CN112292150A - 用于口服递送胰岛素的病毒样纳米衣壳 - Google Patents
用于口服递送胰岛素的病毒样纳米衣壳 Download PDFInfo
- Publication number
- CN112292150A CN112292150A CN201980018882.5A CN201980018882A CN112292150A CN 112292150 A CN112292150 A CN 112292150A CN 201980018882 A CN201980018882 A CN 201980018882A CN 112292150 A CN112292150 A CN 112292150A
- Authority
- CN
- China
- Prior art keywords
- insulin
- hev
- hevnp
- protein
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 279
- 108090001061 Insulin Proteins 0.000 title claims abstract description 145
- 229940125396 insulin Drugs 0.000 title claims abstract description 141
- 102000004877 Insulin Human genes 0.000 title claims abstract description 140
- 238000012384 transportation and delivery Methods 0.000 title claims abstract description 59
- 241000724675 Hepatitis E virus Species 0.000 claims abstract description 113
- 108090000565 Capsid Proteins Proteins 0.000 claims abstract description 69
- 102100023321 Ceruloplasmin Human genes 0.000 claims abstract description 69
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 40
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 39
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 25
- 101710159752 Poly(3-hydroxyalkanoate) polymerase subunit PhaE Proteins 0.000 claims abstract description 24
- 101710130262 Probable Vpr-like protein Proteins 0.000 claims abstract description 24
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 23
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 23
- 239000002245 particle Substances 0.000 claims abstract description 22
- 108700026244 Open Reading Frames Proteins 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 51
- 235000018102 proteins Nutrition 0.000 claims description 38
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 32
- 235000018417 cysteine Nutrition 0.000 claims description 28
- 239000003446 ligand Substances 0.000 claims description 27
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 25
- 230000008685 targeting Effects 0.000 claims description 25
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 23
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical group NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 21
- 239000004472 Lysine Chemical group 0.000 claims description 20
- 206010012601 diabetes mellitus Diseases 0.000 claims description 19
- 229920001184 polypeptide Polymers 0.000 claims description 19
- 210000003494 hepatocyte Anatomy 0.000 claims description 14
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 claims description 13
- 101710113540 ORF2 protein Proteins 0.000 claims description 13
- 101710090523 Putative movement protein Proteins 0.000 claims description 13
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 13
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical group NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 9
- 239000010931 gold Substances 0.000 claims description 8
- 229910052737 gold Inorganic materials 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000012634 fragment Substances 0.000 claims description 6
- 108010045325 cyclic arginine-glycine-aspartic acid peptide Proteins 0.000 claims description 5
- 239000002616 MRI contrast agent Substances 0.000 claims description 3
- 210000005229 liver cell Anatomy 0.000 claims description 2
- 238000005538 encapsulation Methods 0.000 description 44
- 239000012867 bioactive agent Substances 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 26
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 22
- 235000018977 lysine Nutrition 0.000 description 21
- 230000014509 gene expression Effects 0.000 description 20
- 210000004185 liver Anatomy 0.000 description 20
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- 239000003814 drug Substances 0.000 description 17
- 238000011282 treatment Methods 0.000 description 17
- 230000021615 conjugation Effects 0.000 description 16
- 229940079593 drug Drugs 0.000 description 13
- 229940125395 oral insulin Drugs 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000002775 capsule Substances 0.000 description 12
- 239000002105 nanoparticle Substances 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 239000000427 antigen Substances 0.000 description 11
- 108091007433 antigens Proteins 0.000 description 11
- 102000036639 antigens Human genes 0.000 description 11
- 210000001035 gastrointestinal tract Anatomy 0.000 description 10
- 230000002797 proteolythic effect Effects 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 241000701447 unidentified baculovirus Species 0.000 description 10
- 108010057186 Insulin Glargine Proteins 0.000 description 9
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 9
- 108010076181 Proinsulin Proteins 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000012216 imaging agent Substances 0.000 description 9
- 230000028993 immune response Effects 0.000 description 9
- 238000002965 ELISA Methods 0.000 description 8
- 108010065920 Insulin Lispro Proteins 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 210000000234 capsid Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000002299 complementary DNA Substances 0.000 description 8
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 229960002869 insulin glargine Drugs 0.000 description 8
- 229960002068 insulin lispro Drugs 0.000 description 8
- UGOZVNFCFYTPAZ-IOXYNQHNSA-N levemir Chemical compound CCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=2C=CC=CC=2)C(C)C)CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)CSSC[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC2=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 UGOZVNFCFYTPAZ-IOXYNQHNSA-N 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 239000013598 vector Substances 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 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 7
- 241000238631 Hexapoda Species 0.000 description 7
- 108010089308 Insulin Detemir Proteins 0.000 description 7
- 108010007568 Protamines Proteins 0.000 description 7
- 102000007327 Protamines Human genes 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 229960004717 insulin aspart Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 229940048914 protamine Drugs 0.000 description 7
- 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 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108010073961 Insulin Aspart Proteins 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 102000057297 Pepsin A Human genes 0.000 description 6
- 108090000284 Pepsin A Proteins 0.000 description 6
- 239000007983 Tris buffer Substances 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 229940127089 cytotoxic agent Drugs 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 6
- 238000012377 drug delivery Methods 0.000 description 6
- 238000001493 electron microscopy Methods 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 210000000496 pancreas Anatomy 0.000 description 6
- 229940111202 pepsin Drugs 0.000 description 6
- 108091033319 polynucleotide Proteins 0.000 description 6
- 102000040430 polynucleotide Human genes 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- 108010019598 Liraglutide Proteins 0.000 description 5
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 5
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 5
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 239000002738 chelating agent Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 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 5
- 235000013305 food Nutrition 0.000 description 5
- 238000010353 genetic engineering Methods 0.000 description 5
- 230000002440 hepatic effect Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 229960003948 insulin detemir Drugs 0.000 description 5
- 108700039926 insulin glulisine Proteins 0.000 description 5
- -1 intestinal patches Substances 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 239000002157 polynucleotide Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 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 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 238000003917 TEM image Methods 0.000 description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 4
- 101150113720 aunc gene Proteins 0.000 description 4
- 235000013361 beverage Nutrition 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000001415 gene therapy Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 229960000696 insulin glulisine Drugs 0.000 description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
- 150000002669 lysines Chemical class 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 108010066090 neutral insulin Proteins 0.000 description 4
- 210000003240 portal vein Anatomy 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- DOMDXTIMIZCSNC-UHFFFAOYSA-N (2Z)-2-[(2E,4E)-5-[3-[6-(2,5-dioxopyrrolidin-1-yl)oxy-6-oxohexyl]-1,1-dimethyl-6,8-disulfobenzo[e]indol-3-ium-2-yl]penta-2,4-dienylidene]-3-ethyl-1,1-dimethyl-8-sulfobenzo[e]indole-6-sulfonate Chemical compound CC1(C)C(C2=CC(=CC(=C2C=C2)S([O-])(=O)=O)S(O)(=O)=O)=C2N(CC)\C1=C/C=C/C=C/C(C(C1=C2C=C(C=C(C2=CC=C11)S(O)(=O)=O)S(O)(=O)=O)(C)C)=[N+]1CCCCCC(=O)ON1C(=O)CCC1=O DOMDXTIMIZCSNC-UHFFFAOYSA-N 0.000 description 3
- 101000977023 Azospirillum brasilense Uncharacterized 17.8 kDa protein in nodG 5'region Proteins 0.000 description 3
- 101000961984 Bacillus thuringiensis Uncharacterized 30.3 kDa protein Proteins 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108091026890 Coding region Proteins 0.000 description 3
- 101000644901 Drosophila melanogaster Putative 115 kDa protein in type-1 retrotransposable element R1DM Proteins 0.000 description 3
- 101000747702 Enterobacteria phage N4 Uncharacterized protein Gp2 Proteins 0.000 description 3
- 101000758599 Escherichia coli Uncharacterized 14.7 kDa protein Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000768930 Lactococcus lactis subsp. cremoris Uncharacterized protein in pepC 5'region Proteins 0.000 description 3
- 101000976302 Leptospira interrogans Uncharacterized protein in sph 3'region Proteins 0.000 description 3
- 101000778886 Leptospira interrogans serogroup Icterohaemorrhagiae serovar Lai (strain 56601) Uncharacterized protein LA_2151 Proteins 0.000 description 3
- 239000007987 MES buffer Substances 0.000 description 3
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101001121571 Rice tungro bacilliform virus (isolate Philippines) Protein P2 Proteins 0.000 description 3
- 101000818098 Spirochaeta aurantia Uncharacterized protein in trpE 3'region Proteins 0.000 description 3
- 101001026590 Streptomyces cinnamonensis Putative polyketide beta-ketoacyl synthase 2 Proteins 0.000 description 3
- 101000750896 Synechococcus elongatus (strain PCC 7942 / FACHB-805) Uncharacterized protein Synpcc7942_2318 Proteins 0.000 description 3
- 230000024932 T cell mediated immunity Effects 0.000 description 3
- 101000916321 Xenopus laevis Transposon TX1 uncharacterized 149 kDa protein Proteins 0.000 description 3
- 101000760088 Zymomonas mobilis subsp. mobilis (strain ATCC 10988 / DSM 424 / LMG 404 / NCIMB 8938 / NRRL B-806 / ZM1) 20.9 kDa protein Proteins 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- OGWAVGNOAMXIIM-UHFFFAOYSA-N albiglutide Chemical compound O=C(O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)CNC(=O)C(N)CC=1(N=CNC=1))CCC(=O)O)C(O)C)CC2(=CC=CC=C2))C(O)C)CO)CC(=O)O)C(C)C)CO)CO)CC3(=CC=C(O)C=C3))CC(C)C)CCC(=O)O)CCC(=O)N)C)C)CCCCN)CCC(=O)O)CC4(=CC=CC=C4))C(CC)C)C)CC=6(C5(=C(C=CC=C5)NC=6)))CC(C)C)C(C)C)CCCCN)CCCNC(=N)N OGWAVGNOAMXIIM-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 238000011033 desalting Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229960005175 dulaglutide Drugs 0.000 description 3
- 108010005794 dulaglutide Proteins 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 238000001476 gene delivery Methods 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 239000004026 insulin derivative Substances 0.000 description 3
- 229940102988 levemir Drugs 0.000 description 3
- 229960002701 liraglutide Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000012054 meals Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000386 microscopy Methods 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- 239000002539 nanocarrier Substances 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 230000004481 post-translational protein modification Effects 0.000 description 3
- 108010029667 pramlintide Proteins 0.000 description 3
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 108700027806 rGLP-1 Proteins 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 150000003573 thiols Chemical group 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229910000859 α-Fe Inorganic materials 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 2
- CIVGYTYIDWRBQU-UFLZEWODSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid;pyrrole-2,5-dione Chemical compound O=C1NC(=O)C=C1.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 CIVGYTYIDWRBQU-UFLZEWODSA-N 0.000 description 2
- PCFGFYKGPMQDBX-FEKONODYSA-N 78355-50-7 Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 PCFGFYKGPMQDBX-FEKONODYSA-N 0.000 description 2
- NOESYZHRGYRDHS-ZYCCASTOSA-N 8a-l-threonine-10a-l-isoleucine-insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 NOESYZHRGYRDHS-ZYCCASTOSA-N 0.000 description 2
- 101000768957 Acholeplasma phage L2 Uncharacterized 37.2 kDa protein Proteins 0.000 description 2
- 101000823746 Acidianus ambivalens Uncharacterized 17.7 kDa protein in bps2 3'region Proteins 0.000 description 2
- 101000916369 Acidianus ambivalens Uncharacterized protein in sor 5'region Proteins 0.000 description 2
- 101000769342 Acinetobacter guillouiae Uncharacterized protein in rpoN-murA intergenic region Proteins 0.000 description 2
- 101000823696 Actinobacillus pleuropneumoniae Uncharacterized glycosyltransferase in aroQ 3'region Proteins 0.000 description 2
- 101000786513 Agrobacterium tumefaciens (strain 15955) Uncharacterized protein outside the virF region Proteins 0.000 description 2
- 101000618005 Alkalihalobacillus pseudofirmus (strain ATCC BAA-2126 / JCM 17055 / OF4) Uncharacterized protein BpOF4_00885 Proteins 0.000 description 2
- 102100020724 Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1 Human genes 0.000 description 2
- 102000003916 Arrestin Human genes 0.000 description 2
- 108090000328 Arrestin Proteins 0.000 description 2
- 101000967489 Azorhizobium caulinodans (strain ATCC 43989 / DSM 5975 / JCM 20966 / LMG 6465 / NBRC 14845 / NCIMB 13405 / ORS 571) Uncharacterized protein AZC_3924 Proteins 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
- 101000823761 Bacillus licheniformis Uncharacterized 9.4 kDa protein in flaL 3'region Proteins 0.000 description 2
- 101000819719 Bacillus methanolicus Uncharacterized N-acetyltransferase in lysA 3'region Proteins 0.000 description 2
- 101000789586 Bacillus subtilis (strain 168) UPF0702 transmembrane protein YkjA Proteins 0.000 description 2
- 101000792624 Bacillus subtilis (strain 168) Uncharacterized protein YbxH Proteins 0.000 description 2
- 101000790792 Bacillus subtilis (strain 168) Uncharacterized protein YckC Proteins 0.000 description 2
- 101000819705 Bacillus subtilis (strain 168) Uncharacterized protein YlxR Proteins 0.000 description 2
- 101000948218 Bacillus subtilis (strain 168) Uncharacterized protein YtxJ Proteins 0.000 description 2
- 101000718627 Bacillus thuringiensis subsp. kurstaki Putative RNA polymerase sigma-G factor Proteins 0.000 description 2
- 101000641200 Bombyx mori densovirus Putative non-structural protein Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 101000947633 Claviceps purpurea Uncharacterized 13.8 kDa protein Proteins 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 101000948901 Enterobacteria phage T4 Uncharacterized 16.0 kDa protein in segB-ipI intergenic region Proteins 0.000 description 2
- 101000805958 Equine herpesvirus 4 (strain 1942) Virion protein US10 homolog Proteins 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 101000790442 Escherichia coli Insertion element IS2 uncharacterized 11.1 kDa protein Proteins 0.000 description 2
- 101000788354 Escherichia phage P2 Uncharacterized 8.2 kDa protein in gpA 5'region Proteins 0.000 description 2
- 108010011459 Exenatide Proteins 0.000 description 2
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 2
- 101000770304 Frankia alni UPF0460 protein in nifX-nifW intergenic region Proteins 0.000 description 2
- 101000797344 Geobacillus stearothermophilus Putative tRNA (cytidine(34)-2'-O)-methyltransferase Proteins 0.000 description 2
- 101000748410 Geobacillus stearothermophilus Uncharacterized protein in fumA 3'region Proteins 0.000 description 2
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 2
- 101000772675 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) UPF0438 protein HI_0847 Proteins 0.000 description 2
- 101000631019 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) Uncharacterized protein HI_0350 Proteins 0.000 description 2
- 101000768938 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 8.9 kDa protein in int-C1 intergenic region Proteins 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 208000037262 Hepatitis delta Diseases 0.000 description 2
- 241000724709 Hepatitis delta virus Species 0.000 description 2
- 208000037319 Hepatitis infectious Diseases 0.000 description 2
- 241000709721 Hepatovirus A Species 0.000 description 2
- 101000785414 Homo sapiens Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1 Proteins 0.000 description 2
- 101000833492 Homo sapiens Jouberin Proteins 0.000 description 2
- 101000651236 Homo sapiens NCK-interacting protein with SH3 domain Proteins 0.000 description 2
- 102000005561 Human Isophane Insulin Human genes 0.000 description 2
- 108010084048 Human Isophane Insulin Proteins 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 102100024407 Jouberin Human genes 0.000 description 2
- 101000782488 Junonia coenia densovirus (isolate pBRJ/1990) Putative non-structural protein NS2 Proteins 0.000 description 2
- 101000811523 Klebsiella pneumoniae Uncharacterized 55.8 kDa protein in cps region Proteins 0.000 description 2
- 101000818409 Lactococcus lactis subsp. lactis Uncharacterized HTH-type transcriptional regulator in lacX 3'region Proteins 0.000 description 2
- 101000878851 Leptolyngbya boryana Putative Fe(2+) transport protein A Proteins 0.000 description 2
- XVVOERDUTLJJHN-UHFFFAOYSA-N Lixisenatide Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(N)=O)C(=O)NCC(=O)NCC(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N1C(CCC1)C(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)CC)NC(=O)C(NC(=O)C(CC(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCSC)NC(=O)C(CCC(N)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC=1C=CC=CC=1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)CNC(=O)C(N)CC=1NC=NC=1)C(C)O)C(C)O)C(C)C)CC1=CC=CC=C1 XVVOERDUTLJJHN-UHFFFAOYSA-N 0.000 description 2
- 101710125418 Major capsid protein Proteins 0.000 description 2
- 101000758828 Methanosarcina barkeri (strain Fusaro / DSM 804) Uncharacterized protein Mbar_A1602 Proteins 0.000 description 2
- 101001122401 Middle East respiratory syndrome-related coronavirus (isolate United Kingdom/H123990006/2012) Non-structural protein ORF3 Proteins 0.000 description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 101001055788 Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) Pentapeptide repeat protein MfpA Proteins 0.000 description 2
- 102100032946 N-acyl-aromatic-L-amino acid amidohydrolase (carboxylate-forming) Human genes 0.000 description 2
- 101710164334 N-acyl-aromatic-L-amino acid amidohydrolase (carboxylate-forming) Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 101000740670 Orgyia pseudotsugata multicapsid polyhedrosis virus Protein C42 Proteins 0.000 description 2
- 101000769182 Photorhabdus luminescens Uncharacterized protein in pnp 3'region Proteins 0.000 description 2
- 241001505332 Polyomavirus sp. Species 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 101000961392 Pseudescherichia vulneris Uncharacterized 29.9 kDa protein in crtE 3'region Proteins 0.000 description 2
- 101000731030 Pseudomonas oleovorans Poly(3-hydroxyalkanoate) polymerase 2 Proteins 0.000 description 2
- 101001065485 Pseudomonas putida Probable fatty acid methyltransferase Proteins 0.000 description 2
- 101000711023 Rhizobium leguminosarum bv. trifolii Uncharacterized protein in tfuA 3'region Proteins 0.000 description 2
- 101000948156 Rhodococcus erythropolis Uncharacterized 47.3 kDa protein in thcA 5'region Proteins 0.000 description 2
- 101000917565 Rhodococcus fascians Uncharacterized 33.6 kDa protein in fasciation locus Proteins 0.000 description 2
- 101000790284 Saimiriine herpesvirus 2 (strain 488) Uncharacterized 9.5 kDa protein in DHFR 3'region Proteins 0.000 description 2
- 101000936719 Streptococcus gordonii Accessory Sec system protein Asp3 Proteins 0.000 description 2
- 101000788499 Streptomyces coelicolor Uncharacterized oxidoreductase in mprA 5'region Proteins 0.000 description 2
- 101001102841 Streptomyces griseus Purine nucleoside phosphorylase ORF3 Proteins 0.000 description 2
- 101000708557 Streptomyces lincolnensis Uncharacterized 17.2 kDa protein in melC2-rnhH intergenic region Proteins 0.000 description 2
- 101000649826 Thermotoga neapolitana Putative anti-sigma factor antagonist TM1081 homolog Proteins 0.000 description 2
- 101000827562 Vibrio alginolyticus Uncharacterized protein in proC 3'region Proteins 0.000 description 2
- 101000778915 Vibrio parahaemolyticus serotype O3:K6 (strain RIMD 2210633) Uncharacterized membrane protein VP2115 Proteins 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229960004733 albiglutide Drugs 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 238000000429 assembly Methods 0.000 description 2
- 230000000712 assembly Effects 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000008033 biological extinction Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000007969 cellular immunity Effects 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 210000002249 digestive system Anatomy 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 208000028659 discharge Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 230000009881 electrostatic interaction Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229960001519 exenatide Drugs 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 208000005252 hepatitis A Diseases 0.000 description 2
- 230000028996 humoral immune response Effects 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000976 ink Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 229960005232 insulin (human) Drugs 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 210000004347 intestinal mucosa Anatomy 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 229960001093 lixisenatide Drugs 0.000 description 2
- 108010004367 lixisenatide Proteins 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
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000001690 micro-dialysis Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 229960005485 mitobronitol Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002088 nanocapsule Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000012634 optical imaging Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 108010069653 peptide E (adrenal medulla) Proteins 0.000 description 2
- 229960003611 pramlintide Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- QYEAAMBIUQLHFQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-[3-(pyridin-2-yldisulfanyl)propanoylamino]hexanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCNC(=O)CCSSC1=CC=CC=N1 QYEAAMBIUQLHFQ-UHFFFAOYSA-N 0.000 description 1
- OJQLGILETRTDGQ-IRXDYDNUSA-N (2s)-1-[3-[2-[3-[[(5s)-5-amino-5-carboxypentyl]amino]propoxy]ethoxy]propyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H](N)CCCCNCCCOCCOCCCN1CCC[C@H]1C(O)=O OJQLGILETRTDGQ-IRXDYDNUSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- XYPANFGXFLOTDK-CJLNJPJHSA-N 1b-de-l-phenylalanine-insulin Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1 XYPANFGXFLOTDK-CJLNJPJHSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- ZLSZIIAFPPICKE-UHFFFAOYSA-N 4-chloro-3-iodo-1h-quinolin-2-one Chemical compound C1=CC=C2C(Cl)=C(I)C(=O)NC2=C1 ZLSZIIAFPPICKE-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282421 Canidae Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 101000636168 Grapevine leafroll-associated virus 3 (isolate United States/NY1) Movement protein p5 Proteins 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 101900111963 Hepatitis E virus Capsid protein Proteins 0.000 description 1
- 241001122120 Hepeviridae Species 0.000 description 1
- 241001112094 Hepevirus Species 0.000 description 1
- 101710121996 Hexon protein p72 Proteins 0.000 description 1
- 101000619708 Homo sapiens Peroxiredoxin-6 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 108010090613 Human Regular Insulin Proteins 0.000 description 1
- 102000013266 Human Regular Insulin Human genes 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 101710190529 Insulin-like peptide Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 108010081368 Isophane Insulin Proteins 0.000 description 1
- 102000005237 Isophane Insulin Human genes 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
- 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
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102100022239 Peroxiredoxin-6 Human genes 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 241000156302 Porcine hemagglutinating encephalomyelitis virus Species 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 description 1
- 108020004688 Small Nuclear RNA Proteins 0.000 description 1
- 102000039471 Small Nuclear RNA Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 238000012338 Therapeutic targeting Methods 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108020004566 Transfer RNA Proteins 0.000 description 1
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- COQLPRJCUIATTQ-UHFFFAOYSA-N Uranyl acetate Chemical compound O.O.O=[U]=O.CC(O)=O.CC(O)=O COQLPRJCUIATTQ-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 108010067674 Viral Nonstructural Proteins Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 231100000354 acute hepatitis Toxicity 0.000 description 1
- 231100000836 acute liver failure Toxicity 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940112930 apidra Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- NKLPQNGYXWVELD-UHFFFAOYSA-M coomassie brilliant blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
- 238000007728 cost analysis Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000009748 deglutition Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229950004145 efpeglenatide Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000000887 face Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 210000004475 gamma-delta t lymphocyte Anatomy 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 150000002343 gold Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229940103471 humulin Drugs 0.000 description 1
- 229940084776 humulin n Drugs 0.000 description 1
- 229940084769 humulin r Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000012317 liver biopsy Methods 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000012092 media component Substances 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229940103453 novolin Drugs 0.000 description 1
- 229940098815 novolin n Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 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
- 230000006320 pegylation Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000620 pharmacotoxicology Toxicity 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- IMFIKFZWLAWMQE-UHFFFAOYSA-M potassium 2-(N-morpholino)ethanesulfonate Chemical compound [K+].[O-]S(=O)(=O)CCN1CCOCC1 IMFIKFZWLAWMQE-UHFFFAOYSA-M 0.000 description 1
- 229960004457 pramlintide acetate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- PCECOBNFTOWLGE-UHFFFAOYSA-N pyrrole-2,5-dione;azide Chemical compound [N-]=[N+]=[N-].O=C1NC(=O)C=C1 PCECOBNFTOWLGE-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229940118080 saxenda Drugs 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 108010060325 semaglutide Proteins 0.000 description 1
- 229950011186 semaglutide Drugs 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940035447 tanzeum Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229940007428 victoza Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5176—Compounds of unknown constitution, e.g. material from plants or animals
- A61K9/5184—Virus capsids or envelopes enclosing drugs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- 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
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
- C12N2015/8518—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic expressing industrially exogenous proteins, e.g. for pharmaceutical use, human insulin, blood factors, immunoglobulins, pseudoparticles
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/14011—Baculoviridae
- C12N2710/14111—Nucleopolyhedrovirus, e.g. autographa californica nucleopolyhedrovirus
- C12N2710/14141—Use of virus, viral particle or viral elements as a vector
- C12N2710/14144—Chimeric viral vector comprising heterologous viral elements for production of another viral vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/28011—Hepeviridae
- C12N2770/28111—Hepevirus, e.g. hepatitis E virus
- C12N2770/28122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/28011—Hepeviridae
- C12N2770/28111—Hepevirus, e.g. hepatitis E virus
- C12N2770/28123—Virus like particles [VLP]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/28011—Hepeviridae
- C12N2770/28111—Hepevirus, e.g. hepatitis E virus
- C12N2770/28134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/28011—Hepeviridae
- C12N2770/28111—Hepevirus, e.g. hepatitis E virus
- C12N2770/28141—Use of virus, viral particle or viral elements as a vector
- C12N2770/28142—Use of virus, viral particle or viral elements as a vector virus or viral particle as vehicle, e.g. encapsulating small organic molecule
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/28011—Hepeviridae
- C12N2770/28111—Hepevirus, e.g. hepatitis E virus
- C12N2770/28141—Use of virus, viral particle or viral elements as a vector
- C12N2770/28143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/28011—Hepeviridae
- C12N2770/28111—Hepevirus, e.g. hepatitis E virus
- C12N2770/28171—Demonstrated in vivo effect
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Diabetes (AREA)
- Physics & Mathematics (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Endocrinology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Botany (AREA)
- Toxicology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
提供了基于戊型肝炎病毒(HEV)的病毒样颗粒(VLP),其用含有至少一部分的开放阅读框2(ORF2)蛋白的修饰的衣壳蛋白制成并包封胰岛素蛋白或编码胰岛素的核酸。还提供了使用HEV VLP靶向递送胰岛素的方法。
Description
相关申请
本发明要求2018年3月13日提交的第62/642,356号美国专利申请的优先权,出于所有目的将其内容以其整体通过引用特此并入。
关于联邦赞助的研究和开发下作出的发明的权利的声明
本发明是在国立卫生研究院授予的和USDA国家食品和农业研究所拨款的AI095382、EB021230和CA198880合同下由政府支持完成的。政府拥有本发明的某些权利。
发明背景
病毒样颗粒(VLP)可用作用于靶向递送诊断方案和治疗方案(例如DNA/RNA和各种化疗剂)的纳米载体。戊型肝炎病毒(HEV)是引起人类急性肝炎的肠道传播病毒。HEV病毒样颗粒(HEV VLP)是衣壳蛋白二十面体笼,其可以通过在真核表达系统中主要衣壳蛋白HEV开放阅读框2(ORF2)的表达而产生。HEV VLP在酸和蛋白水解环境中是稳定的,这是HEV的自然传递途径所必需的特征。因此,HEV VLP代表了可被开发的例如用于递送治疗剂、成像剂或疫苗的有希望的纳米载体。
已经考虑纳米载体用于治疗的一种疾病是糖尿病,这是非常普遍的疾病,特别是在发达国家。尽管已经开发了许多其它药物来治疗糖尿病,但胰岛素仍然是治疗1型糖尿病(T1D)和晚期2型糖尿病(T2D)的首选药物。尽管糖尿病患者的发病率和死亡率因胰岛素而大大降低,但是60%的患者仍未能获得长期的葡萄糖控制[1]。这可能是由胰岛素给药中与针的典型用法有关的不适和病耻感引起的。相反,胰岛素的口服递送被认为是方便的、成本有效的并具有最高患者依从性的优选给药方法。此外,口服途径模拟了从胰腺通过肝门静脉到肝脏的内源性胰岛素分泌途径,以实现更好的葡萄糖体内平衡[2-4]。由于胰岛素在胃肠(GI)道中作为蛋白质降解,以及其通过肠上皮的渗透性差,因此胰岛素的生物利用度低,这已经严重阻碍了口服胰岛素递送的进展[4,5]。尽管如此,口服递送仍然是相对于针注射的有吸引力的替代方案,特别是因为曾经有利的肺部途径错过了作为真实前景的预测[6]。
已经提出了几种口服胰岛素递送药物,其利用通过诸如片剂、胶囊、肠贴剂、水凝胶、微粒和纳米颗粒的平台通过回肠和结肠的细胞旁和/或跨细胞转运。在几篇综述文献[4,7-10]中,对口服胰岛素的发展现状和临床试验不同阶段的进展进行了综述。其中,以色列的Oram Pharmaceuticals Inc.拥有专利蛋白质口服递送(PODTM)技术,其采用由包封、蛋白酶抑制剂和螯合剂组成的三管齐下的方法。其对T1D和T2D患者的临床试验正在进行。丹麦的Novo Nordisk A/S已经进行了1期和2期的临床试验,其采用在肠溶包衣的凝胶胶囊中的基于油和表面活性剂或脂肪酸衍生物混合物的微乳液的口服胰岛素片剂。尽管在临床试验中取得了初步成功,但由于该系统效率低,Novo Nordisk做出了艰难的决定,决定在2016年底终止其口服胰岛素开发计划。基于这些先驱开发者所学到的技术和经验,本发明人试图解决几个成本有效的因素,例如足够的生物利用度和胰岛素的可再现吸收,这与对膳食依赖的吸收速率和口服胰岛素递送系统的大量生产的理解有关。
自1970年代末克隆胰岛素基因并在培养的细胞中表达时,基因疗法的发展也被提议作为糖尿病的可能的治愈方法[11]。Madison,WI-based startup,Insulete试图将诱导患者肝细胞中产生胰岛素的基因疗法商业化。它们靶向肝脏,而不是胰腺,因为它具有再生的能力。在先前的动物试验中,单次注射裸胰岛素DNA质粒可提供长达6周的血糖控制[12]。然而,该系统缺乏特定的组织/细胞靶向递送,这仍然需要被解决以进行有效治疗。因此,在糖尿病治疗中迫切需要开发用于胰岛素递送的新的有效手段。本发明满足了这种和其它相关的需要。
发明的简要概述
本发明提供了旨在靶向递送胰岛素的HEV VLP以及使用这种HEV VLP递送胰岛素的方法。
在第一方面,本发明提供了组合物,其包含(a)修饰的衣壳蛋白,其包含戊型肝炎病毒(HEV)开放阅读框2(ORF2)蛋白的至少一部分,并且能够形成HEV病毒样颗粒(VLP);和(b)包封在由修饰的衣壳蛋白形成的HEV VLP内的蛋白质形式或多核苷酸编码序列形式的胰岛素。通常,修饰的ORF2蛋白短于全长的野生型蛋白(例如,SEQ ID NOs:1-6中提供的任何一种)。ORF2蛋白的具体修饰可以是本发明人在先前的公开中描述的那些,参见,例如,美国专利号8,906,862和8,906,863、WO2015/179321。
在一些实施方案中,修饰的衣壳蛋白短于全长的HEV ORF2蛋白;其包含SEQ IDNO:1、2、3、4、5或6的HEV ORF2蛋白的片段452-606;并且其包含在SEQ ID NO:1、2、3、4、5或6的片段483-490、530-535、554-561、573-577、582-593或601-603内插入到HEV ORF2蛋白的部分中的异源多肽序列。在一些实施方案中,紧接在SEQ ID NO:1、2、3、4、5或6的残基Y485之后插入异源多肽序列。在一些实施方案中,异源多肽可参与靶向肝细胞以递送胰岛素,例如,最广泛使用的归巢肽,RGD(Arg-Gly-Asp)肽或环状RGD肽[1],其显示对整联蛋白vb 3和vb 5的强亲和力,或特异性靶向HCC的归巢肽,包括TTPRDAY[2]、FQHPSFI(HCBP1)[3]、SFSIIHTPILPL(SP94)[4]、RGWCRPLPKGEG(HC1)[5]、AGKGTPSLETTP(A54)[6]、KSLSRHDHIHHH(HCC79)[7]和AWYPLPP[8]。
在一些实施方案中,修饰的衣壳蛋白能够形成酸和蛋白水解稳定的HEV VLP,并且具有被半胱氨酸或赖氨酸取代的SEQ ID NO:1、2、3、4、5或6的至少一个残基Y485、T489、S533、N573或T586,并且所述半胱氨酸或赖氨酸任选地被化学衍生化。在一些实施方案中,半胱氨酸或赖氨酸被烷基化、酰化、芳基化、琥珀酰化、氧化,或与可检测标记或肝细胞靶向配体缀合。例如,可检测标记可以包括荧光团、超顺磁性标记、MRI造影剂、正电子发射同位素或原子序数大于20的第3族至第18族元素的簇。在一些实施方案中,可检测标记包括金纳米簇。在另一个实例中,肝细胞靶向配体是异源多肽,其可以参与靶向肝细胞以用于递送胰岛素,例如,最广泛使用的归巢肽,RGD(Arg-Gly-Asp)或环状RGD肽[1],或特异性靶向HCC的归巢肽,包括TTPRDAY[2]、FQHPSFI(HCBP1)[3]、SFSIIHTPILPL(SP94)[4]、RGWCRPLPKGEG(HC1)[5]、AGKGTPSLETTP(A54)[6]、KSLSRHDHIHHH(HCC79)[7]和AWYPLPP[8]。
在一些实施方案中,所述组合物可还包含药学上可接受的赋形剂,或其可被配制用于口服施用,例如用于治疗糖尿病患者。
在第二方面,本发明提供了将胰岛素靶向递送至肝细胞的方法,所述方法包括使肝细胞与上文和本文所述的任何种类的组合物接触,尤其是肝细胞与肝细胞靶向配体如RGD(环状RGD)肽接触的步骤[1]。
在一些实施方案中,肝细胞在患者体内,并且接触步骤包括向患者施用包含有效量的上文和本文所述的HEV VLP的组合物。在一些实施方案中,所述施用是口服施用。在一些实施方案中,修饰的衣壳蛋白包含与金纳米簇缀合的半胱氨酸或赖氨酸。在一些实施方案中,患者已被诊断患有糖尿病。在一些实施方案中,患者是动物,特别是哺乳动物,例如灵长类动物,包括人。
附图的简要说明
图1:包封胰岛素的HEVNP的示意图。(左图)包封胰岛素的HEVNP的口服递送途径。HEVNP将通过胃肠道,然后通过肝门静脉到达肝脏。(右图)
图2:胰岛素的TEM显微照片(A);包封胰岛素的HEVNP(B);在TEM观察下的包封胰岛素的HEVNP的大小分布。它们中的大多数具有约52nm的大小(C);包封胰岛素的HEVNP的TEM图像。该条棒的长度为100nm。
图3:包封胰岛素的HEVNP的TEM显微照片:没有胃蛋白酶处理作为对照(A);在pH3、37℃下胃蛋白酶(38U/ml)处理5min后(B);在pH 4、37℃下胃蛋白酶(38U/ml)处理5min(C)。该条棒的长度为100nm。
图4:HEVNP的胰岛素包封:优化封装条件以提高HEVNP中胰岛素包封效率。
图5:HEVNP的胰岛素包封:优化封装条件以提高通过Bradford测定和ELISA测试的HEVNP中胰岛素包封效率;声处理介导的有效载荷增强(下图)。
图6:尺寸排阻柱分析:显示如ELISA所示的具有重叠的胰岛素和HEVNP的不同峰(由在条件#16和#32之间的+符号表示)。
图7:HEVNP的胰岛素包封:冷冻电子显微镜结构引导的胰岛素封装的优化,随后进行胰岛素封装的3D建模和封装机制的计算验证。采集电子显微镜断层扫描倾斜序列数据以重建HEVNP-胰岛素的3D表达。
图8:高稳定性和保存期:将HEVNP-胰岛素样品在4℃储存超过一年,并用cryo-EM检查。显微照片显示完整的颗粒,其在储存条件下显示高稳定性。
图9:经由AuNC的HEVNP的增强的稳定性:基于衣壳表面修饰,经由簇集的金属原子增强的HEVNP稳定性的CryoArm 300kV显微术和3D图像重建。高分辨率结构测定是优化HEVNP粘膜递送的关键。
定义
本说明书和所附权利要求书中使用的单数形式“一个”,“一种”和“该/所述”包括复数引用,除非上下文另外明确规定。
“戊型肝炎病毒”或“HEV”是指病毒、病毒类型或病毒种类,其i)引起水传播的、传染性肝炎;ii)在血清学特征方面区别于甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)或丁型肝炎病毒(HDV);和iii)含有与pTZKF1(ET1.1)中插入的1.33kb cDNA同源的基因组区域,所述pTZKF1(ET1.1)是在美国模式培养物保藏中心(ATCC)存放的登记号为67717的大肠杆菌菌株中呈现的质粒。
关于HEV的术语“衣壳蛋白”和“修饰的衣壳蛋白”是指成熟的或修饰的(例如,截短的、重组突变的或化学衍生的)HEV开放阅读框2(ORF2)多肽。如本文所用,提及这样的ORF2多肽或蛋白意味着包括全长多肽及其片段,并且还包括对ORF2蛋白进行的任何取代、缺失或插入或其它修饰。衣壳蛋白必须能够形成病毒样颗粒(VLP)。通常,衣壳蛋白至少含有HEVORF2的残基112-608,尽管衣壳蛋白可以容忍各种另外的取代、缺失或插入,只要它们耐受而不会消除VLP形成即可。
在一个实施方案中,术语“修饰的衣壳蛋白”是指衣壳蛋白或其部分(即,短于全长的衣壳蛋白),其中存在修饰,例如添加、缺失、取代中的一种或多种,但所得修饰的衣壳蛋白仍然能够形成VLP。这些修饰包括在美国专利号8,906,862和8,906,863、WO2015/179321中描述的那些。例如,可以将异源多肽插入衣壳蛋白或其部分中,在诸如片段483-490、530-535、554-561、573-577、582-593或601-603内的位置插入,或者紧接在残基Y485之后插入,参见美国专利号8,906,862和8,906,863。作为另一个实例,WO2015/179321描述了修饰的衣壳蛋白的其它实例,其中HEV ORF2的P结构域的表面可变环被修饰以掺入一个或多个半胱氨酸或赖氨酸,半胱氨酸或赖氨酸不存在于野生型衣壳蛋白序列中。或者,或另外地,术语“修饰的衣壳蛋白”是指衣壳蛋白或其部分,其中HEV ORF2的C-末端(例如,位置608)被修饰以掺入一个或多个半胱氨酸或赖氨酸,半胱氨酸或赖氨酸不存在于野生型衣壳蛋白序列中。或者,或另外地,术语“修饰的衣壳蛋白”是指衣壳蛋白或其部分,其中半胱氨酸或赖氨酸(例如,HEV ORF2的P-结构域的表面可变环的半胱氨酸或赖氨酸或在位置608处重组引入的半胱氨酸/赖氨酸)被化学衍生化以共价缀合至蛋白质至少一个异源原子或分子。可以插入半胱氨酸或赖氨酸,使得HEV ORF2蛋白长度增加,或者半胱氨酸或赖氨酸可以替换P-结构域表面可变环和/或C-末端的一个或多个残基。
通常,修饰的衣壳蛋白保留了形成HEV VLP的能力。在一些情况下,一个或多个半胱氨酸或赖氨酸与生物活性剂(例如,细胞靶向配体,例如肽LXY30)缀合。P-结构域表面可变环包括例如HEV ORF 2(SEQ ID NO:1、2、3、4、5或6)的残基475-493;残基502-535;残基539-569;残基572-579;和残基581-595中的一个或多个。P-结构域表面可变环还包括多肽的残基,其包含与SEQ ID NO:1、2、3、4、5或6中的一个或多个具有至少约80%、85%、90%、95%、99%或更多同一性的并且对应于SEQ ID NO:1、2、3、4、5或6的残基475-493;残基502-535;残基539-569;残基572-579;和残基581-595中的一个或多个的氨基酸序列。
如本文所用,术语“病毒样颗粒”(VLP)是指由衣壳蛋白形成的二十面体壳(例如,T1或T3)。VLP由于缺少病毒基因组而不是感染性的。“VLP”是指衍生自戊型肝炎病毒衣壳蛋白HEV ORF2或其部分的非复制二十面体病毒壳。VLP可以在适当的表达系统中蛋白质的重组表达时自发地形成。在一些实施方案中,VLP由修饰的衣壳蛋白形成,例如在HEV ORF2或其部分的表面可变环中含有一个或多个半胱氨酸/赖氨酸残基的衣壳蛋白。HEV VLP可以含有修饰的和/或未修饰的HEV ORF2蛋白的混合物。
在HEV VLP的上下文中,术语“酸和蛋白水解稳定的”是指对哺乳动物消化系统的酸和蛋白水解环境具有抗性的HEV VLP。评价酸和蛋白水解稳定性的方法描述于Jariyapong et al.,2013中,并且包括但不限于使HEV VLP经受酸(例如,pH为或约为6、5.5、5、4.5、4、3.5、3、2.5或2)和/或蛋白水解环境(例如,胰蛋白酶和/或胃蛋白酶),并且通过电子显微术、凝胶过滤色谱法或其它合适的方法检查接触的HEV VLP以确定HEV VLP的四级结构(例如,T=1,T=3,二十面体,十二面体等)是否被保留。HEV VLP群体(例如,修饰的或未修饰的)可以在酸和/或蛋白水解条件下孵育合适的时间段(例如,至少或至少约1、2、3、4、5、10、15、20、30、45或60分钟),然后测试以确定四级结构保留的程度。在本文中,酸和蛋白水解稳定的修饰的HEV VLP是指修饰的HEV VLP当在酸和/或蛋白水解条件下作为VLP群体进行孵育并通过电子显微术进行分析时,该群体的至少10%、25%、50%、75%、90%、95%、99%或100%的VLP保持它们的四级结构。
或者,HEV VLP可以通过口服途径递送至个体,并且通过检测和/或定量如下内容评价递送效率:(i)对HEV VLP内的抗原的免疫应答;(ii)与HEV VLP缀合的、重组引入至HEVVLP内的或被HEV VLP包封的可检测标记;或(iii)由于向细胞递送与HEV VLP相关(例如,重组引入至HEV VLP内、与HEV VLP缀合或被HEV VLP包封)的生物活性剂而引起的生物应答。在本文中,酸和蛋白水解稳定的修饰的HEV VLP是指保留未修饰的HEV VLP的至少10%、25%、50%、75%、90%、95%、99%或100%的口服递送功效和/或细胞进入活性的修饰的HEV VLP。
在描述两个元件的相对位置的上下文中使用的术语“异源的”是指在相同的相对位置处不是天然发现的两个元件,例如核酸(例如,启动子或蛋白编码序列)或蛋白质(例如,HEV ORF2蛋白,或其部分,或修饰的衣壳蛋白和另一种蛋白)。因此,基因的“异源启动子”是指与该基因不是天然可操作性连接的启动子。类似地,在HEV VLP或HEV衣壳蛋白的上下文中的“异源多肽”或”异源核酸”是衍生自非HEV源的一种。
已知戊型肝炎病毒(HEV)引起严重的急性肝衰竭。HEV属于肝炎病毒科(Hepeviridae)家族中的肝炎病毒(Hepevirus)属。HEV含有约7.2-kb的单链正义RNA分子。该RNA是3'聚腺苷酸化的并且包括三个开放阅读框(ORF)。ORF1编码病毒非结构蛋白,位于基因组的5'一半。ORF2编码蛋白质形成病毒衣壳,位于基因组的3'末端的。ORF3编码13.5-kDa蛋白质,与ORF1的C-末端和ORF2的N-末端重叠。ORF3与膜以及与细胞骨架部分有关。
本文所用的术语“包封”或“包封的”是指在本文所定义的VLP内包封异源物质,例如异源核酸或蛋白质、化学治疗剂、成像剂、铁氧体纳米颗粒等。
术语“生物活性剂”是指靶向特定生物位置(靶向剂)和/或提供可在体内或体外证实的一些局部或全身性生理或药理学作用的任何药剂、药物、化合物或其混合物。非限制性实例包括药物、激素、疫苗、抗体、抗体片段、维生素和辅因子、多糖、碳水化合物、类固醇、脂质、脂肪、蛋白质、肽、多肽、核苷酸、寡核苷酸、多核苷酸和核酸(例如,mRNA、tRNA、snRNA、RNAi、DNA、cDNA、反义构建体、核酶等)。
“药学上可接受的”或“药理学上可接受的”材料为不是生物学上有害的或在其它方面不合需要的材料,即,该材料可以与衣壳蛋白或HEV VLP或本发明的组合物一起施用于个体而不引起任何不合需要的生物效应。该材料不会以有害的方式与其中包含该材料的组合物的任何组分相互作用。
术语“赋形剂”是指可存在于本发明组合物的最终剂型中的任何基本上辅助物质。例如,术语“赋形剂”包括媒介物、粘合剂、崩解剂、填充剂(稀释剂)、润滑剂、助流剂(流动增强剂)、压制助剂、着色剂、甜味剂、防腐剂、助悬剂/分散剂、成膜剂/包衣剂、矫味剂和印刷油墨。
术语“佐剂”是指当与抗原联合施用时增强对抗原的免疫应答,但当单独施用时不产生对抗原的免疫应答的化合物。佐剂可以通过几种机制增强免疫应答,包括淋巴细胞募集、刺激B细胞和/或T细胞和刺激巨噬细胞。
对抗原或组合物的“免疫原性应答”是在个体中发展对所关注的组合物中存在的抗原的体液免疫应答和/或细胞免疫应答。为了本公开的目的,“体液免疫应答”是指由抗体分子介导的免疫应答,而“细胞免疫应答”是由T-淋巴细胞和/或其它白细胞介导的免疫应答。细胞免疫的一个重要方面涉及通过溶细胞性T细胞(“CTL”)的抗原特异性应答。CTL对肽抗原具有特异性,所述肽抗原与由主要组织相容性复合物(MHC)编码的并在细胞表面上表达的蛋白质联合存在。CTL有助于诱导和促进细胞内微生物的破坏,或这些微生物感染的细胞的溶解。细胞免疫的另一方面涉及通过辅助T细胞的抗原特异性应答。辅助性T细胞有助于帮助刺激非特异性效应细胞的功能,并将非特异性效应细胞的活性集中于在其表面上显示与MHC分子相联系的肽抗原的细胞。“细胞免疫应答”还指产生细胞因子、趋化因子和其它这样的由活化的T细胞和/或其它白细胞(包括衍生自CD4+和CD8+T细胞的那些)产生的分子。因此,免疫应答可包括一种或多种以下效果:通过B细胞产生抗体;和/或特异性针对存在于所关注的组合物或疫苗中的一种或多种抗原的抑制性T细胞和/或γΔT细胞的活化。这些应答可有助于中和感染性,和/或介导抗体-补体,或抗体依赖性细胞介导的细胞毒性(ADCC)以提供对免疫的宿主的保护。这种应答可以使用本领域熟知的标准免疫测定和中和测定来测定。
“标记”、“可检测标记”或“可检测部分”是通过光谱学、光化学、生物化学、免疫化学、化学或其它物理手段可检测的组合物。例如,有用的标记包括32P、荧光染料、电子致密试剂、酶(例如通常用于ELISA的酶)、生物素、地高辛或半抗原和蛋白质,所述蛋白质例如可通过将放射性组分掺入肽中而变得可检测,或所述蛋白质可用于检测与肽特异性反应的抗体。通常,可检测标记是与具有确定的结合特性的探针或分子(例如,具有已知的结合特异性的多肽或多核苷酸)连接的异源部分,从而使得探针/分子(以及因此其结合靶)的存在易于检测。标记的异源性质确保其具有的来源与其标记的探针或分子不同,使得与可检测标记连接的探针/分子不构成天然存在的组合物。
本申请中使用的术语“治疗(treat)”或“治疗(treatment)”描述了导致相关病况的任何症状的消除、减少、缓解、逆转或预防或延迟发作或复发的行为。换句话说,“治疗”病况包括对该病况的治疗和预防性干预。
本文所用的术语“有效量”是指给定物质的在数量上足以产生所需效果的量。例如,包封胰岛素的HEV纳米颗粒(HEVNP)的有效量是实现可检测效果的所述HEVNP的量,使得出于治疗目的在已经给予HEVNP的患者中,目标疾病(例如,糖尿病)的症状、严重性和/或复发机会被减轻、逆转、消除、预防或延迟发作。足以实现此目的的量被定义为“治疗有效剂量”。剂量范围随所施用的治疗剂的性质和其它因素(例如施用途径和患者病况的严重程度)而变化。
本文所用的术语“患者”是指脊椎动物,例如鸟类或哺乳动物的物种,尤其是哺乳动物(例如公牛/母牛、猪、绵羊/山羊、马、兔、啮齿类、狗、猫、狐等),包括灵长类如黑猩猩、猴或人。
发明的详细说明
A.引言
本公开涉及基于病毒的纳米衣壳,其在化学上稳定并且对胃肠道中的酶活性具有抗性,用于胰岛素的口服递送。众所周知,在糖尿病治疗中包括不良的患者依从性在内的某些限制归因于与用于胰岛素给药的普遍使用的针注射相关的不适和不良作用。尽管口服递送是胰岛素(分子量为5.8kDa的蛋白质)的最有利的递送途径,但是它面临着挑战,这包括在胃肠道中被蛋白水解酶降解和严重的酸生理条件以及在吸收和通过肠上皮渗透之后的递送效力。尽管已经开发了几种胰岛素口服递送系统并批准用于临床试验,但需要解决许多与成本相关的因素,包括需要提高低的生物利用度,实现可再现的吸收,获得对膳食依赖性吸收速率和口服施用的胰岛素递送系统的大量生产的理解。
戊型肝炎病毒纳米颗粒(HEVNP)衍生自自组装的非传染性纳米衣壳。HEVNP在酸性环境中是稳定的并且抗蛋白水解消化,因此其作为口服递送媒介物具有巨大的优势。HEVNP可口服施用,然后转运到小肠并最终在HEV的天然传播途径之后转运到肝脏。HEVNP由于其体外解装/重新组装能力,能够包封药物或核酸以将其递送通过胃肠道中的消化系统。特异性靶向配体(例如,靶向递送至肝脏的配体)可以通过基因工程或化学缀合连接至HEVNP的突出结构域。HEVNP结构可以通过缀合单分散的金纳米簇(AuNC)来稳定,以获得口服递送的药物(例如胰岛素)的更好的生物利用度[18]。
本公开的具体方面以及本发明人的较早公开(参见,例如,美国专利号8,906,862和8,906,863,WO2015/179321)概述了HEVNP产生以及在表面修饰、用于口服递送胰岛素至肝脏的包封和模拟其从胰腺至肝脏的生理分泌途径中的方法和应用。
作为口服胰岛素递送胶囊,结构稳定的HEVNP提供以下益处:(1)消除针、相关风险和处置要求;(2)胰岛素,本身作为多肽或多核苷酸编码序列,可以容易地体外包封到HEVNP结构内并递送至肝脏,甚至没有靶向配体。然而,治疗性靶向配体将能够并增强胰岛素(例如,胰岛素基因)特异性递送至胰腺;(3)由衣壳蛋白组成的HEVNP可以通过蛋白降解途径被生物降解,而几乎没有毒理学问题。
各种形式的包封胰岛素的HEVNP的组合可用作综合疗法以更好地控制糖尿病患者的血糖水平。HEVNP的大规模化生产和表达将在关于治疗方案的成本分析的动物测试之后进行。
B.修饰的衣壳蛋白的制备和纯化以及VLP形成
本发明的一个方面涉及用于生产和纯化衣壳蛋白和由其衍生的VLP的方法(参见Expression and self-assembly of empty virus-like particles of hepatitis Evirus.Li TC,Yamakawa Y,Suzuki K,Tatsumi M,Razak MA,Uchida T,Takeda N,MiyamuraT.,J Virol.1997Oct;71(10):7207-13.Essential elements of the capsid proteinfor self-assembly into empty virus-like particles of hepatitis E virus.Li TC,Takeda N,Miyamura T,Matsuura Y,Wang JC,Engvall H,Hammar L,Xing L,Cheng RH.JVirol.2005Oct;79(20):12999-3006.Niikura M et al,Chimeric recombinanthepatitis E virus-like particles as an oral vaccine vehicle presentingforeign epitopes.Virology 2002;293:273-280)。在一个实施方案中,衣壳蛋白是修饰的衣壳蛋白,衍生自它的VLP是半胱氨酸/赖氨酸修饰的HEV VLP。例如,修饰的衣壳蛋白在HEVORF2或其部分的表面可变环中含有一个或多个半胱氨酸/赖氨酸残基。
各种表达系统可用于表达本发明的衣壳蛋白。可用于产生本发明的病毒样颗粒的表达系统的实例包括但不限于细菌表达系统(例如大肠杆菌)、昆虫细胞、酵母细胞和哺乳动物细胞。本发明优选的表达系统包括使用昆虫细胞的杆状病毒表达系统。用于处理和制备杆状病毒载体和杆状病毒DNA的一般方法以及昆虫细胞培养程序在A Manual ofMethods for Baculovirus Vectors and Insect Cell Culture Procedures(杆状病毒载体和昆虫细胞培养程序的方法手册)的中概述。
可以将本发明的衣壳蛋白克隆到杆状病毒载体中,并用于感染合适的宿主细胞(参见,例如,O'Reilly et al.,"Baculovirus Expression Vectors:A Lab Manual,"Freeman&Co.1992.)。可以用含有编码本发明衣壳蛋白的多核酸的转移载体转化昆虫细胞系(例如Sf9或Tn5)。转移载体包括,例如,线性化的杆状病毒DNA和含有所需多核苷酸的质粒。宿主细胞系可以与线性化的杆状病毒DNA和质粒共转染以产生重组杆状病毒。
本发明的病毒样颗粒的纯化可以根据本领域的标准技术进行(参见Li TC,etal.,J Virol.1997Oct;71(10):7207-13.Li TC,et al.,J Virol.2005Oct;79(20):12999-3006.Niikura M et al,Virology 2002;293:273-280)。然后将纯化的VLP重悬浮于合适的缓冲液中。
在一些实施方案中,修饰的衣壳蛋白或自其衍生的VLP可以与一种或多种生物活性剂化学缀合。例如,可以使用本领域已知的方法将衣壳蛋白的一个或多个半胱氨酸/赖氨酸残基酰化、烷基化、芳基化、琥珀酰化或氧化。在一些情况下,可以使用马来酰亚胺官能团将一个或多个半胱氨酸/赖氨酸残基缀合,以将生物活性剂共价缀合至半胱氨酸或赖氨酸的硫醇部分。在一些情况下,可以使用CLICK化学修饰生物活性剂以引入马来酰亚胺官能团。例如,生物活性剂的炔衍生物可以在CuSO4和抗坏血酸的存在下与马来酰亚胺-叠氮化物接触以产生马来酰亚胺生物活性剂。马来酰亚胺然后可以与修饰的衣壳蛋白的一个或多个半胱氨酸/赖氨酸接触以共价连接所述两个分子。在一些情况下,对未组装成VLP的衣壳蛋白实施缀合(例如,在EDTA、EGTA和/或还原剂如DTT或β巯基乙醇的存在下)。在一些情况下,对组装成VLP的衣壳蛋白实施缀合。
C.生物活性剂的包封
本发明的另一方面涉及将一种或多种生物活性剂包封在HEV病毒样颗粒(例如半胱氨酸/赖氨酸修饰的HEV VLP)中(参见,DNA vaccine-encapsulated virus-likeparticles derived from an orally transmissible virus stimulate mucosal andsystemic immune responses by oral administration,Gene Therapy 2004.11,628–635.S Takamura,M Niikura,T-C Li,N Takeda,S Kusagawa,Y Takebe,T Miyamura and YYasutomi)。可以使用本领域中的任何标准技术将异源核酸、蛋白质、多肽、化学治疗剂、成像剂、纳米颗粒等包封到本发明的VLP中。示例性的生物活性剂是蛋白质形式或核酸形式的胰岛素。通用程序包括(1)将根据本发明的由衣壳蛋白形成的VLP解装;以及(2)在生物活性剂存在下重建VLPs。本领域技术人员将认识到,优选地在包封程序之前具有纯化的VLP。特别优选地,在包封程序之前,使VLP中的任何不需要的物质(例如,核酸)被耗尽或基本上被耗尽。
可以使用本领域中的任何标准技术进行VLP的解装。重构的病毒样颗粒可以在生理条件下产生(参见美国专利公开号20080131928)。通常,病毒样颗粒的解装需要破坏VLP的组装的试剂,例如还原剂或螯合剂(参见美国专利公开号20040152181)。本领域技术人员将认识到,影响组装和解装的因素和条件包括:pH、离子强度、病毒衣壳蛋白的翻译后修饰、二硫键和二价阳离子键合等等。例如,对于多瘤病毒(Brady et al.,J.Virol,23:717-724,1977)和轮状病毒(Gajardo et al.,J.Virol,71:2211-2216,1997),已经显示了阳离子键合,特别是钙在保持病毒体完整性中的重要性。另外,二硫键对于稳定多瘤病毒(Walter etal.,Cold Spring Har Symp.Quant.Biol,39:255-257,1975;Brady et al.,J.Virol,23:717-724,1977)和SV40病毒(Christansen et al.,J.Virol,21:1079-1084,1977)似乎是重要的。此外,已知诸如pH和离子强度的因素可能通过影响静电相互作用来影响多瘤病毒衣壳稳定性(Brady et al.,J.Virol,23:717-724,1977;Salunke et al.,Cell,46:895-904,1986;Salunke et al.,Biophys.J,56:887-900,1980)。此外,已知一些病毒衣壳蛋白的翻译后修饰可影响衣壳稳定性和组装,例如糖基化、磷酸化和乙酰化(Garcea et al.,Proc.Natl.Acad.Sci.USA,80:3613-3617,1983;Xi et al.,J.Gen.Virol,72:2981-2988,1991)。因此,存在许多可能影响衣壳稳定性、组装和解装的相关因素。
优选地,本发明的VLP通过除去钙离子而被解装(参见,Touze A,Coursaget P.Invitro gene transfer using human papillomavirus-like particles.Nucleic AcidsRes 1998;26:1317-1323;Takamura et al.,DNA vaccine-encapsulated virus-likeparticles derived from an orally transmissible virus stimulate mucosal andsystemic immune responses by oral administration.Gene Therapy 2004;11:628-635)。根据本发明,使用还原剂或螯合剂或两者解装VLP。可以使用各种还原剂。还原剂的优选实施方案包括但不限于二硫苏糖醇(DTT)。可使用各种螯合剂,例如乙二醇四乙酸(EGTA)或乙二胺四乙酸(EDTA)。VLP解装条件的实例包括但不限于以下条件:通过孵育含有50mMTris-HCl(pH 7.5)、150mM NaCl、1mM EGTA和20mM二硫苏糖醇的缓冲液30分钟来破坏纯化的VLP。
技术人员还将认识到,尽管是优选的,,但是不需要完全解装VLP以包封生物活性剂。技术人员还将认识到,在其它情况下,优选部分解装VLP。根据本发明,可以控制用于部分解装VLP的条件以仍然允许生物活性剂的有效包封。VLP的部分解装可以通过单独用还原剂(例如20mM DTT)处理VLP来实现(Sapp et al,J.Gen.Virol.,76:2407-2412,1995.)。根据本发明,一旦VLP被完全或部分地解装,可以通过在生物活性剂存在下重新组装VLP来进行生物活性剂的包封。在一些情况下,利用具有净负电荷的生物活性剂以增强包封可能是有利的。例如,核酸具有净负电荷,并且与具有正电荷或中性电荷的化合物相比,可以被优先包封。
在本发明的一些实施方案中,VLP的重新组装通过将钙离子重新补充到被破坏的VLP来实现。或者,VLP的重新组装通过除去还原剂或螯合剂来实现。任选地,可以调节诸如pH和离子强度的因素,本发明所述的其它因素,以实现VLP的有效重新组装和生物活性剂的有效包封。
在一些实施方案中,如下进行包封:在室温下孵育30分钟后,将在50mM Tris-HCl缓冲液(pH 7.5)和150mM NaCl中的生物活性剂加入到被破坏的VLP制剂中。然后通过用增加浓度的CaCl2(直至最终浓度为5mM)孵育1小时,将被破坏的VLP制剂再折叠。通过超速离心沉淀VLP并重新悬浮于10mM钾-MES缓冲液(pH 6.2)中。为了估计包封的药剂的量,从任何未包封的生物活性剂中纯化经再折叠的纯化的VLP,并用EGTA(1mM)破坏。上清液的吸光度或其它合适的方法可用于检测生物活性剂。
在一些实施方案中,将待包封的生物活性剂(例如胰岛素蛋白或编码胰岛素的核酸)或成像剂与衣壳化信号缀合。例如,对应于HEV开放阅读框1的密码子35-59的RNA元件是强的衣壳化信号,允许在体外与HEV衣壳蛋白(包括本文所述的HEV ORF2 VLP的截短形式和/或半胱氨酸/赖氨酸修饰形式)特异性相互作用。为了使用VLP作为治疗剂或成像剂的载体,可以在衣壳自组装之前使用化学接头(例如,LC-SPDP或适配体、线性-树枝状嵌段共聚物),所述化学接头用HEV衣壳化信号(例如,前述RNA元件)标记药剂(例如,化学治疗剂)。
在一些实施方案中,可检测标记(成像剂)被包封。可检测标记可以是使其所连接的分子可通过多种机制(包括化学、酶、免疫学或放射学手段)检测的部分。可检测标记的一些实例包括荧光分子(例如荧光素、若丹明、德克萨斯红和藻红蛋白)和酶分子(例如辣根过氧化物酶、碱性磷酸酶和β半乳糖苷酶),其允许基于荧光发射或酶催化的化学反应的产物进行检测。涉及各种同位素的放射性标记物,例如3H、125I、35S、14C或32P,也可以附接到适当的分子上,以能够通过任何合适的方法进行检测,所述方法记录放射性,例如放射自显影。参见,例如,Tijssen,"Practice and Theory of Enzyme Immunoassays,"LaboratoryTechniques in Biochemistry and Molecular Biology,Burdon and van KnippenbergEds.,Elsevier(1985),pp.9 20。在Polak and Van Noorden,Introduction toImmunocytochemistry,2d Ed.,Springer Verlag,NY(1997);和Haugland,Handbook ofFluorescent Probes and Research Chemicals,a combined handbook and cataloguepublished by Molecular Probes,Inc.(1996)中也可以找到标记物的引入、标记程序和标记物的检测。其它可检测标记包括但不限于超顺磁性标记(例如铁氧体)、对比增强剂(例如MRI造影剂)、原子簇(例如金簇)等。可以根据本领域已知的方法和在各种出版物中描述的方法进行单分散的金簇缀合至修饰的衣壳蛋白上,例如缀合至半胱氨酸/赖氨酸残基上,包括修饰的衣壳蛋白中人工引入的半胱氨酸/赖氨酸残基[18]。
在一些实施方案中,生物活性剂被包封。在一些情况下,生物活性剂是化学治疗剂。合适的化疗剂包括但不限于细胞毒性药物。可用于本发明的细胞毒性药物的实例包括:烷基化药物,例如环磷酰胺、异环磷酰胺、苯丁酸氮芥(ehlorambucil)、美法仑、白消安、洛莫司汀、卡莫司汀、chlormethhine(氮芥)、雌莫司汀、曲奥舒凡(treosulfan)、塞替派、二溴甘露醇(mitobronitol);细胞毒性抗生素,例如多柔比星,表柔比星,阿柔比星,伊达比星,柔红霉素,米托蒽醌(mitoxantrone)(米托蒽醌(mitozantrone)),博来霉素,放线菌素和丝裂霉素;抗代谢物,例如甲氨蝶呤,卡培他滨;阿糖胞苷,氟达拉滨,克拉屈滨,吉西他滨,氟尿嘧啶,雷替曲塞(拓优得(Tomudex)),巯嘌呤,替加氟和噻胍(tioguaninc);长春花生物碱,例如长春花碱,长春新碱,长春地辛,长春瑞滨和依托泊苷;其它肿瘤性药物,例如安吖啶、altetarmine、crisantaspase(天冬酰胺酶)、达卡巴嗪和替莫唑胺、羟基尿素(羟基脲)、喷司他丁、铂类化合物,包括:卡铂、顺铂和奥沙利铂、卟吩姆钠、丙卡巴肼、雷佐生;紫杉烷类,包括:多西他赛和紫杉醇;拓扑异构酶I抑制剂,包括INOTECAN和拓扑替康、曲妥珠单抗和维甲酸。在一些情况下,一种或多种前述成像剂和/或生物活性剂或其组合可以另外地或可替代地通过硫醇连接(thiol linkage)与P-结构域表面可变环或C-末端中的半胱氨酸或赖氨酸(例如重组引入的半胱氨酸或赖氨酸)缀合。在一些情况下,一种或多种前述成像剂和/或生物活性剂或其组合可以另外地或可替代地通过硫醇连接与P-结构域表面可变环或C-末端中的第二半胱氨酸或赖氨酸(例如重组引入的半胱氨酸或赖氨酸)缀合。
在一些实施方案中,胰岛素是包封在本发明的HEV VLP构建体中的生物活性剂。在一些情况下使用生物活性多肽形式的胰岛素(其可以包括任选的翻译后修饰,例如糖基化、PEG化或包括D-氨基酸在内的一种或多种人工氨基酸类似物的取代,等等),而在其它情况下,胰岛素是编码胰岛素和/或胰岛素原蛋白的多核苷酸序列形式(例如cDNA),例如,编码胰岛素的核酸是TA1m载体中的人胰岛素基因表达构建体[12]。胰岛素蛋白可以是重组的或者可以分离自天然来源。它可以是人胰岛素或衍生自其它动物,例如牛、猪、猫或犬动物。它可以是胰岛素原。可使用不同形式的胰岛素:速效的(Aspart(天冬胰岛素):Novolog(门冬胰岛素);Glulisine(赖谷胰岛素);Apidra(谷赖胰岛素);Lispro(赖脯胰岛素):Humalog(优泌乐));短效的(常规的:Humulin(优泌林)、Humulin R(优泌林R)、Novolin(诺和灵));中效的(NPH:Humulin N(优泌林N)、Novolin N(诺和灵N));中效至长效(Detemir(地特胰岛素));长效的(例如,Glargine(甘精胰岛素))。此外,生物活性剂可以是胰岛素的类似物,例如市售的胰岛素类似物为Levemir(地特胰岛素/诺和平);或甘精胰岛素,其为长效基础胰岛素类似物并且以名称Lantus(来得时)销售。另外,生物活性剂可以是胰岛素和胰高血糖素样肽(GLP-1)受体或其它药物的组合。GLP-1受体激动剂的实例包括liraglutide(利拉鲁肽)(Victoza(诺和力)、Saxenda(利拉鲁肽))、lixisenatide(利西拉肽)(Lyxumia(利西拉肽))、albiglutide(阿必鲁肽)(Tanzeum(阿必鲁肽))、dulaglutide(度拉糖肽)(Trulicity(度拉鲁肽))和semaglutide(索马鲁肽)(Ozempic(索马鲁肽))。胰岛素的合适形式或组合包括但不限于甘精胰岛素;赖脯胰岛素;天冬胰岛素;地特胰岛素;胰岛素(人);天冬胰岛素+天冬胰岛素鱼精蛋白;赖谷胰岛素;胰岛素(人)+低精蛋白胰岛素[INN];天冬胰岛素+德谷胰岛素;天冬胰岛素+低精蛋白胰岛素[INN];德谷胰岛素+利拉鲁肽;甘精胰岛素+利西拉肽;人胰岛素+低精蛋白胰岛素[INN];低精蛋白胰岛素[INN]+中性胰岛素;人低精蛋白胰岛素[INN]+人胰岛素;胰岛素(牛);德谷胰岛素;人胰岛素锌;低精蛋白胰岛素[INN];人低精蛋白胰岛素[INN];中性胰岛素;人胰岛素+人低精蛋白胰岛素[INN];中性胰岛素+低精蛋白胰岛素[INN];胰岛素(猪);胰岛素,中性;鱼精蛋白锌胰岛素;胰岛素;特戈胰岛素(insulintregopil)[INN];人胰岛素+人胰岛素原;甘精胰岛素+赖脯胰岛素;人胰岛素+醋酸普兰林肽;度拉糖肽;度拉糖肽+甘精胰岛素;艾塞那肽+赖脯胰岛素;甘精胰岛素+利拉鲁肽;赖脯胰岛素+普兰林肽;efpeglenatide[INN];人胰岛素+普兰林肽;艾塞那肽+人胰岛素;赖脯胰岛素+赖脯胰岛素鱼精蛋白;氯碘羟喹[INN]+人胰岛素;甘精胰岛素+赖谷胰岛素;和胰岛素I 131。此外,各种肽基和非肽基胰岛素模拟物,如Nankar et al.(Drug Discovery Today,Volume 18,Issues 15–16,August 2013,Pages 748-755)中描述的那些可用作HEV VLP中包封的生物活性剂。
当使用不同的衣壳蛋白构建体时,VLP的大小可以变化。例如,可以调节衣壳蛋白的N-末端部分以增加或降低VLP的大小和包封能力。在本发明的一些实施方案中,在构建HEV VLP时,利用与一部分的HEV ORF 2蛋白的N-末端融合的一部分的HEV ORF 3蛋白来调节VLP的大小。通常,由至少具有HEV ORF 2的残基112-608的一部分HEV ORF2形成HEV VLP。
D.药物组合物、制剂和施用
本发明还提供了包含HEV VLP的药物组合物或生理组合物,所述HEV VLP由包封生物活性剂(如蛋白形式或核酸形式的胰岛素)的修饰的衣壳蛋白形成。这种药物或生理组合物还包括一种或多种药学上或生理上可接受的赋形剂或载体。本发明的药物组合物适用于多种药物递送系统。用于本发明的合适的制剂可见于Remington's PharmaceuticalSciences,Mack Publishing Company,Philadelphia,PA,17th ed.(1985)。关于药物递送方法的简要综述,参见Langer,Science 249:1527-1533(1990)。
本发明的组合物可以与赋形剂一起施用于宿主。可用于本发明的赋形剂包括但不限于媒介物、粘合剂、崩解剂、填充剂(稀释剂)、润滑剂、助流剂(流动增强剂)、压制助剂、着色剂、甜味剂、防腐剂、助悬剂/分散剂、成膜剂/包衣、矫味剂和印刷油墨。
本发明的一个优点在于本发明的组合物适于口服递送。因为本发明的HEV VLP能够靶向肝细胞,所以可以有效地实现胰岛素的Cite-特异性递送。而且,由于衣壳蛋白的修饰,本发明的HEV VLP在酸性环境中是稳定的,并且在胃肠道中对消化具有抗性,因此它适于口服递送胰岛素。与半胱氨酸或赖氨酸残基缀合的金纳米簇,尤其是在本发明的一些实施方案中被工程化到修饰的衣壳蛋白的表面内的那些金纳米簇,进一步增强HEV VLP的稳定性、生物利用度和递送效率。因此,本发明的组合物的口服递送可以有效地为患有胰岛素不足或失调,例如I型或II型糖尿病以及相关症状的患者提供治疗益处。本发明的HEV VLP可以配制成固体(例如粉末)或液体的形式,使得其可以用作日常生活中消费的普通食品或饮料物品的补充。
另外,本发明的组合物也可以配制用于粘膜递送,例如递送至颊粘膜或唇粘膜或呼吸道粘膜,包括鼻粘膜。
本发明的药物组合物可以通过各种途径施用,例如口服、皮下、透皮、皮内、肌内、静脉内或腹膜内施用。施用药物组合物的优选途径是以约0.01-5000mg、优选5-500mg的HEVVLP的日剂量口服递送。口服施用是优选的施用方式,并且合适的剂量可以以片剂、胶囊的形式施用,或者作为对食物或饮料物品的补充以单一日剂量施用,或者作为以适当间隔提供的分开的剂量施用,例如以每天两次、三次、四次或更多次亚剂量施用。
为了制备本发明的药物组合物,使用惰性的和药学上可接受的载体。药物载体可以是固体或液体。固体形式制剂包括,例如,粉末、片剂、可分散颗粒、胶囊、扁囊剂和栓剂。固体载体可以是一种或多种还可以充当稀释剂、矫味剂、增溶剂、润滑剂、助悬剂、粘合剂或片剂崩解剂的物质;它也可以是包封材料。
在粉末中,载体通常是精细分散的固体,其与精细分散的活性组分混合,例如具有包封的核酸的嵌合病毒样颗粒。在片剂中,将活性成分(具有包封的核酸的嵌合病毒样颗粒)与具有必要结合特性的载体以合适的比例混合,并压制成所需的形状和大小。
对于制备栓剂形式的药物组合物,首先将低熔点蜡如脂肪酸甘油酯和可可脂的混合物熔化,并通过例如搅拌将活性成分分散在其中。然后将熔融的均匀混合物倒入合适尺寸的模具中并使其冷却和固化。
粉末和片剂优选含有约5%重量至约70%重量的活性成分。合适的载体包括,例如,碳酸镁、硬脂酸镁、滑石粉、乳糖、糖、果胶、糊精、淀粉、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。
药物组合物可以包括活性化合物与作为载体的包封材料的制剂,提供胶囊,其中活性组分(具有或不具有其它载体)被该载体包围,使得该载体因此与化合物结合。以类似的方式,也可以包括扁囊剂。片剂、粉末、扁囊剂和胶囊可用作适于口服施用的固体剂型。
液体药物组合物包括,例如,适于口服或肠胃外施用的溶液、悬浮液和适于口服施用的乳液。活性组分(例如,具有包封的核酸的嵌合病毒样颗粒)的无菌水溶液或活性组分在包括水、缓冲的水、盐水、PBS、乙醇或丙二醇的溶剂中的无菌溶液是适于肠胃外施用的液体组合物的实例。所述组合物可以含有接近生理条件所需的药学上可接受的辅助物质,例如pH调节剂和缓冲剂、张力调节剂、润湿剂、洗涤剂等。还预期HEV VLP可以是预先包装的粉末的片剂/胶囊剂形式或销售的浓缩液体形式。这将进一步由患者添加到食物或包括水的饮料中,然后由患者消费。HEV VLP也可以是液体形式并且不经进一步稀释直接消费。
无菌溶液可以通过将活性组分(例如,具有包封的核酸的嵌合病毒样颗粒)悬浮在所需的溶剂系统中,然后使所得溶液通过膜过滤器以将其灭菌来制备,或者可替代地,通过在无菌条件下将无菌化合物溶解在先前灭菌的溶剂中来制备。可以将所得水溶液包装以照原样使用,或冻干,在施用前将冻干制剂与无菌水性载体组合。制剂的pH通常为3-9,更优选5-8,最优选6-7。
可施用本发明的药物组合物以用于预防性和/或治疗性治疗。在治疗应用中,将组合物以足以防止、治愈、逆转或至少部分减缓或阻止病况及其并发症的症状的量施用于已经患有所述病况的患者。足以实现此目的的量被定义为“治疗有效剂量”。对于这种应用有效的量将取决于疾病或病况的严重程度以及患者的体重和一般状态,但是对于70kg的患者,所述量通常为每天约0.1mg至约2,000mg的组合物,对于70kg的患者,更通常使用的剂量为每天约5mg至约500mg的组合物。
在预防性应用中,本发明的药物组合物以足以延迟或防止症状发作的量施用于易于患有或处于发展疾病或病况(例如糖尿病)的风险中的患者。这样的量被定义为“预防有效剂量”。在这种应用中,组合物的精确量再次取决于患者的健康状态和体重,但是对于70kg患者通常为每天约0.1mg至约2,000mg的抑制剂,对于70kg患者更通常为每天约5mg至约500mg。
组合物的单次或多次施用可以由治疗医师选择的剂量水平和模式来进行。在任何情况下,药物制剂应提供足以在患者中治疗地或预防地实现预期效果的量的本发明的组合物。
实施例
仅以示例性说明的方式而不是以限制的方式提供以下实施例。本领域的技术人员将容易认识到可改变或修改各种非关键参数以产生基本上相同或相似的结果。
实施例1:通过HEVNP的口服胰岛素递送
I.背景技术
在过去的八十年中,皮下注射(SC)已经成为用于补充次优的胰岛素分泌的主要途径,以施用胰岛素作为糖尿病的治疗。尽管这种方法是有效的,但SC注射是疼痛的、不方便的,并且携带高感染风险,导致患者依从性差。预期由非传染性戊型肝炎病毒衣壳组成的包封胰岛素的戊型肝炎病毒纳米颗粒(HEVNP)在摄入后将胰岛素从胃肠(GI)道递送至肝脏。HEVNP可以是长期寻找的口服施用胰岛素的有效且有效率方法的答案,所述口服施用胰岛素是具有最高患者依从性的最优选的药物递送途径。
II.用于口服递送胰岛素的结构稳定的HEVNP
从生理学的观点来看,口服施用的胰岛素由于其模拟内源性胰岛素分泌途径的潜力而在肝葡萄糖产生的管理中具有治疗优势[4]。在HEV的自然感染途径之后,包封胰岛素的HEVNP可以通过胃肠道穿过门静脉到达肝脏(图1)。相反,胃肠道外或吸入的胰岛素直接吸收到外周循环中,绕过肝提取,因此不能恢复门静脉-外周胰岛素梯度和生理性肝胰岛素化。此外,这些途径使外周靶标相对于肝脏暴露于更高的胰岛素浓度,使患者易受低血糖的高风险,以及高胰岛素血症的有害作用[4]。
衍生自修饰形式的戊型肝炎病毒(HEV)衣壳蛋白的戊型肝炎病毒纳米颗粒(HEVNP)是非传染性的自组装衣壳,其缺乏病毒基因组并且能够细胞结合和进入。因为HEV已经发展用于口腔粘膜传递,所以组装的衣壳蛋白在蛋白水解条件和酸性粘膜条件下类似地稳定[13]。已经通过昆虫细胞表达系统通过杆状病毒载体实现了高产率的HEVNP生产。由于它们的蛋白水解稳定性,可以直接从细胞上清液中提取和纯化自组装的HEVNP,基本上减少了必需的纯化步骤。此外,HEVNP具有通过柔性铰链与稳定的二十面体基底连接的表面暴露的突出结构域(P结构域)。可以通过经由基因工程[13]或化学缀合[14]插入外源肽来修饰P结构域而不损害基本的二十面体结构。由开放阅读框2(ORF2)编码的HEV衣壳蛋白(CP)的P结构域上的三个暴露良好的表面可变环和C末端被设计为至少一种或多种生物活性剂的基因工程化和/或化学缀合位点[14,15]。
已经提出将靶向药物递送至特定器官和细胞区室以减少对非特异性器官/细胞的副作用。已经提出HEVNP作为细胞靶向的递送系统,因为其表面暴露的半胱氨酸或赖氨酸残基可以采用用于组织靶向的合成配体[14,15]。当HEVNP口服递送质粒cDNA至小肠上皮细胞以瞬时表达胰岛素和/或胰岛素原时,其口服递送基因的能力已在先前研究中被证实[16,17]。HEVNP在小鼠模型中采用远红外(FIR)成像的体内生物分布测定(数据未示出)表明口服递送的HEVNP甚至在没有特异性肝靶向配体的情况下在肝中聚积。
HEVNP的包封是基于电荷相互作用,使得带负电荷的核酸和纳米大小的蛋白质/小分子可以被封装以用于治疗应用。HEVNP可以包封商业的胰岛素类似物,Levemir(诺和平)的地特胰岛素(网站:levemir.com),大小为~52nm(图3)。考虑到HEVNP的药物毒理学,它由单个衣壳蛋白ORF2的拷贝组成并且是生物可降解的。另外,HEVNP可包封胰岛素或胰岛素原cDNA用于口服基因递送。可以通过经由连夜化学缀合或耗时但成本有效的基因工程将特异性靶向细胞配体插入到HEVNP的突出结构域内来增加胰腺β细胞和/或肝脏的靶向能力。HEVNP的组织靶向能力使其成为将胰岛素基因转运至胰腺和/或肝脏的有利的口服递送载体,从而允许温和的原位胰岛素表达。
使用HEVNP作为口服递送载体的概念不仅已经被上述的先前研究证实,而且还得到体外稳定性研究的支持。在不同pH和胃蛋白酶消化试验下的体外稳定性测定(未公开的数据)显示,包封胰岛素的HEVNP可以在具有胃蛋白酶消化的pH 3环境中存活5分钟(图2)。HEVNP含有修饰的ORF2衣壳蛋白,其具有在WO2015/179321、美国专利号8,906,862和美国专利号8,906,863中描述的一个或多个修饰。包封的胰岛素的生物利用度可以通过在餐前饮水以避免胃中恶劣的消化环境来进一步确保。此外,可以通过将单分散的金纳米簇(AuNC)化学缀合至HEVNP的五重对称区域上来稳定生物利用度[18]。此外,已经提出AuNC作为体内成像试剂,因为它的FIR可检测信号可以穿透深层组织[19]。HEVNP的功能的组合,包括胰岛素包封、胰岛素/胰岛素原cDNA包封和经由表面缀合能力的组织/细胞靶向,使其成为用于治疗糖尿病的胰岛素本身或胰岛素基因的理想的口服递送系统。该递送系统通过消除针的使用来提高患者依从性。
本发明在于HEVNP平台,其具有(1)缀合至其表面上的组织/细胞靶向配体(特别是能够将HEVNP特异性引导至肝细胞的配体)以增强其吸收,和(2)包封在其内部用于药物/基因递送的胰岛素(胰岛素多肽形式或编码胰岛素的多核苷酸序列的形式)。HEVNP由本发明人根据先前的公开内容构建,包括美国专利号8,906,862、美国专利号8,906,863和WO2015/179321。
III.发明内容
HEVNP为失去病毒感染性的HEV衍生的纳米胶囊,保留了HEV的基本特征,包括胃肠道稳定性,靶细胞结合和细胞进入。结合其在体外的解装/重新组装能力,已经提出HEVNP作为有吸引力的通过饮用的口服递送纳米胶囊。HEVNP的包封是有效载荷和衣壳蛋白之间的静电相互作用,使得带负电荷的核酸和纳米大小的蛋白/小分子可以被封装用于治疗应用。除了包封胰岛素用于经由胃肠道口服递送至肝脏之外,还可以包封胰岛素基因。如果需要,可以通过经由连夜化学缀合或耗时但成本有效的基因工程将特异性细胞靶向配体插入到HEVNP的突出结构域上来增加胰腺β细胞和/或肝脏的靶向能力。因此,HEVNP被装备为细胞靶向的基因递送载体,其可以将胰岛素基因递送至胰腺并在原位瞬时表达胰岛素。预期通过口服施用(优选的药物施用途径),包封胰岛素的HEVNP将胰岛素从胃肠道递送至肝脏。
在综合疗法方案中,采用两种或更多种改善血糖水平控制的糖尿病治疗来治疗糖尿病患者。通过在胰岛素/胰岛素原多肽形式的胰岛素和胰岛素/胰岛素原cDNA形式之间转换有效载荷以实现所递送的胰岛素的不同体内动力学,由HEVNP可以提供多种模式的糖尿病治疗。另一种模式水平来自在HEVNP的突出结构域上缀合不同的组织/细胞靶向配体。通过口服递送包封胰岛素的HEVNP和/或含有胰岛素/胰岛素原cDNA的HEVNP,这些多种模式治疗的组合可以是替代针注射的糖尿病治疗。
IV.材料和方法
1.胰岛素的HEVNP包封
1.1.HEVNP的解装
1.1.1.在4℃下将HEVNP在20mM DTT、10mM EDTA、O/N中解装
1.1.2.在RT下针对50mM Tris、pH7.5、150mM NaCl透析所解装的HEVNP>1H
1.1.3.通过TEM检查,通过分光光度法测量蛋白质浓度
1.2.将胰岛素包封到HEVNP中
1.2.1.在4℃下将所解装的HEVNP与胰岛素在50mM Tris、pH7.5、150mM NaCl中混合,加入CaCl2至使终浓度为2-5mM CaCl2,O/N
1.2.2.通过尺寸排阻柱以去除游离的胰岛素。
1.2.3.收集级分并通过分光光度计测量蛋白质浓度
1.2.4.通过TEM检查包封胰岛素的HEVNP
2.HEVNP表征
2.1.使用分光光度计记录A280nm读数和A260/A280 nm比率。HEVNP ORF2的摩尔消光系数为60,280,相当于在280nm处的1.019×蛋白质吸光度值。这如此接近1:1,使得HEVNP的浓度可以通过分光光度计在A280nm处的蛋白质浓度测量值来表示。考虑HEVNP,ORF2的构件块,其分子量为53.318kDa:
例如:根据分光光度计在280nm的测量值,HEVNP具有1mg/mL的浓度,相当于18.8μM的ORF2。(每个ORF2含有1个Cys位点和1个Lys位点用于化学缀合。)
2.2.根据用户手册14制备SDS PAGE 4-12%Bis-Tris蛋白凝胶,1.0mm,17-孔:
2.2.1.将2μl的4x加样缓冲液加入到6μl的蛋白质样品中。在加热块中在100℃下孵育样品混合物10分钟以使蛋白质变性。将蛋白质样品上样到NuPAGE凝胶装置上。
2.2.2.通过将DC电源设置在100V下持续10分钟,然后在150V下持续45分钟运行SDS-PAGE,直到样品运行到凝胶底部上方约1cm处。
2.2.3.用考马斯蓝(0.25%(w/v)考马斯亮蓝R250、30%(v/v)甲醇、10%(v/v)乙酸)将SDS PAGE凝胶染色1小时。
2.2.4.在染色程序之后,除去考马斯蓝染色,并在室温下将脱色(distaining)缓冲液(30%(v/v)甲醇、10%(v/v)乙酸)施加到蛋白凝胶上>12h。
2.2.5.在白光下记录凝胶以确认在52kDa条带处存在HEVNP ORF2。
2.3.使用TEM观察HEVNP
2.3.1.用10mM MES pH6.2制备或稀释HEVNP样品至0.5-2mg/mL以用于TEM成像。
2.3.2.用40mA辉光放电将碳涂覆的栅格(grids)电离30秒以产生亲水性碳表面。辉光放电设备可以是EMS辉光放电器。在辉光放电处理后,栅格的亲水性碳表面只能持续30分钟。
2.3.3.握住镊子,将2μL的HEVNP样品加入到栅格中,等待15-30秒,并用滤纸吸干。
2.3.4.立即用ddH2O洗涤栅格并用滤纸吸干。
2.3.5.立即将2μL的2%乙酸铀酰加入到栅格中,等待15秒,然后用滤纸吸干。通过将样品栅格置于电子除湿干燥箱中过夜以干燥样品栅格。
2.3.6.将栅格转移到透射电子显微镜(TEM)中并在10K至80K放大倍率下成像。由于不存在病毒RNA,HEVNP在TEM中表现为直径约27nm的空二十面体蛋白。
3.HEVNP与生物素、组织/细胞靶向配体和荧光团的化学缀合
3.1.HEVNP与马来酰亚胺连接的生物素的一步缀合
3.1.1.更换缓冲液:将HEVNP应用于微型透析单元中,并根据制造商的方案(Zeba SpinDesalting Columns,40K MWCO,0.5mL)在室温下对0.01M PBS pH=7.4透析1小时。将HEVNP转移到1.5mL试管中并使用分光光度计在280nm下测量蛋白质浓度。
3.1.2.将1mg/mL的HEVNP(这相当于18.8μM的Cys反应位点(参见步骤2.2.4中的细节))与等量的马来酰亚胺-生物素(100μM)在0.01M PBS pH7.4中混合,以形成1∶5摩尔比,并在4℃下反应O/N。根据制造商的方案(Zeba Spin Desalting Columns,40K MWCO,0.5mL),用40K MWCO Spin Desalting(旋转脱盐)柱程序除去未结合的马来酰亚胺-生物素。
3.1.3.通过标准还原SDS-PAGE分析样品(步骤3.1)。
3.1.4.准备化学发光的蛋白质印迹,HRP连接的链霉亲和素。通过X射线胶片捕获化学发光信号(图2)。
3.2.组织靶向配体(RGD肽)与HEV NP上的表面暴露的半胱氨酸的两步缀合。
3.2.1.更换缓冲液:将HEVNP应用于微型透析单元中,并在室温下对0.01M PBS pH=7.4透析1小时。将HEVNP转移到1.5mL试管中并使用分光光度计在280nm下测量蛋白质浓度。
3.2.2.在含有200μM CuSO4和1mM抗坏血酸的0,01M PBS pH7.4中加入650μM马来酰亚胺-叠氮化物和650μM炔-配体X以形成650μM的马来酰亚胺-连接的配体X(Mal-配体X)。将混合物在4℃孵育过夜。
3.2.3.在0.01M PBS pH7.4中将1mg/mL的HEVNP(这相当于18.8μM的Cys反应位点(参见步骤2.2.4中的细节))与约10%体积的Mal-配体X(650μM)混合,以形成1:3摩尔比,并且在4℃下反应O/N。由于相对高浓度的马来酰亚胺连接的LXY30,在混合后反应物(如CuSO4)的最终浓度降低约10倍以避免其损坏HEVNP。另一个选择是无Cu缀合方法15。
3.2.4.根据制造商的方案(材料表),用40K MWCO旋转脱盐柱除去未结合的马来酰亚胺-点击-配体X。将LXY30-连接的HEVNP(LXY30-HEVNP)保持在4℃。
3.3.LXY30-连接的HEVNP(配体X-HEVNP)与Cy5.5 NHS酯(NHS-Cy5.5)的一步缀合
3.3.1.在0.01M PBS pH7.4中将1mg/ml的配体X-连接的HEVNP(配体X-VLP)(这相当于18.8μM的Cys反应位点(参见步骤2.2.4中的细节))与等体积的Cy5.5 NHS酯(NHS-Cy5.5,100μM)混合,以形成1:5摩尔比,并在4℃下反应O/N。
3.3.2.根据制造商的方案(Zeba Spin Desalting Columns,40K MWCO,0.5mL),通过经过40K MWCO旋转脱盐柱程序除去未结合的Cy5.5-NHS。将RGD,Cy5.5-连接的HEVNP(RGD-HEVNP-Cy5.5)保持在4℃。
实施例2:体内研究
I.HEVNP包封设计
在制剂中,HEVNP可以被配制成片剂、胶囊、散剂或包含在饮料中的液体。已经证明HEVNP亚组分是用于人和动物的安全疫苗。与其它建议的口服胰岛素给药增强剂相反,HEVNP胶囊能够作为专注于粘膜的递送系统(mucosa-focused delivery system),其通过口服途径增强诸如胰岛素的蛋白质有效载荷的生物利用度。基于四级结构的有效载荷被设计成利用大分子属性来延长可执行的保留时间的持续时间。
为了优化胰岛素的包封效率,进行多种测定以检查最佳条件。如图4所示,在包封期间和包封之后,胰岛素在HEVNP中的包封在Tris缓冲液中显示出最高的稳定性和结构均匀性。最佳包封条件被缩小至10-50mM Tris、0-150mM NaCl、在中性pH范围内。相反,MES缓冲液对有效载荷包封提供最少的有利条件,而PBS缓冲液产生高度沉淀。由于Tris缓冲液提供了在溶液中具有蛋白质有效载荷的稳定的单分散的HEVNP,在使用Tris缓冲液的条件下进一步鉴定了最高的包封率。
对于包封,将HEVNP亚基与相应摩尔比的蛋白质有效载荷(如胰岛素)一起孵育,利用在系统中所添加的氯化钙以逐渐组装胶囊。按照如下监测和评估胰岛素包封效率:
1.氯化铯密度梯度分离;通过ELISA(针对HEV和胰岛素)显示了HEVNP和胰岛素的共存(图5)。
2.尺寸排阻柱分离;通过(针对HEV和胰岛素)显示了HEVNP和胰岛素的共存(图6)。
II.具有密度评估的HEVNP封装
在优化缓冲液时,CsCl梯度清楚地显示了在ELISA读数的单个峰内胰岛素和HEVNP的共存,以示例性说明在HEVNP中胰岛素包封效率。“+”表示来自ELISA的正读数,以及HEV和胰岛素在级分6-13中共存。
尺寸评估鉴定了携带胰岛素有效载荷的HEVNP的新构象
SEC显示如ELISA所示的具有重叠的胰岛素和HEVNP的不同峰(由在级分#16和#32之间的+符号表示)。
如第一个峰(红色峰)所示,鉴定胰岛素和HEVNP胶囊共存的另外的证据通过分别按照抗胰岛素抗体和抗HEVNP抗体的特异性的ELISA测定来验证。进一步系统地监测了进一步的包封,以鉴定声处理介导的有效载荷优化为新形式的HEVNP(图5下图):单峰(排除超过35的异常值级分),显示具有胰岛素和HEV的统一峰(通过ELISA验证,在492nm下的吸光度读数)。
III.延长的HEVNP保存期
对于有效的药物递送系统,产品的高稳定性和保存期是关键的。将HEVNP-胰岛素样品在4℃下储存超过一年,并用cryo-EM检查。显微照片显示完整的颗粒,其在储存条件下显示高稳定性。如图8所示,利用冷冻电子显微术以检查具有包封的地特胰岛素的HEVNP颗粒。
IV.HEVNP-胰岛素的结构表征:
已经提供了来自电子显微术的表明胰岛素包封的结果;然而,这些纳米颗粒的2维分布和3维结构特征尚未完全表征。使用内部协议和商购的图像处理包的组合,已经收集并分析了大型数据集,以便1)统计分析颗粒分布,和2)确定胰岛素封装的HEVNP的高分辨率3D结构。
评价TEM图像,表明产生了新构象的HEVNP-胰岛素,其直径为~45nm,几乎是我们先前提交的第一代HEVNP(27nm)的两倍。在这些HEVNP中,新的形状和尺寸似乎最优于携带具有可目视的六聚体节点的挤出链(extruded strands of hexameric nodes)的胰岛素有效载荷。通过冷冻电子显微镜进一步进行3D体积表征以实现结构引导的胰岛素封装效率的优化。通过计算建模,实现了新一代的HEVNP对抗,以完善预先加载封装。使用200kV电子显微镜(JEOL 2100F)以1度增量从-60度至+60度,利用数据分割实施电子3D断层扫描倾斜序列数据的收集以重建HEVNP-胰岛素的3D表达以分析封装机制。使用同步迭代重建技术(Simultaneous Iterative Reconstruction Technique)方法进行3D重建,在图7中其清楚地显示了从HEVNP挤出的胰岛素的分段链。
V.通过大动物模型和小动物模型验证的HEVNP包封:
将小鼠随机分配到2个处理组中的一个,并进行如下的胰岛素耐受试验:
A.以0.1U/小鼠口服施用胰岛素(HEVNP包封的)
B.以1U/小鼠口服施用胰岛素(HEVNP包封的)
假设IP胰岛素给药后血糖浓度降低50%,而口服胰岛素给药后血糖浓度平均降低25%,标准偏差为15%,期望的α误差为5%和80%效力,放置10%小鼠亚组以检测组间的显著差异。
使用轻度异氟烷麻醉和柔性管饲针,通过管饲法进行口服递送。将26G针用于IP注射。将胰岛素和/或HEVNP溶解在0.9%盐水中。如果口服胰岛素制剂通过粘膜吸收以实现所预期的血糖水平降低。
此外,对用糖尿病病症建模的8-10只狗作为"患者"进行试验以葡萄糖监测测量。
VI.全动物成像以追踪包封的有效载荷
使用花青-5.5(Cy5.5)-标记的HEVNP的小鼠体内光学成像先前已在Chen等人的"Chemically activatable viral capsid functionalized for cancer targeting."Nanomedicine 11,no.4(2016):377-390中证实,其中乳腺肿瘤靶向分子(LXY30)与工程化的半胱氨酸臂缀合并且Cy5.5与暴露的赖氨酸残基连接。全动物成像证实具有LXY30的HEVNP将在肿瘤部位积聚。这里,在室温下,在含有0.01M PBS,pH=7.2的缓冲液中将包封胰岛素的HEVNP的表面用Cy5.5 NHS酯(Limiprobe)以300∶1的摩尔比(Cy5.5比HEVNP)装饰2h,然后在4℃下孵育过夜。然后通过7000MWCO脱盐柱(Zeba Spin Desalting Columns,ThermoScientific)除去游离的Cy5.5 NHS酯。Cy5.5在682nm下具有最大激发,在702nm下具有最大发射,并且摩尔消光系数为250,000cm^-1M^-1。
进行全动物成像以追踪HEVNP-胰岛素分布,具有关于光学成像的IVIS光谱(具有~20μm–5mm的分辨力)和关于高分辨率CT的MicroXCT-200(具有~1–20μm的分辨力)。口服胰岛素递送途径为经过胃后通过GI的粘膜内层,经肝门静脉向肝脏递送;因此,纳米颗粒在肝脏中积聚并释放胰岛素。
VII.通过电子显微术描述的分子特征
为了在细胞水平上研究HEVNP分布,实施肝活检并采用高压冷冻方法和冷冻固定法包埋组织。将提取的组织用甲醛进行光固定,随后将其置于样品架中。然后将冷冻的组织固定在树脂块中,然后用超微切片机切片并用透射电子显微术(TEM)筛选。HEVNP通过所添加的对比度(通过金原子簇或通过10nm铁氧体氧化物颗粒)来追踪。电子致密的HEVNP颗粒提供了足够的对比度以通过TEM进行识别。
用JEM 2100F电子显微镜,高压冷冻和TEM准备是为获得细胞水平的超微结构的高分辨率3D图像,如下所述,参见例如Paavolainen et al.,"Compensation of missingwedge effects with sequential statistical reconstruction in electrontomography."PloS one 9,no.10(2014):e108978;Soonsawad et al.,"Permeabilitychanges of integrin-containing multivesicular structures triggered bypicornavirus entry."PloS one 9,no.10(2014):e108948;和Soonsawad et al.,"Structural evidence of glycoprotein assembly in cellular membranecompartments prior to Alphavirus budding."Journal of virology 84,no.21(2010):11145-11151。
本申请中引用的所有专利、专利申请和其它出版物,包括GenBank登录号,出于所有目的通过引用整体并入本文。
参考文献
1.Saaddine JB,Cadwell B,Gregg EW,Et Al.Improvements in diabetes processesof care and intermediate outcomes:United states,1988–2002.Annals of InternalMedicine 144(7),465-474(2006).
2.Hoffman A,Ziv E.Pharmacokinetic considerations of new insulinformulations and routes of administration.Clinical pharmacokinetics 33(4),285-301(1997).
3.Owens DR.New horizons--alternative routes for insulin therapy.Naturereviews.Drug discovery 1(7),529-540(2002).
4.Arbit E,Kidron M.Oral Insulin Delivery in a Physiologic Context:Review.J Diabetes Sci Technol 11(4),825-832(2017).
5.Carino GP,Mathiowitz E.Oral insulin delivery1Abbreviations:GI,gastrointestinal;IDDM,insulin-dependent diabetes mellitus;IU,internationalunits;NIDDM,non-insulin-dependent diabetes mellitus;PIN,phase inversionnanoencapsulation;ZOT,zona occludens toxin.1.Advanced drug delivery reviews35(2),249-257(1999).
6.Heinemann L.New ways of insulin delivery.International journal ofclinical practice.Supplement doi:10.1111/j.1742-1241.2010.02577.x(170),31-46(2011).
7.Fonte P,Araujo F,Reis S,Sarmento B.Oral insulin delivery:how far arewe?J Diabetes Sci Technol 7(2),520-531(2013).
8.Zijlstra E,Heinemann L,Plum-Morschel L.Oral insulin reloaded:astructured approach.J Diabetes Sci Technol 8(3),458-465(2014).
9.Zaykov AN,Mayer JP,Dimarchi RD.Pursuit of a perfect insulin.Naturereviews.Drug discovery 15(6),425-439(2016).
10.Wong CY,Martinez J,Dass CR.Oral delivery of insulin for treatment ofdiabetes:status quo,challenges and opportunities.The Journal of pharmacy andpharmacology 68(9),1093-1108(2016).
11.Samson SL,Chan L.Gene therapy for diabetes:reinventing theislet.Trends Endocrinol Metab 17(3),92-100(2006).
12.Alam T,Wai P,Held D,Vakili ST,Forsberg E,Sollinger H.Correction ofDiabetic Hyperglycemia and Amelioration of Metabolic Anomalies by MinicircleDNA Mediated Glucose-Dependent Hepatic Insulin Production.PloS one 8(6),e67515(2013).
13.Jariyapong P,Xing L,Van Houten NE et al.Chimeric hepatitis E virus-like particle as a carrier for oral-delivery.Vaccine 31(2),417-424(2013).
14.Chen CC,Xing L,Stark M et al.Chemically activatable viral capsidfunctionalized for cancer targeting.Nanomedicine(Lond)11(4),377-390(2016).
15.Cheng RH,Xing L,Chen CC,Stark MC:WO/2015/179321(2015).
16.Takamura S,Niikura M,Li TC et al.DNA vaccine-encapsulated virus-likeparticles derived from an orally transmissible virus stimulate mucosal andsystemic immune responses by oral administration.Gene therapy 11(7),628-635(2004).
17.Cheng RH,Xing L:US8906863(2014).
18.Stark MC,Baikoghli MA,Lahtinen T et al.Structural characterization ofsite-modified nanocapsid with monodispersed gold clusters.Scientific reports7(1),17048(2017).
19.Li W,Chen X.Gold nanoparticles for photoacoustic imaging.Nanomedicine10(2),299-320(2015).
Claims (16)
1.组合物,其包含:
(a)修饰的衣壳蛋白,所述修饰的衣壳蛋白包含戊型肝炎病毒(HEV)开放阅读框2(ORF2)蛋白的至少一部分并且能够形成HEV病毒样颗粒(VLP);和
(b)包封在由所述修饰的衣壳蛋白形成的所述HEV VLP内的胰岛素蛋白或编码胰岛素蛋白的核酸。
2.如权利要求1所述的组合物,其中所述修饰的衣壳蛋白短于全长的HEV ORF2蛋白,包含SEQ ID NO:1、2、3、4、5或6的所述HEV ORF 2蛋白的片段452-606,并且包含在SEQ ID NO:1、2、3、4、5或6的片段483-490、530-535、554-561、573-577、582-593或601-603内插入到HEVORF2蛋白的部分中的异源多肽序列。
3.如权利要求2所述的组合物,其中所述异源多肽序列紧接在SEQ ID NO:1、2、3、4、5或6的残基Y485之后插入。
4.如权利要求2或3所述的组合物,其中所述异源多肽是RGD或环状RGD肽。
5.如权利要求1所述的组合物,其中所述修饰的衣壳蛋白能够形成酸和蛋白水解稳定的HEV VLP,并且具有被半胱氨酸或赖氨酸取代的SEQ ID NO:1、2、3、4、5或6的至少一个残基Y485、T489、S533、N573或T586,其任选地被化学衍生化。
6.如权利要求4所述的组合物,其中所述半胱氨酸或赖氨酸是烷基化的、酰化的、芳基化的、琥珀酰化的、氧化的,或是与可检测标记或肝细胞靶向配体缀合的。
7.如权利要求6所述的组合物,其中所述可检测标记包括荧光团、超顺磁性标记、MRI造影剂、正电子发射同位素或原子序数大于20的第3族至第18族元素的簇。
8.如权利要求7所述的组合物,其中所述可检测标记包括金纳米簇。
9.如权利要求6所述的组合物,其中所述肝细胞靶向配体是RGD或环状RGD肽。
10.如权利要求9所述的组合物,其还包含药学上可接受的赋形剂。
11.如权利要求9所述的组合物,其被配制用于口服施用。
12.靶向递送胰岛素的方法,其包括使肝细胞与权利要求1-11中任一项所述的组合物接触。
13.如权利要求12所述的方法,其中所述肝细胞在患者体内,并且其中所述接触步骤包括向所述患者施用权利要求1所述的组合物。
14.如权利要求12所述的方法,其中所述施用是口服施用。
15.如权利要求13所述的方法,其中所述修饰的衣壳蛋白包含与金纳米簇缀合的半胱氨酸或赖氨酸。
16.如权利要求13所述的方法,其中所述患者已被诊断患有糖尿病。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862642356P | 2018-03-13 | 2018-03-13 | |
US62/642,356 | 2018-03-13 | ||
PCT/US2019/022137 WO2019178288A2 (en) | 2018-03-13 | 2019-03-13 | Virus-like nanocapsid for oral delivery of insulin |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112292150A true CN112292150A (zh) | 2021-01-29 |
Family
ID=67908035
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980018882.5A Pending CN112292150A (zh) | 2018-03-13 | 2019-03-13 | 用于口服递送胰岛素的病毒样纳米衣壳 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20210038697A1 (zh) |
EP (1) | EP3765074A4 (zh) |
JP (2) | JP2021518342A (zh) |
CN (1) | CN112292150A (zh) |
WO (1) | WO2019178288A2 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112218879A (zh) * | 2018-06-06 | 2021-01-12 | 加利福尼亚大学董事会 | 用于口服递送的改进的病毒样纳米颗粒 |
WO2023215560A1 (en) | 2022-05-05 | 2023-11-09 | Atoosa Corporation | Tumor cell/immune cell multivalent receptor engager – bio-nanoparticle (timre-bnp) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1826414A (zh) * | 2003-06-30 | 2006-08-30 | 加利福尼亚大学董事会 | 突变型腺伴随病毒的病毒颗粒及其使用方法 |
CN101400366A (zh) * | 2006-03-09 | 2009-04-01 | 特兰斯吉恩股份有限公司 | 丙型肝炎病毒非结构性融合蛋白 |
US20090325860A1 (en) * | 2006-08-04 | 2009-12-31 | Nastech Pharmaceutical Company Inc. | Compositions for intranasal delivery of human insulin and uses thereof |
US20130058999A1 (en) * | 2010-01-12 | 2013-03-07 | Novo Nordisk A/S | Pharmaceutical compositions for oral administration of insulin peptides |
US20140336245A1 (en) * | 2011-11-22 | 2014-11-13 | The Children Hospital Of Philadelphia | Virus vectors for highly efficient transgene delivery |
US20170107261A1 (en) * | 2014-05-19 | 2017-04-20 | The Regents Of The University Of California | Chemically Activated Nanocapsid Functionalized for Cancer Targeting |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7741283B2 (en) * | 2003-10-17 | 2010-06-22 | St. Louis University | Compositions and methods for inhibiting cell proliferation |
EP2400982B1 (en) * | 2009-02-27 | 2016-05-11 | The Regents of The University of California | Multiple antigen delivery system using hepatitis e virus-like particle |
US8906863B2 (en) * | 2009-02-27 | 2014-12-09 | The Regents Of The University Of California | Proteolysis-resistant capsid of chimeric hepatitis E virus as an oral delivery vector |
JP2012139193A (ja) * | 2011-01-04 | 2012-07-26 | Osaka Univ | 融合タンパク質 |
WO2015101666A1 (en) * | 2014-01-03 | 2015-07-09 | Fundación Biofísica Bizkaia | VLPs, METHODS FOR THEIR OBTENTION AND APPLICATIONS THEREOF |
-
2019
- 2019-03-13 CN CN201980018882.5A patent/CN112292150A/zh active Pending
- 2019-03-13 US US16/969,143 patent/US20210038697A1/en active Pending
- 2019-03-13 WO PCT/US2019/022137 patent/WO2019178288A2/en unknown
- 2019-03-13 EP EP19768199.2A patent/EP3765074A4/en active Pending
- 2019-03-13 JP JP2020548984A patent/JP2021518342A/ja active Pending
-
2023
- 2023-11-06 JP JP2023189679A patent/JP2024012529A/ja active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1826414A (zh) * | 2003-06-30 | 2006-08-30 | 加利福尼亚大学董事会 | 突变型腺伴随病毒的病毒颗粒及其使用方法 |
CN101400366A (zh) * | 2006-03-09 | 2009-04-01 | 特兰斯吉恩股份有限公司 | 丙型肝炎病毒非结构性融合蛋白 |
US20090325860A1 (en) * | 2006-08-04 | 2009-12-31 | Nastech Pharmaceutical Company Inc. | Compositions for intranasal delivery of human insulin and uses thereof |
US20130058999A1 (en) * | 2010-01-12 | 2013-03-07 | Novo Nordisk A/S | Pharmaceutical compositions for oral administration of insulin peptides |
US20140336245A1 (en) * | 2011-11-22 | 2014-11-13 | The Children Hospital Of Philadelphia | Virus vectors for highly efficient transgene delivery |
US20170107261A1 (en) * | 2014-05-19 | 2017-04-20 | The Regents Of The University Of California | Chemically Activated Nanocapsid Functionalized for Cancer Targeting |
Non-Patent Citations (1)
Title |
---|
黄涛 等: "肝源性胰岛素抵抗的研究进展", 世界华人消化杂志, vol. 16, no. 6, pages 653 - 657 * |
Also Published As
Publication number | Publication date |
---|---|
EP3765074A4 (en) | 2021-12-29 |
JP2024012529A (ja) | 2024-01-30 |
WO2019178288A9 (en) | 2019-11-07 |
EP3765074A2 (en) | 2021-01-20 |
WO2019178288A3 (en) | 2019-10-10 |
WO2019178288A2 (en) | 2019-09-19 |
US20210038697A1 (en) | 2021-02-11 |
JP2021518342A (ja) | 2021-08-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5686468B2 (ja) | B型肝炎ウイルス(HBV)の疎水性修飾されたpreS由来ペプチド及び肝臓に化合物を特異的に送達するためのビヒクルとしてのそれらの使用 | |
Lee et al. | Adaptations of nanoscale viruses and other protein cages for medical applications | |
JP2024012529A (ja) | インスリンの経口送達のためのウイルス様ナノカプシド | |
US10513539B2 (en) | Hydrophobic modified peptides and their use for liver specific targeting | |
EP3313527B1 (en) | Anticancer drug-containing plant virus particles | |
JP6533232B2 (ja) | 親水性活性化合物のナノカプセル化 | |
JP2010254700A (ja) | 膜転位剤および製薬学的有効成分の複合物 | |
CN109069656A (zh) | 用于基因递送的口服纳米颗粒和包含其的药物组合物 | |
US20190031720A1 (en) | Chemically activated nanocapsid functionalized for cancer targeting | |
CN113456810A (zh) | 一种新型抗新冠病毒治疗性疫苗及其制备方法和应用 | |
CN111569082A (zh) | 一种包载蛋白多肽类药物外泌体的口服递送系统 | |
JP4799790B2 (ja) | 膜転位ペプチド、同ペプチドを含有する組成物、同ペプチドを含有する医薬製剤及び同ペプチドの製剤の調製における使用 | |
Yuan et al. | Virus-like particle-based nanocarriers as an emerging platform for drug delivery | |
US20230159596A1 (en) | Virus-like nanoparticles for oral delivery | |
Aljabali et al. | Protein-based drug delivery nanomedicine platforms: Recent developments | |
KR100674325B1 (ko) | 단백질 중공 나노 입자 및 이를 이용한 약제 | |
Tan et al. | Next-generation viral nanoparticles for targeted delivery of therapeutics: Fundamentals, methods, biomedical applications, and challenges | |
US20060165726A1 (en) | Remedies with the use of hollow protein nanoparticles presenting growth factor or the like | |
Arora et al. | Nanoparticle-assisted oral delivery of small and large peptides | |
Hangad et al. | Using nanomaterials to address SARS-CoV-2 variants through development of vaccines and therapeutics | |
JP2003286199A (ja) | タンパク質中空ナノ粒子を用いる肝臓疾患治療用薬剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |