CA2845357A1

CA2845357A1 - Method of treating or ameliorating type 1 diabetes using fgf21

Method of treating or ameliorating type 1 diabetes using fgf21 Download PDF

Info

Publication number: CA2845357A1
Authority: CA; Canada
Prior art keywords: fgf21; polypeptide; variant; human; seq
Prior art date: 2011-08-31
Legal status : Abandoned

Application number

CA2845357A

Other languages

English (en)

French (fr)

Inventor

Murielle Marie Ellison

Shanaka STANISLAUS

Jing Xu

Current Assignee

Amgen Inc

Original Assignee

Amgen Inc

Priority date

2011-08-31

Filing date

2012-08-30

Publication date

2013-03-07

2012-08-30 Application filed by Amgen Inc filed Critical Amgen Inc

2013-03-07 Publication of CA2845357A1 publication Critical patent/CA2845357A1/en

Status Abandoned legal-status Critical Current

Links

102000003973 Fibroblast growth factor 21 Human genes 0.000 title claims abstract description 519
108090000376 Fibroblast growth factor 21 Proteins 0.000 title claims abstract description 519
238000000034 method Methods 0.000 title claims abstract description 135
206010067584 Type 1 diabetes mellitus Diseases 0.000 title claims abstract description 32
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 claims abstract description 175
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 claims abstract description 115
239000008103 glucose Substances 0.000 claims abstract description 115
229940125396 insulin Drugs 0.000 claims abstract description 88
102000004877 Insulin Human genes 0.000 claims abstract description 87
108090001061 Insulin Proteins 0.000 claims abstract description 82
208000030159 metabolic disease Diseases 0.000 claims abstract description 30
208000008589 Obesity Diseases 0.000 claims abstract description 9
235000020824 obesity Nutrition 0.000 claims abstract description 9
208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 8
208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 8
208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 6
208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 6
230000035772 mutation Effects 0.000 claims description 137
108090000765 processed proteins & peptides Proteins 0.000 claims description 126
101000846529 Homo sapiens Fibroblast growth factor 21 Proteins 0.000 claims description 120
102000056713 human FGF21 Human genes 0.000 claims description 120
102000004196 processed proteins & peptides Human genes 0.000 claims description 120
229920001184 polypeptide Polymers 0.000 claims description 114
210000004369 blood Anatomy 0.000 claims description 65
239000008280 blood Substances 0.000 claims description 65
150000001413 amino acids Chemical group 0.000 claims description 53
239000008194 pharmaceutical composition Substances 0.000 claims description 36
241000124008 Mammalia Species 0.000 claims description 7
239000003937 drug carrier Substances 0.000 claims description 3
210000002966 serum Anatomy 0.000 claims description 3
208000018262 Peripheral vascular disease Diseases 0.000 abstract description 3
208000017442 Retinal disease Diseases 0.000 abstract description 3
206010038923 Retinopathy Diseases 0.000 abstract description 3
208000026106 cerebrovascular disease Diseases 0.000 abstract description 3
208000031225 myocardial ischemia Diseases 0.000 abstract description 3
201000001119 neuropathy Diseases 0.000 abstract description 3
230000007823 neuropathy Effects 0.000 abstract description 3
208000033808 peripheral neuropathy Diseases 0.000 abstract description 3
208000016097 disease of metabolism Diseases 0.000 abstract 1
241000699670 Mus sp. Species 0.000 description 98
102200070479 rs28933693 Human genes 0.000 description 88
ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 87
ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 86
229960001052 streptozocin Drugs 0.000 description 86
239000003981 vehicle Substances 0.000 description 82
239000007924 injection Substances 0.000 description 75
238000002347 injection Methods 0.000 description 75
235000001014 amino acid Nutrition 0.000 description 57
238000011282 treatment Methods 0.000 description 54
229940024606 amino acid Drugs 0.000 description 53
229910052739 hydrogen Inorganic materials 0.000 description 52
229920000642 polymer Polymers 0.000 description 51
125000005647 linker group Chemical group 0.000 description 49
229910052717 sulfur Inorganic materials 0.000 description 49
230000002829 reductive effect Effects 0.000 description 48
206010012601 diabetes mellitus Diseases 0.000 description 46
150000007523 nucleic acids Chemical class 0.000 description 46
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 44
230000000694 effects Effects 0.000 description 43
239000013598 vector Substances 0.000 description 39
239000002202 Polyethylene glycol Substances 0.000 description 38
229920001223 polyethylene glycol Polymers 0.000 description 38
239000000203 mixture Substances 0.000 description 37
125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 36
102000039446 nucleic acids Human genes 0.000 description 33
108020004707 nucleic acids Proteins 0.000 description 33
235000018417 cysteine Nutrition 0.000 description 32
229910052700 potassium Inorganic materials 0.000 description 32
230000037396 body weight Effects 0.000 description 30
238000006206 glycosylation reaction Methods 0.000 description 29
XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 24
210000004027 cell Anatomy 0.000 description 24
230000013595 glycosylation Effects 0.000 description 24
108090000623 proteins and genes Proteins 0.000 description 23
125000003275 alpha amino acid group Chemical group 0.000 description 22
235000018102 proteins Nutrition 0.000 description 22
102000004169 proteins and genes Human genes 0.000 description 22
UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 22
-1 methacryloyl Chemical group 0.000 description 21
238000009472 formulation Methods 0.000 description 20
230000002776 aggregation Effects 0.000 description 19
238000004220 aggregation Methods 0.000 description 19
125000000539 amino acid group Chemical group 0.000 description 18
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
230000002503 metabolic effect Effects 0.000 description 18
238000012384 transportation and delivery Methods 0.000 description 18
230000015556 catabolic process Effects 0.000 description 17
238000006731 degradation reaction Methods 0.000 description 17
238000006467 substitution reaction Methods 0.000 description 17
230000001225 therapeutic effect Effects 0.000 description 17
208000001072 type 2 diabetes mellitus Diseases 0.000 description 16
BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 15
150000001875 compounds Chemical class 0.000 description 15
208000035475 disorder Diseases 0.000 description 15
238000005259 measurement Methods 0.000 description 15
230000017854 proteolysis Effects 0.000 description 15
108091028043 Nucleic acid sequence Proteins 0.000 description 14
238000004458 analytical method Methods 0.000 description 14
150000002632 lipids Chemical class 0.000 description 14
239000002245 particle Substances 0.000 description 14
210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 13
238000011284 combination treatment Methods 0.000 description 13
238000001727 in vivo Methods 0.000 description 13
230000009467 reduction Effects 0.000 description 13
238000006722 reduction reaction Methods 0.000 description 13
239000000126 substance Substances 0.000 description 13
102220485772 Glycophorin-A_E91C_mutation Human genes 0.000 description 12
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 12
238000007912 intraperitoneal administration Methods 0.000 description 12
210000000496 pancreas Anatomy 0.000 description 12
239000013603 viral vector Substances 0.000 description 12
238000006243 chemical reaction Methods 0.000 description 11
235000021588 free fatty acids Nutrition 0.000 description 11
229910052727 yttrium Inorganic materials 0.000 description 11
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 10
229960004666 glucagon Drugs 0.000 description 10
230000010030 glucose lowering effect Effects 0.000 description 10
239000000017 hydrogel Substances 0.000 description 10
230000001965 increasing effect Effects 0.000 description 10
150000005830 nonesterified fatty acids Chemical class 0.000 description 10
210000001519 tissue Anatomy 0.000 description 10
229920002307 Dextran Polymers 0.000 description 9
102000051325 Glucagon Human genes 0.000 description 9
108060003199 Glucagon Proteins 0.000 description 9
241000699666 Mus <mouse, genus> Species 0.000 description 9
230000001668 ameliorated effect Effects 0.000 description 9
210000004899 c-terminal region Anatomy 0.000 description 9
238000007385 chemical modification Methods 0.000 description 9
229910052731 fluorine Inorganic materials 0.000 description 9
MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=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](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 9
230000003612 virological effect Effects 0.000 description 9
229920003169 water-soluble polymer Polymers 0.000 description 9
108010010803 Gelatin Proteins 0.000 description 8
206010022489 Insulin Resistance Diseases 0.000 description 8
239000003795 chemical substances by application Substances 0.000 description 8
235000012000 cholesterol Nutrition 0.000 description 8
229920000159 gelatin Polymers 0.000 description 8
239000008273 gelatin Substances 0.000 description 8
235000019322 gelatine Nutrition 0.000 description 8
235000011852 gelatine desserts Nutrition 0.000 description 8
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 8
102000040430 polynucleotide Human genes 0.000 description 8
108091033319 polynucleotide Proteins 0.000 description 8
239000002157 polynucleotide Substances 0.000 description 8
239000000243 solution Substances 0.000 description 8
238000010561 standard procedure Methods 0.000 description 8
229910052720 vanadium Inorganic materials 0.000 description 8
102100031734 Fibroblast growth factor 19 Human genes 0.000 description 7
108090000379 Fibroblast growth factor 2 Proteins 0.000 description 7
102000003974 Fibroblast growth factor 2 Human genes 0.000 description 7
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 description 7
241000700605 Viruses Species 0.000 description 7
230000015572 biosynthetic process Effects 0.000 description 7
238000004132 cross linking Methods 0.000 description 7
229940084769 humulin r Drugs 0.000 description 7
239000011159 matrix material Substances 0.000 description 7
230000001404 mediated effect Effects 0.000 description 7
238000002360 preparation method Methods 0.000 description 7
230000008569 process Effects 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
102220562235 Disintegrin and metalloproteinase domain-containing protein 11_K69C_mutation Human genes 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
101000976075 Homo sapiens Insulin Proteins 0.000 description 6
241001465754 Metazoa Species 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
108010076504 Protein Sorting Signals Proteins 0.000 description 6
125000003277 amino group Chemical group 0.000 description 6
238000003556 assay Methods 0.000 description 6
230000001580 bacterial effect Effects 0.000 description 6
238000004422 calculation algorithm Methods 0.000 description 6
238000000338 in vitro Methods 0.000 description 6
239000000463 material Substances 0.000 description 6
238000010369 molecular cloning Methods 0.000 description 6
230000006320 pegylation Effects 0.000 description 6
238000011808 rodent model Methods 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
230000009466 transformation Effects 0.000 description 6
108020004414 DNA Proteins 0.000 description 5
LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical group CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 5
241000283984 Rodentia Species 0.000 description 5
240000004808 Saccharomyces cerevisiae Species 0.000 description 5
239000002253 acid Substances 0.000 description 5
238000013459 approach Methods 0.000 description 5
150000001720 carbohydrates Chemical class 0.000 description 5
235000014633 carbohydrates Nutrition 0.000 description 5
239000003814 drug Substances 0.000 description 5
230000004927 fusion Effects 0.000 description 5
201000001421 hyperglycemia Diseases 0.000 description 5
238000002513 implantation Methods 0.000 description 5
230000006698 induction Effects 0.000 description 5
125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 5
238000001823 molecular biology technique Methods 0.000 description 5
239000000546 pharmaceutical excipient Substances 0.000 description 5
238000006366 phosphorylation reaction Methods 0.000 description 5
239000013612 plasmid Substances 0.000 description 5
102000005962 receptors Human genes 0.000 description 5
108020003175 receptors Proteins 0.000 description 5
230000004044 response Effects 0.000 description 5
238000013268 sustained release Methods 0.000 description 5
239000012730 sustained-release form Substances 0.000 description 5
239000003826 tablet Substances 0.000 description 5
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 4
241000588724 Escherichia coli Species 0.000 description 4
102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 4
101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 4
102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 4
101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 4
PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 4
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 4
108010029485 Protein Isoforms Proteins 0.000 description 4
102000001708 Protein Isoforms Human genes 0.000 description 4
108020004511 Recombinant DNA Proteins 0.000 description 4
235000004279 alanine Nutrition 0.000 description 4
150000001299 aldehydes Chemical class 0.000 description 4
UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 4
230000004071 biological effect Effects 0.000 description 4
230000008859 change Effects 0.000 description 4
238000010367 cloning Methods 0.000 description 4
230000003247 decreasing effect Effects 0.000 description 4
230000002950 deficient Effects 0.000 description 4
238000004520 electroporation Methods 0.000 description 4
230000002124 endocrine Effects 0.000 description 4
238000006911 enzymatic reaction Methods 0.000 description 4
239000013604 expression vector Substances 0.000 description 4
150000004676 glycans Chemical class 0.000 description 4
230000036541 health Effects 0.000 description 4
230000001976 improved effect Effects 0.000 description 4
238000005462 in vivo assay Methods 0.000 description 4
230000000977 initiatory effect Effects 0.000 description 4
229910052740 iodine Inorganic materials 0.000 description 4
238000001638 lipofection Methods 0.000 description 4
210000004185 liver Anatomy 0.000 description 4
210000004962 mammalian cell Anatomy 0.000 description 4
238000004519 manufacturing process Methods 0.000 description 4
239000002773 nucleotide Substances 0.000 description 4
125000003729 nucleotide group Chemical group 0.000 description 4
238000002515 oligonucleotide synthesis Methods 0.000 description 4
238000007410 oral glucose tolerance test Methods 0.000 description 4
239000000825 pharmaceutical preparation Substances 0.000 description 4
230000000144 pharmacologic effect Effects 0.000 description 4
229910052698 phosphorus Inorganic materials 0.000 description 4
229920001451 polypropylene glycol Polymers 0.000 description 4
229920001282 polysaccharide Polymers 0.000 description 4
239000005017 polysaccharide Substances 0.000 description 4
235000013930 proline Nutrition 0.000 description 4
238000000746 purification Methods 0.000 description 4
230000010076 replication Effects 0.000 description 4
102220218940 rs781647403 Human genes 0.000 description 4
FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 4
230000011664 signaling Effects 0.000 description 4
229910052721 tungsten Inorganic materials 0.000 description 4
208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 4
206010003694 Atrophy Diseases 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
238000011740 C57BL/6 mouse Methods 0.000 description 3
241001092081 Carpenteria Species 0.000 description 3
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
241000282412 Homo Species 0.000 description 3
239000004472 Lysine Substances 0.000 description 3
229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
239000004372 Polyvinyl alcohol Substances 0.000 description 3
108091006629 SLC13A2 Proteins 0.000 description 3
238000012300 Sequence Analysis Methods 0.000 description 3
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
238000005917 acylation reaction Methods 0.000 description 3
239000000654 additive Substances 0.000 description 3
230000000996 additive effect Effects 0.000 description 3
210000001789 adipocyte Anatomy 0.000 description 3
230000037444 atrophy Effects 0.000 description 3
239000000090 biomarker Substances 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
229910052799 carbon Inorganic materials 0.000 description 3
229920001577 copolymer Polymers 0.000 description 3
201000010099 disease Diseases 0.000 description 3
PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
239000003651 drinking water Substances 0.000 description 3
235000020188 drinking water Nutrition 0.000 description 3
229940079593 drug Drugs 0.000 description 3
125000004185 ester group Chemical group 0.000 description 3
230000001747 exhibiting effect Effects 0.000 description 3
230000006870 function Effects 0.000 description 3
125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 3
229960002591 hydroxyproline Drugs 0.000 description 3
230000000670 limiting effect Effects 0.000 description 3
239000002502 liposome Substances 0.000 description 3
239000007788 liquid Substances 0.000 description 3
238000003670 luciferase enzyme activity assay Methods 0.000 description 3
239000011859 microparticle Substances 0.000 description 3
230000003562 morphometric effect Effects 0.000 description 3
238000013425 morphometry Methods 0.000 description 3
229910052757 nitrogen Inorganic materials 0.000 description 3
230000001019 normoglycemic effect Effects 0.000 description 3
238000007911 parenteral administration Methods 0.000 description 3
229920002451 polyvinyl alcohol Polymers 0.000 description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
239000000047 product Substances 0.000 description 3
125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
230000006337 proteolytic cleavage Effects 0.000 description 3
238000011160 research Methods 0.000 description 3
239000000523 sample Substances 0.000 description 3
239000000600 sorbitol Substances 0.000 description 3
238000003860 storage Methods 0.000 description 3
230000002459 sustained effect Effects 0.000 description 3
238000002560 therapeutic procedure Methods 0.000 description 3
125000003396 thiol group Chemical group [H]S* 0.000 description 3
150000003573 thiols Chemical class 0.000 description 3
238000001890 transfection Methods 0.000 description 3
238000013519 translation Methods 0.000 description 3
DQLHSFUMICQIMB-VIFPVBQESA-N (2s)-2-amino-3-(4-methylphenyl)propanoic acid Chemical compound CC1=CC=C(C[C@H](N)C(O)=O)C=C1 DQLHSFUMICQIMB-VIFPVBQESA-N 0.000 description 2
UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 2
RIJNIVWHYSNSLQ-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-2-ylazaniumyl)acetate Chemical compound C1=CC=C2CC(NCC(=O)O)CC2=C1 RIJNIVWHYSNSLQ-UHFFFAOYSA-N 0.000 description 2
FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 2
CMUHFUGDYMFHEI-QMMMGPOBSA-N 4-amino-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N)C=C1 CMUHFUGDYMFHEI-QMMMGPOBSA-N 0.000 description 2
PZNQZSRPDOEBMS-QMMMGPOBSA-N 4-iodo-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(I)C=C1 PZNQZSRPDOEBMS-QMMMGPOBSA-N 0.000 description 2
108091093088 Amplicon Proteins 0.000 description 2
108090001008 Avidin Proteins 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
108020004705 Codon Proteins 0.000 description 2
239000004971 Cross linker Substances 0.000 description 2
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
239000004471 Glycine Substances 0.000 description 2
108010023302 HDL Cholesterol Proteins 0.000 description 2
108010010234 HDL Lipoproteins Proteins 0.000 description 2
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
206010020880 Hypertrophy Diseases 0.000 description 2
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 2
OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 2
MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 2
AKCRVYNORCOYQT-YFKPBYRVSA-N N-methyl-L-valine Chemical compound CN[C@@H](C(C)C)C(O)=O AKCRVYNORCOYQT-YFKPBYRVSA-N 0.000 description 2
KSPIYJQBLVDRRI-UHFFFAOYSA-N N-methylisoleucine Chemical compound CCC(C)C(NC)C(O)=O KSPIYJQBLVDRRI-UHFFFAOYSA-N 0.000 description 2
241000283973 Oryctolagus cuniculus Species 0.000 description 2
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
108010066816 Polypeptide N-acetylgalactosaminyltransferase Proteins 0.000 description 2
NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
108010077895 Sarcosine Proteins 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
229930006000 Sucrose Natural products 0.000 description 2
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
108010067390 Viral Proteins Proteins 0.000 description 2
230000002378 acidificating effect Effects 0.000 description 2
230000002730 additional effect Effects 0.000 description 2
238000010171 animal model Methods 0.000 description 2
239000003242 anti bacterial agent Substances 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
239000011324 bead Substances 0.000 description 2
230000009286 beneficial effect Effects 0.000 description 2
230000008901 benefit Effects 0.000 description 2
239000011230 binding agent Substances 0.000 description 2
230000008512 biological response Effects 0.000 description 2
JCZLABDVDPYLRZ-AWEZNQCLSA-N biphenylalanine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1C1=CC=CC=C1 JCZLABDVDPYLRZ-AWEZNQCLSA-N 0.000 description 2
239000002775 capsule Substances 0.000 description 2
239000000969 carrier Substances 0.000 description 2
239000001913 cellulose Substances 0.000 description 2
229920002678 cellulose Polymers 0.000 description 2
239000007795 chemical reaction product Substances 0.000 description 2
230000002759 chromosomal effect Effects 0.000 description 2
238000004590 computer program Methods 0.000 description 2
238000013270 controlled release Methods 0.000 description 2
239000003431 cross linking reagent Substances 0.000 description 2
239000013078 crystal Substances 0.000 description 2
230000006378 damage Effects 0.000 description 2
230000007850 degeneration Effects 0.000 description 2
YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 2
229950006137 dexfosfoserine Drugs 0.000 description 2
238000013118 diabetic mouse model Methods 0.000 description 2
239000003085 diluting agent Substances 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
238000012377 drug delivery Methods 0.000 description 2
239000003623 enhancer Substances 0.000 description 2
230000007613 environmental effect Effects 0.000 description 2
YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 2
125000000524 functional group Chemical group 0.000 description 2
BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
210000001035 gastrointestinal tract Anatomy 0.000 description 2
230000002068 genetic effect Effects 0.000 description 2
230000004110 gluconeogenesis Effects 0.000 description 2
229920000669 heparin Polymers 0.000 description 2
229960002897 heparin Drugs 0.000 description 2
238000004128 high performance liquid chromatography Methods 0.000 description 2
229920001519 homopolymer Polymers 0.000 description 2
229940088597 hormone Drugs 0.000 description 2
239000005556 hormone Substances 0.000 description 2
230000028993 immune response Effects 0.000 description 2
238000003364 immunohistochemistry Methods 0.000 description 2
230000036512 infertility Effects 0.000 description 2
238000001802 infusion Methods 0.000 description 2
238000007689 inspection Methods 0.000 description 2
239000007928 intraperitoneal injection Substances 0.000 description 2
238000001990 intravenous administration Methods 0.000 description 2
210000004153 islets of langerhan Anatomy 0.000 description 2
208000017169 kidney disease Diseases 0.000 description 2
125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
239000000314 lubricant Substances 0.000 description 2
RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 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
239000012528 membrane Substances 0.000 description 2
DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 description 2
229930182817 methionine Chemical group 0.000 description 2
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
239000004005 microsphere Substances 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
230000007935 neutral effect Effects 0.000 description 2
210000000056 organ Anatomy 0.000 description 2
239000005022 packaging material Substances 0.000 description 2
238000004806 packaging method and process Methods 0.000 description 2
239000012071 phase Substances 0.000 description 2
OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 2
229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
229920000747 poly(lactic acid) Polymers 0.000 description 2
229920001583 poly(oxyethylated polyols) Polymers 0.000 description 2
230000000291 postprandial effect Effects 0.000 description 2
238000011809 primate model Methods 0.000 description 2
239000013615 primer Substances 0.000 description 2
230000000069 prophylactic effect Effects 0.000 description 2
230000001681 protective effect Effects 0.000 description 2
238000001742 protein purification Methods 0.000 description 2
230000002797 proteolythic effect Effects 0.000 description 2
238000003259 recombinant expression Methods 0.000 description 2
238000005932 reductive alkylation reaction Methods 0.000 description 2
GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
230000002441 reversible effect Effects 0.000 description 2
239000005720 sucrose Substances 0.000 description 2
208000024891 symptom Diseases 0.000 description 2
238000012360 testing method Methods 0.000 description 2
FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
229950002929 trinitrophenol Drugs 0.000 description 2
241000701447 unidentified baculovirus Species 0.000 description 2
GMKMEZVLHJARHF-UHFFFAOYSA-N (2R,6R)-form-2.6-Diaminoheptanedioic acid Natural products OC(=O)C(N)CCCC(N)C(O)=O GMKMEZVLHJARHF-UHFFFAOYSA-N 0.000 description 1
YOWXRBVUSFLFJO-ZETCQYMHSA-N (2S)-7-amino-2-(methylamino)heptanoic acid Chemical compound CN[C@@H](CCCCCN)C(=O)O YOWXRBVUSFLFJO-ZETCQYMHSA-N 0.000 description 1
KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
NMDDZEVVQDPECF-LURJTMIESA-N (2s)-2,7-diaminoheptanoic acid Chemical compound NCCCCC[C@H](N)C(O)=O NMDDZEVVQDPECF-LURJTMIESA-N 0.000 description 1
PIVJVCRQCUYKNZ-HNNXBMFYSA-N (2s)-2-(benzylazaniumyl)-3-phenylpropanoate Chemical compound C([C@@H](C(=O)O)NCC=1C=CC=CC=1)C1=CC=CC=C1 PIVJVCRQCUYKNZ-HNNXBMFYSA-N 0.000 description 1
BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
FYMNTAQFDTZISY-QMMMGPOBSA-N (2s)-2-amino-3-[4-(diaminomethylideneamino)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N=C(N)N)C=C1 FYMNTAQFDTZISY-QMMMGPOBSA-N 0.000 description 1
XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
OPOTYPXOKUZEKY-QMMMGPOBSA-N (2s)-2-nitramido-3-phenylpropanoic acid Chemical compound [O-][N+](=O)N[C@H](C(=O)O)CC1=CC=CC=C1 OPOTYPXOKUZEKY-QMMMGPOBSA-N 0.000 description 1
VVUFHVWLWLUHEI-GSVOUGTGSA-N (4R)-4-amino-5-carboxyoxy-5-oxopentanoic acid Chemical compound N[C@H](CCC(O)=O)C(=O)OC(O)=O VVUFHVWLWLUHEI-GSVOUGTGSA-N 0.000 description 1
125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 1
WHBMMWSBFZVSSR-GSVOUGTGSA-N (R)-3-hydroxybutyric acid Chemical compound C[C@@H](O)CC(O)=O WHBMMWSBFZVSSR-GSVOUGTGSA-N 0.000 description 1
108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
XQUPVDVFXZDTLT-UHFFFAOYSA-N 1-[4-[[4-(2,5-dioxopyrrol-1-yl)phenyl]methyl]phenyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(C=C1)=CC=C1CC1=CC=C(N2C(C=CC2=O)=O)C=C1 XQUPVDVFXZDTLT-UHFFFAOYSA-N 0.000 description 1
YMBIICKZNSTXJA-UHFFFAOYSA-N 2-(carboxyamino)pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)NC(O)=O YMBIICKZNSTXJA-UHFFFAOYSA-N 0.000 description 1
LRHRHAWNXCGABU-UHFFFAOYSA-N 2-(cyclopentylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCC1 LRHRHAWNXCGABU-UHFFFAOYSA-N 0.000 description 1
GLDQOLDJQPPFQL-UHFFFAOYSA-N 2-[bis(2-carbamimidoylsulfanylethyl)amino]ethyl carbamimidothioate;tetrahydrobromide Chemical compound Br.Br.Br.Br.NC(=N)SCCN(CCSC(N)=N)CCSC(N)=N GLDQOLDJQPPFQL-UHFFFAOYSA-N 0.000 description 1
RDFMDVXONNIGBC-UHFFFAOYSA-N 2-aminoheptanoic acid Chemical compound CCCCCC(N)C(O)=O RDFMDVXONNIGBC-UHFFFAOYSA-N 0.000 description 1
JUQLUIFNNFIIKC-UHFFFAOYSA-N 2-aminopimelic acid Chemical compound OC(=O)C(N)CCCCC(O)=O JUQLUIFNNFIIKC-UHFFFAOYSA-N 0.000 description 1
OFYAYGJCPXRNBL-UHFFFAOYSA-N 2-azaniumyl-3-naphthalen-1-ylpropanoate Chemical compound C1=CC=C2C(CC(N)C(O)=O)=CC=CC2=C1 OFYAYGJCPXRNBL-UHFFFAOYSA-N 0.000 description 1
BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 1
YXDGRBPZVQPESQ-QMMMGPOBSA-N 4-[(2s)-2-amino-2-carboxyethyl]benzoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(C(O)=O)C=C1 YXDGRBPZVQPESQ-QMMMGPOBSA-N 0.000 description 1
125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
RCPSZERYYLEKBV-UHFFFAOYSA-N 4-aminooxyphthalic acid Chemical compound NOC1=CC=C(C(O)=O)C(=C1)C(O)=O RCPSZERYYLEKBV-UHFFFAOYSA-N 0.000 description 1
229940117976 5-hydroxylysine Drugs 0.000 description 1
239000013607 AAV vector Substances 0.000 description 1
241000701242 Adenoviridae Species 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
241000283690 Bos taurus Species 0.000 description 1
241000283707 Capra Species 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
241001133757 Carpentaria Species 0.000 description 1
241000700199 Cavia porcellus Species 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
108091026890 Coding region Proteins 0.000 description 1
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
125000002038 D-arginyl group Chemical group N[C@@H](C(=O)*)CCCNC(=N)N 0.000 description 1
239000003155 DNA primer Substances 0.000 description 1
230000006820 DNA synthesis Effects 0.000 description 1
102220605452 DNA-(apurinic or apyrimidinic site) endonuclease_C93S_mutation Human genes 0.000 description 1
208000002249 Diabetes Complications Diseases 0.000 description 1
206010012655 Diabetic complications Diseases 0.000 description 1
206010061818 Disease progression Diseases 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
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 1
108010011459 Exenatide Proteins 0.000 description 1
206010016654 Fibrosis Diseases 0.000 description 1
FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
IKAIKUBBJHFNBZ-LURJTMIESA-N Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CN IKAIKUBBJHFNBZ-LURJTMIESA-N 0.000 description 1
241000175212 Herpesvirales Species 0.000 description 1
241000238631 Hexapoda Species 0.000 description 1
101001129187 Homo sapiens Patatin-like phospholipase domain-containing protein 2 Proteins 0.000 description 1
YZJSUQQZGCHHNQ-UHFFFAOYSA-N Homoglutamine Chemical compound OC(=O)C(N)CCCC(N)=O YZJSUQQZGCHHNQ-UHFFFAOYSA-N 0.000 description 1
102000008100 Human Serum Albumin Human genes 0.000 description 1
108091006905 Human Serum Albumin Proteins 0.000 description 1
LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
208000013016 Hypoglycemia Diseases 0.000 description 1
108060003951 Immunoglobulin Proteins 0.000 description 1
OYIFNHCXNCRBQI-BYPYZUCNSA-N L-2-aminoadipic acid Chemical compound OC(=O)[C@@H](N)CCCC(O)=O OYIFNHCXNCRBQI-BYPYZUCNSA-N 0.000 description 1
SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 description 1
AGPKZVBTJJNPAG-UHNVWZDZSA-N L-allo-Isoleucine Chemical compound CC[C@@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-UHNVWZDZSA-N 0.000 description 1
ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical group OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 description 1
XIGSAGMEBXLVJJ-YFKPBYRVSA-N L-homocitrulline Chemical compound NC(=O)NCCCC[C@H]([NH3+])C([O-])=O XIGSAGMEBXLVJJ-YFKPBYRVSA-N 0.000 description 1
UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical group OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical group CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical group C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 description 1
QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Chemical group CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-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
240000007472 Leucaena leucocephala Species 0.000 description 1
235000010643 Leucaena leucocephala Nutrition 0.000 description 1
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
229930195725 Mannitol Natural products 0.000 description 1
IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
241000713333 Mouse mammary tumor virus Species 0.000 description 1
241001529936 Murinae Species 0.000 description 1
241000699660 Mus musculus Species 0.000 description 1
JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
JJIHLJJYMXLCOY-BYPYZUCNSA-N N-acetyl-L-serine Chemical compound CC(=O)N[C@@H](CO)C(O)=O JJIHLJJYMXLCOY-BYPYZUCNSA-N 0.000 description 1
YPIGGYHFMKJNKV-UHFFFAOYSA-N N-ethylglycine Chemical compound CC[NH2+]CC([O-])=O YPIGGYHFMKJNKV-UHFFFAOYSA-N 0.000 description 1
108010065338 N-ethylglycine Proteins 0.000 description 1
PYUSHNKNPOHWEZ-YFKPBYRVSA-N N-formyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC=O PYUSHNKNPOHWEZ-YFKPBYRVSA-N 0.000 description 1
RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
230000004989 O-glycosylation Effects 0.000 description 1
108091034117 Oligonucleotide Proteins 0.000 description 1
238000012408 PCR amplification Methods 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
102100031248 Patatin-like phospholipase domain-containing protein 2 Human genes 0.000 description 1
102000035195 Peptidases Human genes 0.000 description 1
108091005804 Peptidases Proteins 0.000 description 1
239000004698 Polyethylene Substances 0.000 description 1
229920000954 Polyglycolide Polymers 0.000 description 1
239000004365 Protease Substances 0.000 description 1
241000125945 Protoparvovirus Species 0.000 description 1
108091034057 RNA (poly(A)) Proteins 0.000 description 1
108091028664 Ribonucleotide Proteins 0.000 description 1
102000007562 Serum Albumin Human genes 0.000 description 1
108010071390 Serum Albumin Proteins 0.000 description 1
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
235000021355 Stearic acid Nutrition 0.000 description 1
102000004357 Transferases Human genes 0.000 description 1
108090000992 Transferases Proteins 0.000 description 1
108700019146 Transgenes Proteins 0.000 description 1
239000007983 Tris buffer Substances 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
239000003070 absorption delaying agent Substances 0.000 description 1
238000010521 absorption reaction Methods 0.000 description 1
239000008351 acetate buffer Substances 0.000 description 1
SNEIUMQYRCDYCH-UHFFFAOYSA-N acetylarginine Chemical compound CC(=O)NC(C(O)=O)CCCN=C(N)N SNEIUMQYRCDYCH-UHFFFAOYSA-N 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
230000010933 acylation Effects 0.000 description 1
108700010877 adenoviridae proteins Proteins 0.000 description 1
210000000577 adipose tissue Anatomy 0.000 description 1
239000000443 aerosol Substances 0.000 description 1
125000003172 aldehyde group Chemical group 0.000 description 1
125000003545 alkoxy group Chemical group 0.000 description 1
125000000217 alkyl group Chemical group 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
229940124277 aminobutyric acid Drugs 0.000 description 1
150000008064 anhydrides Chemical class 0.000 description 1
230000000844 anti-bacterial effect Effects 0.000 description 1
239000003429 antifungal agent Substances 0.000 description 1
229940121375 antifungal agent Drugs 0.000 description 1
239000013011 aqueous formulation Substances 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
125000004104 aryloxy group Chemical group 0.000 description 1
229960001230 asparagine Drugs 0.000 description 1
235000009582 asparagine Nutrition 0.000 description 1
CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical group N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
235000019445 benzyl alcohol Nutrition 0.000 description 1
229940000635 beta-alanine Drugs 0.000 description 1
230000001588 bifunctional effect Effects 0.000 description 1
230000003115 biocidal effect Effects 0.000 description 1
238000010170 biological method Methods 0.000 description 1
229920001222 biopolymer Polymers 0.000 description 1
238000006664 bond formation reaction Methods 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
239000000872 buffer Substances 0.000 description 1
239000007975 buffered saline Substances 0.000 description 1
DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
229910000019 calcium carbonate Inorganic materials 0.000 description 1
239000001506 calcium phosphate Substances 0.000 description 1
229910000389 calcium phosphate Inorganic materials 0.000 description 1
235000011010 calcium phosphates Nutrition 0.000 description 1
238000004364 calculation method Methods 0.000 description 1
125000001314 canonical amino-acid group Chemical group 0.000 description 1
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
210000001175 cerebrospinal fluid Anatomy 0.000 description 1
125000003636 chemical group Chemical group 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
230000001684 chronic effect Effects 0.000 description 1
229960002173 citrulline Drugs 0.000 description 1
235000013477 citrulline Nutrition 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
238000000576 coating method Methods 0.000 description 1
239000002299 complementary DNA Substances 0.000 description 1
238000013329 compounding Methods 0.000 description 1
230000001010 compromised effect Effects 0.000 description 1
230000021615 conjugation Effects 0.000 description 1
239000000356 contaminant Substances 0.000 description 1
230000001186 cumulative effect Effects 0.000 description 1
230000006240 deamidation Effects 0.000 description 1
230000007423 decrease Effects 0.000 description 1
239000003405 delayed action preparation Substances 0.000 description 1
238000012217 deletion Methods 0.000 description 1
230000037430 deletion Effects 0.000 description 1
239000005547 deoxyribonucleotide Substances 0.000 description 1
125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
238000013461 design Methods 0.000 description 1
VEVRNHHLCPGNDU-MUGJNUQGSA-O desmosine Chemical compound OC(=O)[C@@H](N)CCCC[N+]1=CC(CC[C@H](N)C(O)=O)=C(CCC[C@H](N)C(O)=O)C(CC[C@H](N)C(O)=O)=C1 VEVRNHHLCPGNDU-MUGJNUQGSA-O 0.000 description 1
238000001514 detection method Methods 0.000 description 1
238000011161 development Methods 0.000 description 1
235000005911 diet Nutrition 0.000 description 1
230000037213 diet Effects 0.000 description 1
238000009792 diffusion process Methods 0.000 description 1
230000003292 diminished effect Effects 0.000 description 1
230000005750 disease progression Effects 0.000 description 1
239000002612 dispersion medium Substances 0.000 description 1
239000012153 distilled water Substances 0.000 description 1
AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
231100000673 dose–response relationship Toxicity 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
230000037149 energy metabolism Effects 0.000 description 1
230000002708 enhancing effect Effects 0.000 description 1
239000004174 erythrosine Substances 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
239000005038 ethylene vinyl acetate Substances 0.000 description 1
210000003527 eukaryotic cell Anatomy 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
230000029142 excretion Effects 0.000 description 1
229960001519 exenatide Drugs 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
230000004761 fibrosis Effects 0.000 description 1
238000001914 filtration Methods 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
238000004108 freeze drying Methods 0.000 description 1
239000000499 gel Substances 0.000 description 1
229960001381 glipizide Drugs 0.000 description 1
ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
229930195712 glutamate Natural products 0.000 description 1
229940049906 glutamate Drugs 0.000 description 1
229960002989 glutamic acid Drugs 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
235000004554 glutamine Nutrition 0.000 description 1
108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 1
108010015792 glycyllysine Proteins 0.000 description 1
230000012010 growth Effects 0.000 description 1
239000003102 growth factor Substances 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
102000053391 human F Human genes 0.000 description 1
108700031895 human F Proteins 0.000 description 1
229920002674 hyaluronan Polymers 0.000 description 1
229960003160 hyaluronic acid Drugs 0.000 description 1
150000002431 hydrogen Chemical group 0.000 description 1
239000001257 hydrogen Substances 0.000 description 1
230000002209 hydrophobic effect Effects 0.000 description 1
125000001165 hydrophobic group Chemical group 0.000 description 1
QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
206010020718 hyperplasia Diseases 0.000 description 1
230000002218 hypoglycaemic effect Effects 0.000 description 1
230000001900 immune effect Effects 0.000 description 1
102000018358 immunoglobulin Human genes 0.000 description 1
229940072221 immunoglobulins Drugs 0.000 description 1
238000000099 in vitro assay Methods 0.000 description 1
230000001939 inductive effect Effects 0.000 description 1
239000003701 inert diluent Substances 0.000 description 1
230000008595 infiltration Effects 0.000 description 1
238000001764 infiltration Methods 0.000 description 1
230000028709 inflammatory response Effects 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
238000001361 intraarterial administration Methods 0.000 description 1
238000000185 intracerebroventricular administration Methods 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
239000007927 intramuscular injection Substances 0.000 description 1
238000010255 intramuscular injection Methods 0.000 description 1
PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
RGXCTRIQQODGIZ-UHFFFAOYSA-O isodesmosine Chemical compound OC(=O)C(N)CCCC[N+]1=CC(CCC(N)C(O)=O)=CC(CCC(N)C(O)=O)=C1CCCC(N)C(O)=O RGXCTRIQQODGIZ-UHFFFAOYSA-O 0.000 description 1
238000002955 isolation Methods 0.000 description 1
FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
239000000644 isotonic solution Substances 0.000 description 1
239000007951 isotonicity adjuster Substances 0.000 description 1
238000005304 joining Methods 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
238000004989 laser desorption mass spectroscopy Methods 0.000 description 1
230000037356 lipid metabolism Effects 0.000 description 1
210000005228 liver tissue Anatomy 0.000 description 1
239000008176 lyophilized powder Substances 0.000 description 1
125000001288 lysyl group Chemical group 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
239000000594 mannitol Substances 0.000 description 1
235000010355 mannitol Nutrition 0.000 description 1
239000003550 marker Substances 0.000 description 1
238000013178 mathematical model Methods 0.000 description 1
239000002609 medium Substances 0.000 description 1
238000002844 melting Methods 0.000 description 1
230000008018 melting Effects 0.000 description 1
GMKMEZVLHJARHF-SYDPRGILSA-N meso-2,6-diaminopimelic acid Chemical compound [O-]C(=O)[C@@H]([NH3+])CCC[C@@H]([NH3+])C([O-])=O GMKMEZVLHJARHF-SYDPRGILSA-N 0.000 description 1
230000037323 metabolic rate Effects 0.000 description 1
XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
229960003105 metformin Drugs 0.000 description 1
CERQOIWHTDAKMF-UHFFFAOYSA-M methacrylate group Chemical group C(C(=C)C)(=O)[O-] CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
229960002216 methylparaben Drugs 0.000 description 1
LSDPWZHWYPCBBB-UHFFFAOYSA-O methylsulfide anion Chemical compound [SH2+]C LSDPWZHWYPCBBB-UHFFFAOYSA-O 0.000 description 1
239000003094 microcapsule Substances 0.000 description 1
229960001110 miglitol Drugs 0.000 description 1
230000003278 mimic effect Effects 0.000 description 1
238000002156 mixing Methods 0.000 description 1
108091005601 modified peptides Proteins 0.000 description 1
238000007491 morphometric analysis Methods 0.000 description 1
238000010172 mouse model Methods 0.000 description 1
210000000663 muscle cell Anatomy 0.000 description 1
ZVEZMVFBMOOHAT-UHFFFAOYSA-N nonane-1-thiol Chemical group CCCCCCCCCS ZVEZMVFBMOOHAT-UHFFFAOYSA-N 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
238000001216 nucleic acid method Methods 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
CQYBNXGHMBNGCG-RNJXMRFFSA-N octahydroindole-2-carboxylic acid Chemical compound C1CCC[C@H]2N[C@H](C(=O)O)C[C@@H]21 CQYBNXGHMBNGCG-RNJXMRFFSA-N 0.000 description 1
210000004923 pancreatic tissue Anatomy 0.000 description 1
230000002023 papillomaviral effect Effects 0.000 description 1
238000010647 peptide synthesis reaction Methods 0.000 description 1
239000000816 peptidomimetic Substances 0.000 description 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
230000026731 phosphorylation Effects 0.000 description 1
230000037081 physical activity Effects 0.000 description 1
239000002504 physiological saline solution Substances 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920001308 poly(aminoacid) Polymers 0.000 description 1
229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
108010087782 poly(glycyl-alanyl) Proteins 0.000 description 1
229920000728 polyester Polymers 0.000 description 1
229920000570 polyether Polymers 0.000 description 1
229920000573 polyethylene Polymers 0.000 description 1
229920000232 polyglycine polymer Polymers 0.000 description 1
239000004633 polyglycolic acid Substances 0.000 description 1
229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
239000004626 polylactic acid Substances 0.000 description 1
230000004481 post-translational protein modification Effects 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
239000000843 powder Substances 0.000 description 1
229960003611 pramlintide Drugs 0.000 description 1
108010029667 pramlintide Proteins 0.000 description 1
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 1
239000002244 precipitate Substances 0.000 description 1
239000002243 precursor Substances 0.000 description 1
238000002953 preparative HPLC Methods 0.000 description 1
238000004321 preservation Methods 0.000 description 1
230000002265 prevention Effects 0.000 description 1
150000003147 proline derivatives Chemical class 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
230000001737 promoting effect Effects 0.000 description 1
239000003380 propellant Substances 0.000 description 1
230000009145 protein modification Effects 0.000 description 1
230000002685 pulmonary effect Effects 0.000 description 1
229920005604 random copolymer Polymers 0.000 description 1
229920013730 reactive polymer Polymers 0.000 description 1
230000029964 regulation of glucose metabolic process Effects 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
229960002354 repaglinide Drugs 0.000 description 1
230000001177 retroviral effect Effects 0.000 description 1
239000002336 ribonucleotide Substances 0.000 description 1
125000002652 ribonucleotide group Chemical group 0.000 description 1
102220028713 rs111976362 Human genes 0.000 description 1
102220266304 rs1170214930 Human genes 0.000 description 1
229940043230 sarcosine Drugs 0.000 description 1
230000007017 scission Effects 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
230000009450 sialylation Effects 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
239000007787 solid Substances 0.000 description 1
239000007909 solid dosage form Substances 0.000 description 1
238000010532 solid phase synthesis reaction Methods 0.000 description 1
239000002904 solvent Substances 0.000 description 1
125000006850 spacer group Chemical group 0.000 description 1
241000894007 species Species 0.000 description 1
230000006641 stabilisation Effects 0.000 description 1
238000011105 stabilization Methods 0.000 description 1
238000010186 staining Methods 0.000 description 1
238000012289 standard assay Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
238000011146 sterile filtration Methods 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
230000001954 sterilising effect Effects 0.000 description 1
238000004659 sterilization and disinfection Methods 0.000 description 1
239000007929 subcutaneous injection Substances 0.000 description 1
238000010254 subcutaneous injection Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
239000013589 supplement Substances 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
230000002195 synergetic effect Effects 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
235000012222 talc Nutrition 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
238000011285 therapeutic regimen Methods 0.000 description 1
YSMODUONRAFBET-WHFBIAKZSA-N threo-5-hydroxy-L-lysine Chemical compound NC[C@@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-WHFBIAKZSA-N 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
230000001131 transforming effect Effects 0.000 description 1
238000011830 transgenic mouse model Methods 0.000 description 1
150000003626 triacylglycerols Chemical class 0.000 description 1
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
230000007306 turnover Effects 0.000 description 1
241001529453 unidentified herpesvirus Species 0.000 description 1
238000011144 upstream manufacturing Methods 0.000 description 1
210000002700 urine Anatomy 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
239000001993 wax Substances 0.000 description 1
235000019786 weight gain Nutrition 0.000 description 1
210000005253 yeast cell Anatomy 0.000 description 1
JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1