豆、羽扇豆、豌豆或豆。
在另一实施方案中,植物蛋白质源为来自藜科的一种多种植物的材料,例如甜菜(beet)、甜菜(sugar beet)、菠菜或昆诺阿藜(quinoa)。
植物蛋白质源的其它实例为油菜籽及卷心菜。
大豆为优选的植物蛋白质源。
植物蛋白质源的其它实例为谷类如大麦、小麦、黑麦、燕麦、玉米(玉蜀黍)、稻及高梁。
抗微生物多肽可以任意形式加入到饲料中,所述任意形式可以是相对纯的抗微生物多肽或与欲用于加入到动物饲料的其它组分混合,即以动物饲料添加剂的形式,如所称作的动物饲料的预混物。
又一方面本发明涉及在动物饲料中应用的组合物,如动物饲料及动物饲料添加剂,例如预混物。
除了本发明的抗微生物多肽外,本发明的动物饲料添加剂含有至少一种脂溶性维生素和/或至少一种水溶性维生素和/或至少一种微量矿物质、和/或至少一种大量矿物质。
此外,任选地,饲料添加剂成分为着色剂、芳香化合物、稳定剂和/或至少一种选自植酸酶EC 3.1.3.8或3.1.3.26;木聚糖酶EC 3.2.1.8;半乳聚糖酶EC 3.2.1.89;和/或β-葡聚糖酶EC 3.2.1.4中的其它酶。
在特定实施方案中,这些其它酶是明确定义的(如以上对于抗微生物多肽制剂定义的)。
其它抗微生物肽(AMP’s)的实例为CAP18、Leucocin A、Tritrpticin、Protegrin-1、Thanatin、防卫素、Ovispirin如Novispirin(Robert Lehrer,2000)及其保持抗微生物活性的变体或片段。
其他抗真菌多肽(AFP’s)的实例为如在WO 94/01459及PCT/DK02/00289[一旦公开用WO号替换]中公开的巨大曲霉(Aspergillusgiganteus)及黑曲霉肽,其以及保持抗真菌活性的变体及片段。
通常脂溶性及水溶性维生素,以及微量矿物质形成部分所称作的预混物以用于加入到饲料中,而大量矿物质通常单独加到饲料中。这些组合物类型当富含本发明的抗微生物多肽,为本发明的动物饲料添加剂。
在特定实施方案中,在动物膳食或饲料中欲包括(或规定应当包括)0.01至10.0%水平;更特别是0.05至5.0%;或0.2至1.0%(%表示每100g饲料g添加剂)的本发明的动物饲料添加剂。这对于预混物尤其如此。
以下为这些组分实例的非排他性列表:
脂溶性维生素的实例为维生素A、维生素D3、维生素E及维生素K,例如维生素K3。
水溶性维生素的实例为维生素B12、生物素及胆碱、维生素B1、维生素B2、维生素B6、烟酸、叶酸及泛酸盐,例如Ca-D-泛酸盐。
微量矿物质的实例为锰、锌、铁、铜、碘、硒及钴。
大量矿物质的实例为钙、磷及钠。
这些组分的营养需要量(用家禽及小猪/猪示例)在WO 01/58275表A中列出。营养需要量表示这些组分在膳食中以标明的浓度提供。
备选地,本发明的动物饲料添加剂包含在WO 01/58275表A中详细说明的至少一种单独组分。至少一种表示一种或多种,一种、或两种、或三种、或四种等等直到所有十三种、或直到所有十五种单独组分。更特别地,这至少一种单独组分以提供表A中第四列或第五列或第六列中标明范围内的饲料浓度量包括在本发明的添加剂中。
本发明还涉及动物饲料组合物。动物饲料组合物或膳食具有相对高含量的蛋白质。家禽及猪的膳食可如WO 01/58275表B的第2-3列中标明的表征。鱼膳食可如这个表B第4列中标明的表征。此外此类鱼膳食通常具有200-310g/kg的粗脂肪含量。
根据本发明的动物饲料组合物具有50-800g/kg的粗蛋白质含量,且此外包含如文中要求保护的至少一种抗微生物多肽。
此外,或备选地(对于以上标明的粗蛋白质含量),本发明的动物饲料组合物具有10-30MJ/kg可代谢能量含量;和/或0.1-200g/kg的钙含量;和/或0.1-200g/kg的有效磷含量;和/或0.1-100g/kg甲硫氨酸含量;和/或0.1-150g/kg甲硫氨酸加半胱氨酸含量;和/或0.5-50g/kg赖氨酸含量。
在特定实施方案中,可代谢能量、粗蛋白质、钙、磷、甲硫氨酸、甲硫氨酸加半胱氨酸和/或赖氨酸含量在WO 01/58275(R.2-5)表B中的2、3、4或5行中的任意一行中。
粗蛋白质通过氮(N)乘以因子6.25计算,即粗蛋白质(g/kg)=N(g/kg)x 6.25。氮含量通过凯氏定氮法(A.O.A.C.,1984,Official Methods ofAnalysis第14版,Association of Official Analytical Chemists,华盛顿)确定。
可基于NRC出版物Nutrient requirements in swine,第九次修订版,1988,subcommittee on swine nutrition,committee on animal nutrition,board of agriculture,national research council.National Academy Press,华盛顿,第2-6页一书中,以及European Table of Energy Values forPoultry Feed-stuffs,Spelderholt centre for poultry research and extension,7361DA Beekbergen,荷兰一书中,Grafisch bedrijf Ponsen & looijen bv,Wageningen.ISBN 90-71463-12-5计算可代谢能量。
完全动物膳食中钙、有效磷及氨基酸膳食含量通过在饲料表如Veevoedertabel 1997,gegevens over chemische samenstelling,verteerbaarheid en voederwaarde van voedermiddelen,CentralVeevoederbureau,Runderweg 6,8219 pk Lelystad.ISBN 90-72839-13-7一书饲料表基础上进行计算。
在特定实施方案中,本发明的动物饲料组合物含有至少一种以上定义的植物蛋白质或蛋白质源。
在又一特定实施方案中,本发明的动物饲料组合物含有0-80%玉米;和/或0-80%高梁;和/或0-70%小麦;和/或0-70%大麦;和/或0-30%燕麦;和/或0-40%大豆粉;和/或0-10%鱼粉;和/或0-20%乳清。动物膳食可例如作为碎饲料(非颗粒)或颗粒饲料进行制备。一般地,将磨碎饲料进行混合并根据用于相关物种的说明书加入足量必需维生素及矿物质。酶可作为固体或液体酶剂型加入。例如固体酶剂型一般在混合步骤之前或期间加入;液体制剂一般在造粒步骤之后加入。酶也可掺合到饲料添加剂或预混物中。
膳食中的最终酶浓度在每kg膳食0.01-200mg酶蛋白质范围内,例如在每kg动物膳食中5-30mg酶蛋白质的范围。
抗微生物多肽可以以下量(剂量范围)的一种或多种进行施用:0.01-200;或0.01-100;或0.05-100;或0.05-50;或0.10-10,所有这些范围为mg抗微生物多肽蛋白质/kg饲料(ppm)。
为确定每kg饲料中所含mg抗微生物多肽蛋白质,将抗微生物多肽自饲料组合物中纯化,且经纯化抗微生物多肽的比活用相关测定法(参见以下抗微生物活性、底物及测定法)测定。如此类的饲料组合物中抗微生物活性也可用相同测定法测定,且在这两个测定基础上,计算以每kg饲料所含mg抗微生物多肽蛋白质表示的剂量。
相同原理用于测定饲料添加剂中mg抗微生物多肽蛋白质。当然,如果用于制备饲料添加剂或饲料的抗微生物多肽的样品是可获得的,那么自这个样品确定比活(不需要自饲料组合物或添加剂中纯化抗微生物多肽)。
洗涤剂组合物
可向洗涤剂组合物中加入本发明的抗微生物多肽并且其因此成为洗涤剂组合物的组分。
本发明的洗涤剂组合物可例如作为手工或机器洗衣洗涤剂组合物制备,所述手工或机器洗衣洗涤剂组合物包括适合用于预处理经染色织物的洗衣添加组合物及漂洗添加织物软化剂组合物,或可作为用于一般家庭硬表面清洗操作的洗涤剂组合物制备,或用于手工或机器洗盘操作制备。
在特定方面中,本发明提供了包含本发明的抗微生物多肽及表面活性剂的洗涤添加剂。洗涤添加剂以及洗涤剂组合物可包含一种或多种其它酶,如蛋白酶、脂肪酶、角化酶、淀粉酶、糖酶、纤维素酶、果胶酶、甘露聚糖酶、阿拉伯糖酶、半乳聚糖酶、木聚糖酶、氧化酶(如漆酶)和/或过氧化物酶(如卤过氧化物酶)。
通常,所选酶的性质应与所选洗涤剂相容(即最适pH、与其它酶和非酶成分等的相容性),且酶应以有效量存在。
蛋白酶:合适的蛋白酶包括来自动物、植物、微生物的蛋白酶。来源于微生物的蛋白酶是优选的。也包括经化学修饰或蛋白工程化的突变体。所述的蛋白酶可以是丝氨酸蛋白酶或金属蛋白酶,优选碱性微生物蛋白酶或胰蛋白酶样蛋白酶。碱性蛋白酶的实例为枯草杆菌蛋白酶,特别是来自芽孢杆菌的枯草杆菌蛋白酶,例如,枯草杆菌蛋白酶Novo、枯草杆菌蛋白酶Carlsberg、枯草杆菌蛋白酶309、枯草杆菌蛋白酶147和枯草杆菌蛋白酶168(WO 89/06279中描述)。胰蛋白酶样蛋白酶的实例为胰蛋白酶(例如来自猪或牛的)和如WO 89/06270和WO 94/25583中所公开的镰孢霉属的蛋白酶。
有用的蛋白酶的实例是如WO 92/19729,WO 98/20115,WO98/20116和WO 98/34946所描述的变体,特别是在一个或多个下述位置发生替换的变体:27,36,57,76,87,97,101,104,120,123,167,170,194,206,218,222,224,235和274。
脂肪酶:合适的脂肪酶包括那些来源于细菌或真菌的脂肪酶。也包括经化学修饰或蛋白工程化的突变体。有用的脂肪酶的实例包括如EP258068和EP 305216中所公开的来自腐质霉属(Thermomyces与之同物异名),例如来自H.lanuginosa(T.lanuginosus)的脂肪酶或如WO96/13580中所公开的来自H.Insolens的脂肪酶,假单胞菌脂肪酶,例如来自产碱假单胞菌(P.Alcaligenes)或类产碱假单胞菌(P.Pseudoalcaligenes)(EP 218 272),洋葱假单胞菌(P.Cepacia)(EP 331376),施氏假单胞菌(P.stutzeri)(GB 1,372,034),荧光假单胞菌(P.Fluorescens),假单胞菌菌株SD 705(WO 95/06720和WO 96/27002),P.wisconsinensis(WO 96/12012),芽孢杆菌脂肪酶,例如来自枯草芽孢杆菌(Dartois等人(1993),生物化学与生物物理学学报(Biochemica etBiophysica Acta),1131,253-360),嗜热脂肪芽孢杆菌(JP 64/744992)或短小芽孢杆菌(B.Pumilus)(WO 91/16422)。
其它的实例为如WO 92/05249,WO 94/01541,EP 407225,EP 260105,WO 95/35381,WO 96/00292,WO 95/30744,WO 94/25578,WO95/14783,WO 95/22615,WO 97/04079和WO 97/07202中所公开的脂肪酶变体。
淀粉酶:合适的淀粉酶(α和/或β)包括那些来源于细菌或真菌的淀粉酶。也包括经化学修饰或蛋白工程化的突变体。淀粉酶包括例如来源于芽孢杆菌的α-淀粉酶,例如来自地衣芽孢杆菌的特定菌株,详细内容参见GB 1,296,839。
有用的淀粉酶的实例是如WO 94/02597,WO 94/18314,WO96/23873和WO 97/43424中所描述的变体,尤其是那些在一个或多个下列位置发生替换的变体:15,23,105,106,124,128,133,154,156,181,188,190,197,202,208,209,243,264,304,305,391,408和444。
纤维素酶:合适的纤维素酶包括来源于细菌或真菌的纤维素酶。也包括其经化学修饰或蛋白工程突变体。合适的纤维素酶包括来自芽孢杆菌属、假单胞菌属、腐质霉属、镰孢霉属、草根霉属、枝顶孢霉属的纤维素酶,例如可由在US 4,435,307,US 5,648,263,US 5,691,178,US5,776,757和WO 89/09259中公开的Humicola insolens、嗜热毁丝霉和尖孢镰孢产生的所述真菌纤维素酶。
特别合适的纤维素酶是具有颜色保护优势的碱性或中性纤维素酶。这样的纤维素酶的实例为如EP 0495257,EP 0531372,WO 96/11262,WO 96/29397,WO 98/08940中所公开的纤维素酶。其它的实例为如那些在WO 94/07998,EP 0531315,US 5,457,046,US 5,686,593,US5,763,254,WO 95/24471,WO 98/12307和PCT/DK98/00299中所公开的纤维素酶变体。
过氧化物酶/氧化酶:合适的过氧化物酶/氧化酶包括那些来源于植物、细菌或真菌的过氧化物酶/氧化酶。也包括化学修饰或蛋白工程化的突变体。有用的过氧化物酶的实例包括如WO 93/24618,WO 95/10602和WO 98/15257所述的来自鬼伞属(Coprinus)(例如来自灰盖鬼伞(C.cinereus))和其变体的过氧化物酶。
所述的洗涤剂酶可以通过添加含一种或多种酶的独立添加剂,或通过添加含所有这些酶的组合添加剂而被包含于洗涤剂组合物中。本发明的洗涤剂添加剂,也就是独立添加剂或组合添加剂可以制成例如颗粒状、液体、浆状等等。优选的洗涤剂添加剂形式为颗粒状(特别是非粉末化颗粒)、液体(特别是稳定的液体)或浆。
非粉末化颗粒可依照例如US 4,106,991和4,661,452所述进行生产并可任选地用已知的方法包被。蜡状包被材料的实例是平均分子量为1000到20000的聚(环氧乙烷)产物(聚乙二醇,PEG);含有16到50个环氧乙烷单位的乙氧基化的壬基酚;乙氧基脂肪醇,其中,醇含12到20个碳原子且其中存在15到80个环氧乙烷单位;脂肪醇;脂肪酸;和脂肪酸的单-、二-和三酸甘油酯。GB 1483591中给出了适合于通过流化床技术应用的成膜包被材料的实例。液体酶制剂可以依照现成的方法通过例如添加多元醇如丙二醇、糖或糖醇、乳酸或硼酸得以稳定。受保护的酶可依照EP 238,216中所公开的方法进行制备。
本发明的洗涤剂组合物可以是任何方便的形式,例如棒状、片状、粉末、颗粒、粘团或液体。液体洗涤剂可以是含水的,一般含高达70%的水和0-30%的有机溶剂,或不含水的。
所述的洗涤剂组合物一般包含一种或多种表面活性剂,它们可以是非离子表面活性剂,包括半极性的和/或阴离子和/或阳离子和/或两性离子表面活性剂。所述的表面活性剂一般占到0.1%到60%的重量。当包含在所述洗涤剂中时,通常包含约1%到约40%的阴离子表面活性剂,如直链烷基苯磺酸酯、α-烯属磺酸酯、硫酸烷基酯(硫酸脂肪醇酯)、乙氧基硫酸醇酯、仲链烷磺酸酯、α-磺基脂肪酸甲酯、烷基-或链烯基琥珀酸或皂。
当包含在所述洗涤剂中时,通常含有约0.2%到约40%的非离子表面活性剂例如乙氧基化脂肪醇、乙氧基化壬基酚、烷基多苷、烷基二甲基胺氧化物、乙氧基化脂肪酸单乙醇酰胺、脂肪酸单乙醇酰胺、多羟基烷基脂肪酸酰胺或葡糖胺的N-酰基N-烷基衍生物(“葡糖酰胺”)。
所述的洗涤剂可以包含0-65%的洗涤剂增洁剂或络合剂例如沸石、二磷酸盐、三磷酸盐、磷酸盐、碳酸盐、柠檬酸盐、次氮基三乙酸、乙二胺四乙酸、二亚乙基三胺五乙酸、烷基-或链烯基琥珀酸、可溶性硅酸盐或层叠式硅酸盐(例如购自Hoechst的SKS-6)。
所述的洗涤剂还可以包含一种或多种聚合物。实例为羧甲基纤维素、聚(乙烯吡咯烷酮)、聚(乙二醇)、聚(乙烯醇)、聚(乙烯基吡啶-N-氧化物)、聚(乙烯基咪唑)、聚羧酸酯如聚丙烯酸酯、马来酸/丙烯酸共聚物和甲基丙烯酸月桂醇酯/丙烯酸共聚物。
所述的洗涤剂还可以含有可能包含H2O2来源的漂白体系,如可以与形成过酸的漂白活化剂如四乙酰基乙二胺或壬酰氧基苯磺酸盐结合的过硼酸盐或过碳酸盐。可选择地,所述的漂白体系可以包含例如酰胺、二酰亚胺或砜类的过氧酸。
本发明的洗涤剂组合物中的酶可以通过诸如以下的常规稳定剂稳定:多元醇如丙二醇或丙三醇、糖或糖醇、乳酸、硼酸或硼酸衍生物如芳香硼酸酯或苯基硼酸衍生物如4-甲酰基苯基硼酸,且所述的组合物也可制备为如WO 92/19709和WO 92/19708中所述的组合物。
所述的洗涤剂还可以包含其它的常规洗涤剂成分例如纤维调节剂包括黏土、增泡剂、泡沫抑制剂、抗腐蚀剂、污物悬浮剂、抗污物再沉淀剂、染料、杀菌剂、光学增白剂、助溶剂、失泽抑制剂或香料。
目前认为在本发明的洗涤剂组合物中,任意酶及本发明的抗微生物多肽可以以相当于每升洗涤液中具有0.01-100mg酶蛋白质,优选每升洗涤液0.05-10mg酶蛋白质,更优选每升洗涤液中0.1-5mg酶蛋白质,特别优选每升洗涤液中具有0.1-1mg酶蛋白质的量加入。
本发明的抗微生物多肽可额外掺入到如WO 97/07202所公开的洗涤剂制剂中,该文献引入本文作为参考。
本发明通过以下实例进一步描述,所述实例不应理解为限制本发明范围。
实施例
用作缓冲剂及底物的化学试剂为至少试剂级的商品。
实施例1
抗微生物多肽(Gen2)的克隆、表达及活性评估
编码Gen2的合成基因的克隆
为了产生抗微生物多肽
Gen2(SEQ ID NO:2)用于抗微生物活性测定,制备合成基因(见下文)并将其插入到表达载体pET31b+(NovagenInc.)。合成基因由特别设计的寡核苷酸(引物1及引物2)构成。
编码
Gen2的合成基因(SEQ ID NO:47):
GGC CTG CTG AGC AAA CTG AAG AAG GCG GCG AAA AAA GCG CTG AAA CAT GTG CTG TAG
G L L S K L K K A A K K A L K H V L *
引物1(SEQ ID NO:49):
ATTATTCAGA TGCTGGATCC GGCGGAAGGC CTGCTGAGCA AACTGAAGAA GGCGGCGAAA
AAAGCGCTGA AACATGTGCT GTAGCTCGAG ATTATT
引物2(SEQ ID NO:50):
AATAATCTCG AGCTACAGCA CATGTTTCAG CGCTTTTTTC GCCGCCTTCT TCAGTTTGCT
CAGCAGGCCT TCCGCCGGAT CCAGCATCTG AATAAT
侧翼限制性内切酶位点(AlwNI/AvaI)的酶消化使我们能克隆在pET31b+中作为融合构建体的这个合成基因(如通过生产商NeW EnglandBiolabs Inc.描述的标准方法)。所有标准方法在别处已经描述(Sambrook,Fritsch和Maniatis,1989)。
Gen2在大肠杆菌中的转化及表达
如通过生产商(Novagen)描述的,将重组pET31b+转化到大肠杆菌Novablue中。通过QIAprep小柱(QIAGEN Inc.)制备质粒且用质粒特异引物(引物3及引物4)通过自动测序对质粒测序。
引物3(SEQ ID NO:51):
TGCTA GTTAT TGCTC AGCGG
引物4(SEQ ID NO:52):
ACCGT AGTTG CGCCC ATCG
根据生产商(Novagen)将质粒转化到大肠杆菌BLR-DE3中。将细菌在LB培养基中培养至OD600~0.8且通过1mM IPTG(异丙基β-D-硫代半乳糖吡喃糖苷)起始重组蛋白质合成。经过3小时诱导作用,收获细菌,在1/10体积的缓冲液A(50mM Tris-HCl,1mM EDTA,100mM NaCl,pH 8)中重悬浮并通过压力破裂(1500mBar)裂解。产生的沉淀物在缓冲液B(50mM Tris-HCl,10mM EDTA,0.5%TritonX-100,100mMNaCl,pH 8)中洗两次。所有标准方案在别处已经描述(Sambrook,Fritsch和Maniatis,1989)。
自大肠杆菌内合体中纯化Gen2
自以上纯化得到的沉淀物包含经纯化内含体。为了自KSI融合配偶体中释放肽,在经改造的导入编码
Gen2的基因的N-端的Asp-Pro位点进行酸性水解。将内含体在100mM磷酸钠(pH 2.3)中重悬浮并于85摄氏度孵育过夜。得到的上清液包含肽(PAE-
Gen2)。样品通过加入100mM磷酸钠(pH 12.3)中和。为了使肽成熟,将肽用谷氨酰内肽酶I(来自地衣芽孢杆菌)进行处理。经成熟肽通过质谱分析法证实并进一步通过标准层析方法纯化。
评估最低抑制浓度(MIC)
在微肉汤(microbroth)稀释测定中用经阳离子调节的Mueller hinton培养基(MHB)测定
Gen2的最低抑制浓度,其中如以下表1描述的,以不同修饰应用MHB。所选受试生物为产气假单胞菌(ATCC 27853)。
表1
试验条件 | MIC(μg/ml) |
MHB | 15 |
MHB+1.5mM Mg2+ | 40 |
MHB+人血清白蛋白(1mg/ml) | 36 |
MHB+1%人血清 | 28 |
MHB+1%经裂解的人红细胞 | 36 |
将MHB调节至pH 6.5 | 16 |
将MHB调节至pH 5.5 | 16 |
杀灭动力学
用产气假单胞菌(ATCC 27853)作为受试生物在MHB中测定
Gen2的杀灭率。将细菌与
Gen2(在4xMIC浓度)孵育。在不同时间点,将制剂的几种稀释液涂平板并确定活细胞的估计(CFU/ml)。表2中的结果表明
Gen2快速杀死细菌,在30分钟内将CFU降低至约1/1000。
表2
时间 | CFU/ml | |
对照 | Gen2 | |
0小时 | 100,000 | 100,000 |
0.5小时 | 100,000 | 115 |
1.5小时 | 300,000 | 60 |
24小时 | >1,000,000 | <20 |
通过辐射扩散测定法(MEC)测定抗微生物活性
在抗微生物活性检测中应用以前发表方案的经修饰形式(Lehrer等人,(1991)Ultra sensitive assays for endogenous antimicrobial polypeptidesJ Immunol Methods 137:167-173)。将靶细菌(106个菌落形成单位(CFU))加入到10ml底层琼脂糖(1%低电渗琼脂糖,0.03%胰胨豆胨培养液,10mM磷酸钠pH 7.4,37摄氏度)中。悬浮液在INTEGRID培养皿(BectonDickinson Labware)上固化。用3mm凝胶打孔器在底层琼脂糖上打孔(Amersham Pharmacia Biotech,瑞典)。将样品加入孔中并于37摄氏度孵育3小时。在上面铺上一层琼脂糖并将平板孵育过夜(LB培养基,7.5%琼脂)。通过观察孔周围细菌清除区确定抗微生物活性。通过加入10ml 0.2mM MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物噻唑蓝)对活细胞进行复染。这个测定揭示了
Gen2针对枯草芽孢杆菌和大肠杆菌的 抗微生物活性(<64ug/ml)。
实施例2
抗微生物活性的评估
如在国际专利申请WO 00/73433实施例1中公开的(有较小变更),用阿拉伯糖作为诱导物,在大肠杆菌TOP10(Invitrogen)中表达一系列合成的抗微生物多肽。本发明的抗微生物多肽的表达使宿主细胞的生长受到抑制。
简而言之,在微量滴定板中,将含有0.2%葡萄糖及氨苄青霉素(100μg/ml)的RM培养基中生长的新鲜过夜培养物稀释300倍至含有0.2%甘油及氨苄青霉素(100μg/ml)以及不同浓度阿拉伯糖(0、0.01%或0.1%)的150微升RM的并于37摄氏度剧烈摇动下孵育。通过用Bioscreen C微生物读出器(Thermo Electron Corporation)以30分钟间隔测定OD450(关于缓冲剂及培养基组合物参见Invitrogen方案的pBAD/gIIIA、B及C载体目录号V450-01)14小时对生长曲线进行监测。
通过每个样品的终点OD测量值除以获自含有对照载体的细胞的终点OD测量值并乘以100计算生长抑制百分率。公式如下:
其中“空白OD”对应于空孔的OD。
Gen2的氨基酸序列及经选择的改进合成变体在表3中列出。
表3
氨基酸序列 | SEQIDNO: | 使用0.01%阿拉伯糖的生长抑制(%) | 使用0.1%阿拉伯糖的生长抑制(%) |
GLLSKLKKAAKKALKHVL (Gen2) | 2 | 51 | 48 |
GLFTKLRKATKRILEHVL | 3 | 81 | 87 |
GLLKTIRKKIKRVLKHVR | 4 | 96 | 99 |
GLWRKLKKALKRAVQGVR | 5 | 91 | 96 |
GMLSKLGITIKIAVKHIR | 6 | 98 | 100 |
GWFSKLKKTAKKLLQRVL | 7 | 76 | 82 |
GMLRKLKRKVKRTLQHVL | 8 | 78 | 88 |
GLFSIIMRAVKKVWQRVR | 9 | 97 | 100 |
GLLRKLGKKIKRVVKHVG | 10 | 98 | 100 |
GWFNKLKTKIKKTLKHVL | 11 | 72 | 90 |
GLLEKLRKALKRILQHVL | 12 | 91 | 97 |
GLWRKLRRKAKKVLQHIL | 13 | 94 | 100 |
GLLSRLRRATKIILKGIR | 14 | 72 | 88 |
GLWNMLKKKLKKIAQGIR | 15 | 73 | 88 |
GLLSKIMKAVKRTLKHIL | 16 | 89 | 99 |
GMLIKLEMEAKKVVKNVL | 17 | 96 | g9 |
GLLNKIKKTIKRAVQHVL | 18 | 76 | 92 |
GLLSKLKKTVKRVVKHVR | 19 | 84 | 99 |
GLLSKIRKKLKRVLQSIR | 20 | 77 | 94 |
GLVTLLKKAMKNALEDVL | 21 | 98 | 99 |
GLLRKIKMKAKKVLKNIL | 22 | 72 | 83 |
GLFRKLRKKVKKVLKHVL | 23 | 91 | 98 |
GLLSILKRKSKRILKHIL | 24 | 88 | 96 |
GILNIIGRAVKTVLESIR | 25 | 97 | 99 |
GLLSMLGKAVKRAVQHVL | 26 | 97 | 100 |
GILNKLRKKLKRVLQRIL | 27 | 84 | 97 |
GLLSKLGKAVKNILEDVV | 28 | 98 | 100 |
GLWSSIKKEAKHALKHIL | 2g | 55 | 81 |
GLLSKLKRKIKKAVKHIL | 30 | 82 | 95 |
GLFRKLKKTIKRVLKHVP | 31 | 86 | 96 |
GLFSLLRKTIKKVLQHIR | 32 | 91 | 99 |
GLLNKLKRALKKVVKHVR | 33 | 84 | 94 |
GWLRKIGKAVKKVVKRVL | 34 | 90 | 99 |
GLLGKLKRKIKKALEGIR | 35 | 96 | 99 |
GWLKILEKAAKITVKNVL | 36 | 98 | 97 |
GLLRILKKKAKKALQHIL | 37 | 86 | 93 |
GLLGKIRKEGRMFWRVFRRWL | 38 | 86 | 92 |
GLLRKLRKEVKKVLSIFFRWL | 39 | 97 | 99 |
GLLNKLKKNVKNIVQHILRWL | 40 | 77 | 95 |
GLFSILKREIKRTFSMFYRWL | 41 | 86 | 99 |
GLLGKLKKELKNVLEHIYRWL | 42 | 75 | 93 |
GILSKLKKAIKRILQDVLRWL | 43 | 82 | 99 |
GMLKKLKKKTKRAFSVFCRWL | 44 | 96 | 98 |
GILSMLERRWSMYCSIFCRWL | 45 | 98 | 100 |
GILSKLKKKAKNAVKMFCRWL | 46 | 92 | 96 |
表3中显示的结果令人信服地表明所有检测的抗微生物多肽都显示强抗微生物活性。
序列表
<110>诺和酶股份有限公司
<120>抗微生物多肽
<130>10496.204-W0
<160>52
<170>PatentIn版本3.1
<210>1
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物多肽
<220>
<221>MISC_FEATURE
<222>(2)..(2)
<223>Xaa=亮氨酸、异亮氨酸、色氨酸或甲硫氨酸
<220>
<221>MISC_FEATURE
<222>(3)..(3)
<223>Xaa=亮氨酸、苯丙氨酸、色氨酸或缬氨酸
<220>
<221>MISC_FEATURE
<222>(4)..(4)
<223>Xaa=丝氨酸、甘氨酸、赖氨酸、苏氨酸、精氨酸、异亮氨酸、天冬酰胺、天冬氨酸或谷氨酸
<220>
<221>MISC_FEATURE
<222>(5)..(5)
<223>Xaa=赖氨酸、苏氨酸、苯丙氨酸、精氨酸、亮氨酸、异亮氨酸、甲硫氨酸或丝氨酸
<220>
<221>MISC_FEATURE
<222>(6)..(6)
<223>Xaa=亮氨酸或异亮氨酸
<220>
<221>MISC_FEATURE
<222>(7)..(7)
<223>Xaa=赖氨酸、甘氨酸、精氨酸、甲硫氨酸或谷氨酸
<220>
<221>MISC_FEATURE
<222>(8)..(8)
<223>Xaa=赖氨酸、丝氨酸、异亮氨酸、精氨酸、苏氨酸或甲硫氨酸
<220>
<221>MISC_FEATURE
<222>(9)..(9)
<223>Xaa=丙氨酸、赖氨酸、苏氨酸、天冬酰胺、精氨酸或谷氨酸
<220>
<221>MISC_FEATURE
<222>(10)..(10)
<223>Xaa=丙氨酸、甘氨酸、丝氨酸、异亮氨酸、亮氨酸、苏氨酸、缬氨酸、甲硫氨酸或色氨酸
<220>
<221>MISC_FEATURE
<222>(11)..(11)
<223>Xaa=丝氨酸、精氨酸、赖氨酸或谷氨酸
<220>
<221>MISC_FEATURE
<222>(12)..(12)
<223>Xaa=赖氨酸、甲硫氨酸、精氨酸、组氨酸、异亮氨酸、天冬酰胺或苏氨酸
<220>
<221>MISC_FEATURE
<222>(13)..(13)
<223>Xaa=丙氨酸、缬氨酸、异亮氨酸、亮氨酸、酪氨酸、苯丙氨酸或苏氨酸
<220>
<221>MISC_FEATURE
<222>(14)..(14)
<223>Xaa=亮氨酸、丙氨酸、甘氨酸、半胱氨酸、苯丙氨酸、缬氨酸或色氨酸
<220>
<221>MISC_FEATURE
<222>(15)..(15)
<223>Xaa=赖氨酸、谷氨酰胺、丙氨酸、丝氨酸、精氨酸或谷氨酸
<220>
<221>MISC_FEATURE
<222>(16)..(16)
<223>Xaa=组氨酸、甘氨酸、天冬酰胺、精氨酸、丝氨酸,甲硫氨酸、异亮氨酸、缬氨酸或天冬氨酸
<220>
<221>MISC_FEATURE
<222>(17)..(17)
<223>Xaa=缬氨酸、异亮氨酸、丙氨酸或苯丙氨酸
<220>
<221>MISC_FEATURE
<222>(18)..(18)
<223>Xaa=Z或Z-精氨酸-色氨酸-亮氨酸;其中Z=苯丙氨酸、亮氨酸、精氨酸、丙氨酸、甘氨酸、缬氨酸、酪氨酸、半胱氨酸或脯氨酸
<400>1
Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Xaa
<210>2
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>2
Gly Leu Leu Ser Lys Leu Lys Lys Ala Ala Lys Lys Ala Leu Lys His
1 5 10 15
Val Leu
<210>3
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>3
Gly Leu Phe Thr Lys Leu Arg Lys Ala Thr Lys Arg Ile Leu Glu His
1 5 10 15
Val Leu
<210>4
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>4
Gly Leu Leu Lys Thr Ile Arg Lys Lys Ile Lys Arg Val Leu Lys His
1 5 10 15
Val Arg
<210>5
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>5
Gly Leu Trp Arg Lys Leu Lys Lys Ala Leu Lys Arg Ala Val Gln Gly
1 5 10 15
Val Arg
<210>6
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>6
Gly Met Leu Ser Lys Leu Gly Ile Thr Ile Lys Ile Ala Val Lys His
1 5 10 15
Ile Arg
<210>7
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>7
Gly Trp Phe Ser Lys Leu Lys Lys Thr Ala Lys Lys Leu Leu Gln Arg
1 5 10 15
Val Leu
<210>8
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>8
Gly Met Leu Arg Lys Leu Lys Arg Lys Val Lys Arg Thr Leu Gln His
1 5 10 15
Val Leu
<210>9
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>9
Gly Leu Phe Ser Ile Ile Met Arg Ala Val Lys Lys Val Trp Gln Arg
1 5 10 15
Val Arg
<210>10
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>10
Gly Leu Leu Arg Lys Leu Gly Lys Lys Ile Lys Arg Val Val Lys His
1 5 10 15
Val Gly
<210>11
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>11
Gly Trp Phe Asn Lys Leu Lys Thr Lys Ile Lys Lys Thr Leu Lys His
1 5 10 15
Val Leu
<210>12
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>12
Gly Leu Leu Glu Lys Leu Arg Lys Ala Leu Lys Arg Ile Leu Gln His
1 5 10 15
Val Leu
<210>13
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>13
Gly Leu Trp Arg Lys Leu Arg Arg Lys Ala Lys Lys Val Leu Gln His
1 5 10 15
Ile Leu
<210>14
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>14
Gly Leu Leu Ser Arg Leu Arg Arg Ala Thr Lys Ile Ile Leu Lys Gly
1 5 10 15
Ile Arg
<210>15
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>15
Gly Leu Trp Ash Met Leu Lys Lys Lys Leu Lys Lys Ile Ala Gln Gly
1 5 10 15
Ile Arg
<210>16
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>16
Gly Leu Leu Ser Lys Ile Met Lys Ala Val Lys Arg Thr Leu Lys His
1 5 10 15
Ile Leu
<210>17
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>17
Gly Met Leu Ile Lys Leu Glu Met Glu Ala Lys Lys Val Val Lys Asn
1 5 10 15
Val Leu
<210>18
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>18
Gly Leu Leu Asn Lys Ile Lys Lys Thr Ile Lys Arg Ala Val Gln His
1 5 10 15
Val Leu
<210>19
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>19
Gly Leu Leu Ser Lys Leu Lys Lys Thr Val Lys Arg Val Val Lys His
1 5 10 15
Val Arg
<210>20
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>20
Gly Leu Leu Ser Lys Ile Arg Lys Lys Leu Lys Arg Val Leu Gln Ser
1 5 10 15
lle Arg
<210>21
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>21
Gly Leu Val Thr Leu Leu Lys Lys Ala Met Lys Asn Ala Leu Glu Asp
1 5 10 15
Val Leu
<210>22
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>22
Gly Leu Leu Arg Lys Ile Lys Met Lys Ala Lys Lys Val Leu Lys Ash
1 5 10 15
Ile Leu
<210>23
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>23
Gly Leu Phe Arg Lys Leu Arg Lys Lys Val Lys Lys Val Leu Lys His
1 5 20 15
Val Leu
<210>24
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>24
Gly Leu Leu Ser Ile Leu Lys Arg Lys Ser Lys Arg Ile Leu Lys His
1 5 10 15
Ile Leu
<210>25
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>25
Gly Ile Leu Ash Ile Ile Gly Arg Ala Val Lys Thr Val Leu Glu Ser
1 5 10 15
Ile Arg
<210>26
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>26
Gly Leu Leu Ser Met Leu Gly Lys Ala Val Lys Arg Ala Val Gln His
1 5 10 15
Val Leu
<210>27
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>27
Gly Ile Leu Asn Lys Leu Arg Lys Lys Leu Lys Arg Val Leu Gln Arg
1 5 10 15
Ile Leu
<210>28
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>28
Gly Leu Leu Ser Lys Leu Gly Lys Ala Val Lys Asn Ile Leu Glu Asp
1 5 10 15
Val Val
<210>29
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>29
Gly Leu Trp Ser Ser Ile Lys Lys Glu Ala Lys His Ala Leu Lys His
1 5 10 15
Ile Leu
<210>30
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>30
Gly Leu Leu Ser Lys Leu Lys Arg Lys Ile Lys Lys Ala Val Lys His
1 5 10 15
Ile Leu
<210>31
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>31
Gly Leu Phe Arg Lys Leu Lys Lys Thr Ile Lys Arg Val Leu Lys His
1 5 10 15
Val Pro
<210>32
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>32
Gly Leu Phe Ser Leu Leu Arg Lys Thr Ile Lys Lys Val Leu Gln His
1 5 10 15
Ile Arg
<210>33
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>33
Gly Leu Leu Asn Lys Leu Lys Arg Ala Leu Lys Lys Val Val Lys His
1 5 10 15
Val Arg
<210>34
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>34
Gly Trp Leu Arg Lys Ile Gly Lys Ala Val Lys Lys Val Val Lys Arg
1 5 10 15
Val Leu
<210>35
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>35
Gly Leu Leu Gly Lys Leu Lys Arg Lys Ile Lys Lys Ala Leu Glu Gly
1 5 10 15
Ile Arg
<210>36
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>36
Gly Trp Leu Lys Ile Leu Glu Lys Ala Ala Lys Ile Thr Val Lys Asn
1 5 10 15
Val Leu
<210>37
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>37
Gly Leu Leu Arg Ile Leu Lys Lys Lys Ala Lys Lys Ala Leu Gln His
1 5 10 15
Ile Leu
<210>38
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>38
Gly Leu Leu Gly Lys Ile Arg Lys Glu Gly Arg Met Phe Trp Arg Val
1 5 10 15
Phe Arg Arg Trp Leu
20
<210>39
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>39
Gly Leu Leu Arg Lys Leu Arg Lys Glu Val Lys Lys Val Leu Ser Ile
1 5 10 15
Phe Phe Arg Trp Leu
20
<210>40
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>40
Gly Leu Leu Asn Lys Leu Lys Lys Asn Val Lys Asn Ile Val Gln His
1 5 10 15
Ile Leu Arg Trp Leu
20
<210>41
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>41
Gly Leu Phe Ser Ile Leu Lys Arg Glu Ile Lys Arg Thr Phe Ser Met
1 5 10 15
Phe Tyr Arg Trp Leu
20
<210>42
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>42
Gly Leu Leu Gly Lys Leu Lys Lys Glu Leu Lys Asn Val Leu Glu His
1 5 10 15
Ile Tyr Arg Trp Leu
20
<210>43
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>43
Gly Ile Leu Ser Lys Leu Lys Lys Ala Ile Lys Arg Ile Leu Gln Asp
1 5 10 15
Val Leu Arg Trp Leu
20
<210>44
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>44
Gly Met Leu Lys Lys Leu Lys Lys Lys Thr Lys Arg Ala Phe Ser Val
1 5 10 15
Phe Cys Arg Trp Leu
20
<210>45
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>45
Gly Ile Leu Ser Met Leu Glu Arg Arg Trp Ser Met Tyr Cys Ser Ile
1 5 10 15
Phe Cys Arg Trp Leu
20
<210>46
<211>21
<212>PRT
<213>人工的
<220>
<223>合成的抗微生物肽
<400>46
Gly Ile Leu Ser Lys Leu Lys Lys Lys Ala Lys Asn Ala Val Lys Met
1 5 10 15
Phe Cys Arg Trp Leu
20
<210>47
<211>57
<212>DNA
<213>人工的
<220>
<223>合成的Gen2基因
<220>
<221>CDS
<222>(1)..(57)
<223>
<400>47
ggc ctg ctg agc aaa ctg aag aag gcg gcg aaa aaa gcg ctg aaa cat 48
Gly Leu Leu Ser Lys Leu Lys Lys Ala Ala Lys Lys Ala Leu Lys His
1 5 10 15
gtg ctg tag 57
Val Leu
<210>48
<211>18
<212>PRT
<213>人工的
<220>
<223>合成的Gen2基因
<400>48
Gly Leu Leu Ser Lys Leu Lys Lys Ala Ala Lys Lys Ala Leu Lys His
1 5 10 15
Val Leu
<210>49
<211>96
<212>DNA
<213>人工的
<220>
<223>引物1序列
<400>49
attattcaga tgctggatcc ggcggaaggc ctgctgagca aactgaagaa ggcggcgaaa 60
aaagcgctga aacatgtgct gtagctcgag attatt 96
<210>50
<211>96
<212>DNA
<213>人工的
<220>
<223>引物2序列
<400>50
aataatctcg agctacagca catgtttcag cgcttttttc gccgccttct tcagtttgct 60
cagcaggcct tccgccggatccagcatctg aataat 96
<210>51
<211>20
<212>DNA
<213>人工的
<220>
<223>引物3序列
<400>51
tgctagttat tgctcagcgg 20
<210>52
<211>19
<212>DNA
<213>人工的
<220>
<223>引物4序列
<400>52
accgtagttg cgcccatcg 19
Claims (23)
1.具有抗微生物活性的多肽,其包含在SEQ ID NO:1中列出的氨基酸序列,或其具有抗微生物活性的至少18个氨基酸的片段,所述SEQ IDNO:1为:
G-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-Z;
其中
X1=L、I、W或M;
X2=L、F、W或V;
X3=S、G、K、T、R、I、N、D或E;
X4=K、T、F、I、R、M、L或S;
X5=L或I;
X6=K、G、R、M或E;
X7=K、S、I、R、T或M;
X8=A、K、T、N、R或E;
X9=A、G、S、I、L、T、V、M或W;
X10=S、R、K或E;
X11=K、M、R、H、I、N或T;
X12=A、V、I、L、Y、F或T;
X13=L、A、G、C、F、V或W;
X14=K、Q、A、S、R或E;
X15=H、G、N、R、S、M、I、V或D;
X16=V、I、A或F;
Z=X17或X17-R-W-L;其中X17=F、L、R、A、G、V、Y、C或P;并且其中组成所述多肽的氨基酸独立地选自D或者L型。
2.具有抗微生物活性的多肽,其由18个氨基酸组成和通过氨基酸序列R-W-L延伸的氨基酸序列组成;其中组成所述多肽的氨基酸独立地选自D或者L型。
3.权利要求1的多肽,其包含SEQ ID NO:1至SEQ ID NO:46中任意一项的氨基酸。
4.权利要求1的多肽,其由SEQ ID NO:1至SEQ ID NO:46中任意一项的氨基酸组成。
5.多核苷酸,其具有编码权利要求1-4任意一项中定义的多肽的核苷酸序列。
6.核酸构建体,其包含权利要求5中定义的核苷酸序列,所述核苷酸序列与在适宜宿主中指导所述多肽产生的一种或多种控制序列有效连接。
7.重组表达载体,其包含权利要求6中定义的核酸构建体。
8.重组宿主细胞,其包含权利要求6中定义的核酸构建体。
9.用于产生如权利要求1-4中任意一项定义的多肽的方法,所述方法包括:
(a)在有益于产生所述多肽的条件下,培养如权利要求10中定义的重组宿主细胞;和
(b)回收所述多肽。
10.组合物,其包含如权利要求1-4中任意一项定义的抗微生物多肽。
11.权利要求10的组合物,其还包含额外的杀生物剂。
12.杀灭微生物细胞或抑制微生物细胞生长的方法,其包括将所述微生物细胞与如权利要求1-4中任意一项定义的抗微生物多肽接触。
13.洗涤剂组合物,其包含表面活性剂和如权利要求1-4中任意一项定义的抗微生物多肽。
14.如权利要求1-4中任意一项定义的抗微生物多肽,其用作药物。
15.如权利要求1-4中任意一项定义的抗微生物多肽,其用作兽医用的或者用于人的抗微生物治疗或预防剂。
16.如权利要求1-4中任意一项定义的抗微生物多肽的用途,其用于制备兽医用或者用于人的治疗剂,所述治疗剂用于治疗微生物感染或用于预防用途。
17.如权利要求1-4中任意一项定义的抗微生物多肽的用途,用于杀灭微生物细胞或抑制微生物细胞生长。
18.转基因植物、植物部分或植物细胞,其已经用编码如权利要求1-4中任意一项定义的具有抗微生物活性的多肽的核苷酸序列转化。
19.如权利要求1-4中任意一项定义的至少一种抗微生物多肽的用途,用于动物饲料中。
20.如权利要求1-4中任意一项定义的至少一种抗微生物多肽的用途,用于制备用于动物饲料中的组合物。
21.动物饲料添加剂,其包含
(a)至少一种如权利要求1-4中任意一项定义的抗微生物多肽;和
(b)至少一种脂溶性维生素,和/或
(c)至少一种水溶性维生素,和/或
(d)至少一种微量矿物质,和/或
(e)至少一种大量矿物质。
22.权利要求21的动物饲料添加剂,其还包含植酸酶、木聚糖酶、半乳聚糖酶和/或β-葡聚糖酶。
26.动物饲料组合物,其具有50至800g/kg的粗蛋白质含量并且包含至少一种如权利要求1-4中任意一项定义的抗微生物多肽。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA200300865 | 2003-06-11 | ||
DKPA200300865 | 2003-06-11 | ||
DKPA200300924 | 2003-06-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1820019A true CN1820019A (zh) | 2006-08-16 |
CN100497376C CN100497376C (zh) | 2009-06-10 |
Family
ID=33495514
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004800196613A Expired - Fee Related CN100497376C (zh) | 2003-06-11 | 2004-06-10 | 抗微生物多肽 |
CNB200480019203XA Expired - Fee Related CN100497375C (zh) | 2003-06-11 | 2004-06-10 | 抗微生物多肽 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB200480019203XA Expired - Fee Related CN100497375C (zh) | 2003-06-11 | 2004-06-10 | 抗微生物多肽 |
Country Status (22)
Country | Link |
---|---|
US (1) | US7829524B2 (zh) |
EP (1) | EP1664096B1 (zh) |
JP (1) | JP4782674B2 (zh) |
CN (2) | CN100497376C (zh) |
AR (1) | AR044680A1 (zh) |
AT (1) | ATE445634T1 (zh) |
AU (1) | AU2004245173B2 (zh) |
BR (1) | BRPI0411227A (zh) |
CA (1) | CA2529062C (zh) |
CL (1) | CL2004001443A1 (zh) |
CY (1) | CY1109675T1 (zh) |
DE (1) | DE602004023624D1 (zh) |
DK (1) | DK1664096T3 (zh) |
ES (1) | ES2334792T3 (zh) |
HK (1) | HK1090653A1 (zh) |
NZ (1) | NZ543978A (zh) |
PL (1) | PL1664096T3 (zh) |
PT (1) | PT1664096E (zh) |
SI (1) | SI1664096T1 (zh) |
TW (1) | TWI343922B (zh) |
WO (1) | WO2004108752A1 (zh) |
ZA (1) | ZA200509928B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2603645A (en) * | 2019-07-22 | 2022-08-10 | Oneskin Inc | Polypeptides having anti-senescent effects and uses thereof |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7388077B2 (en) | 2004-11-12 | 2008-06-17 | Novozymes A/S | Polypeptides having antimicrobial activity and polynucleotides encoding the same |
WO2006053565A2 (en) | 2004-11-19 | 2006-05-26 | Novozymes A/S | Polypeptides having antimicrobial activity and polynucleotides encoding same |
AU2006224628B2 (en) * | 2005-03-16 | 2012-04-12 | Novozymes Adenium Biotech A/S | Recombinant expression of defensins in filamentous fungi |
WO2010080819A1 (en) | 2009-01-06 | 2010-07-15 | C3 Jian, Inc. | Targeted antimicrobial moieties |
WO2015042583A2 (en) * | 2013-09-23 | 2015-03-26 | Anand Srinivasan | Systems, devices, & methods for microbial detection & identification, and antimicrobial susceptibility testing |
GB201409451D0 (en) | 2014-05-28 | 2014-07-09 | Ipabc Ltd | Antimicrobial preparations, methods for preparing the same and uses thereof to combat microorganisms |
CN104945467B (zh) * | 2015-06-23 | 2018-12-18 | 中山大学 | 一种抗菌肽的人工合成方法 |
WO2021247965A2 (en) * | 2020-06-04 | 2021-12-09 | The Curators Of The University Of Missouri | Novel peptide inhibitors against beta-lactam resistance in bacteria |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5654273A (en) | 1994-09-22 | 1997-08-05 | Children's Medical Center Corporation | Synducin mediated modulation of tissue repair |
WO2001012668A1 (en) | 1999-08-18 | 2001-02-22 | University Of Iowa Research Foundation | Cathelicidin-derived peptides with broad spectrum antimicrobial activity |
-
2004
- 2004-06-10 CL CL200401443A patent/CL2004001443A1/es unknown
- 2004-06-10 DK DK04736507.7T patent/DK1664096T3/da active
- 2004-06-10 BR BRPI0411227-0A patent/BRPI0411227A/pt not_active IP Right Cessation
- 2004-06-10 NZ NZ543978A patent/NZ543978A/en not_active IP Right Cessation
- 2004-06-10 US US10/560,260 patent/US7829524B2/en not_active Expired - Fee Related
- 2004-06-10 ES ES04736507T patent/ES2334792T3/es not_active Expired - Lifetime
- 2004-06-10 WO PCT/DK2004/000400 patent/WO2004108752A1/en active Application Filing
- 2004-06-10 PL PL04736507T patent/PL1664096T3/pl unknown
- 2004-06-10 CA CA2529062A patent/CA2529062C/en not_active Expired - Lifetime
- 2004-06-10 DE DE602004023624T patent/DE602004023624D1/de not_active Expired - Lifetime
- 2004-06-10 CN CNB2004800196613A patent/CN100497376C/zh not_active Expired - Fee Related
- 2004-06-10 CN CNB200480019203XA patent/CN100497375C/zh not_active Expired - Fee Related
- 2004-06-10 JP JP2006515708A patent/JP4782674B2/ja not_active Expired - Fee Related
- 2004-06-10 AU AU2004245173A patent/AU2004245173B2/en not_active Ceased
- 2004-06-10 EP EP04736507A patent/EP1664096B1/en not_active Expired - Lifetime
- 2004-06-10 PT PT04736507T patent/PT1664096E/pt unknown
- 2004-06-10 SI SI200431309T patent/SI1664096T1/sl unknown
- 2004-06-10 AT AT04736507T patent/ATE445634T1/de active
- 2004-06-11 TW TW093116812A patent/TWI343922B/zh not_active IP Right Cessation
- 2004-06-11 AR ARP040102032A patent/AR044680A1/es active IP Right Grant
-
2005
- 2005-12-07 ZA ZA200509928A patent/ZA200509928B/en unknown
-
2006
- 2006-10-17 HK HK06111341.7A patent/HK1090653A1/xx not_active IP Right Cessation
-
2009
- 2009-12-30 CY CY20091101345T patent/CY1109675T1/el unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2603645A (en) * | 2019-07-22 | 2022-08-10 | Oneskin Inc | Polypeptides having anti-senescent effects and uses thereof |
GB2603645B (en) * | 2019-07-22 | 2023-03-01 | Uniao Brasileira De Educacao Catolica | Polypeptides having anti-senescent effects and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
AR044680A1 (es) | 2005-09-21 |
DE602004023624D1 (de) | 2009-11-26 |
CA2529062C (en) | 2011-03-15 |
DK1664096T3 (da) | 2010-02-08 |
US20080213430A1 (en) | 2008-09-04 |
CL2004001443A1 (es) | 2005-05-20 |
ATE445634T1 (de) | 2009-10-15 |
WO2004108752A1 (en) | 2004-12-16 |
NZ543978A (en) | 2008-04-30 |
JP4782674B2 (ja) | 2011-09-28 |
CN1816561A (zh) | 2006-08-09 |
CN100497375C (zh) | 2009-06-10 |
HK1090653A1 (en) | 2006-12-29 |
JP2007537694A (ja) | 2007-12-27 |
TW200510460A (en) | 2005-03-16 |
BRPI0411227A (pt) | 2006-07-11 |
CY1109675T1 (el) | 2014-08-13 |
CA2529062A1 (en) | 2004-12-16 |
PL1664096T3 (pl) | 2010-05-31 |
CN100497376C (zh) | 2009-06-10 |
EP1664096A1 (en) | 2006-06-07 |
ES2334792T3 (es) | 2010-03-16 |
ZA200509928B (en) | 2008-01-30 |
PT1664096E (pt) | 2010-01-08 |
SI1664096T1 (sl) | 2010-02-26 |
AU2004245173A1 (en) | 2004-12-16 |
AU2004245173B2 (en) | 2010-12-02 |
US7829524B2 (en) | 2010-11-09 |
EP1664096B1 (en) | 2009-10-14 |
TWI343922B (en) | 2011-06-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1606567A (zh) | 来自假黑盘菌的抗微生物多肽 | |
CN101035892A (zh) | 具有肌醇六磷酸酶活性的多肽及编码其的多核苷酸 | |
AU2005238127B2 (en) | Antimicrobial polypeptides | |
CN1630719A (zh) | 肌醇六磷酸酶变体 | |
CN1809635A (zh) | 蛋白酶 | |
CN1867668A (zh) | 蛋白酶变体 | |
CN1774504A (zh) | 蛋白酶 | |
CN101248085B (zh) | 具有抗微生物活性的多肽和编码该多肽的多核苷酸 | |
ZA200509928B (en) | Antimicrobial polypeptides | |
CN1809634A (zh) | 蛋白酶 | |
US20070259087A1 (en) | Antimicrobial Peptides | |
CN1878791A (zh) | 合成的抗微生物多肽 | |
CN101175770A (zh) | 具有抗微生物活性的多肽和编码该多肽的多核苷酸 | |
CN1980951B (zh) | 抗微生物多肽 | |
CN101035898A (zh) | 具有肌醇六磷酸酶活性的多肽和编码它的多核苷酸 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1096690 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090610 Termination date: 20100610 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1096690 Country of ref document: HK |