CN114907490B - 强效双功能hiv进入抑制剂及其应用 - Google Patents
强效双功能hiv进入抑制剂及其应用 Download PDFInfo
- Publication number
- CN114907490B CN114907490B CN202210438141.6A CN202210438141A CN114907490B CN 114907490 B CN114907490 B CN 114907490B CN 202210438141 A CN202210438141 A CN 202210438141A CN 114907490 B CN114907490 B CN 114907490B
- Authority
- CN
- China
- Prior art keywords
- hiv
- gly
- protein
- ser
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 230000001588 bifunctional effect Effects 0.000 title abstract description 55
- 239000002835 hiv fusion inhibitor Substances 0.000 title abstract description 14
- 229940126154 HIV entry inhibitor Drugs 0.000 title abstract description 10
- 230000003389 potentiating effect Effects 0.000 title description 17
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 89
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 70
- 241000700605 Viruses Species 0.000 claims abstract description 36
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 31
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 18
- 229920001184 polypeptide Polymers 0.000 claims abstract description 17
- 229950010245 ibalizumab Drugs 0.000 claims abstract description 8
- 208000031886 HIV Infections Diseases 0.000 claims description 92
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 58
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 35
- 108020004414 DNA Proteins 0.000 claims description 34
- 241000713340 Human immunodeficiency virus 2 Species 0.000 claims description 34
- 239000013598 vector Substances 0.000 claims description 33
- 230000014509 gene expression Effects 0.000 claims description 23
- 230000002401 inhibitory effect Effects 0.000 claims description 21
- 230000004927 fusion Effects 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 150000007523 nucleic acids Chemical class 0.000 claims description 16
- 239000012620 biological material Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 102000039446 nucleic acids Human genes 0.000 claims description 15
- 108020004707 nucleic acids Proteins 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 12
- 102000053602 DNA Human genes 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 229940121292 leronlimab Drugs 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 230000003612 virological effect Effects 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 7
- 244000005700 microbiome Species 0.000 claims description 7
- 208000036142 Viral infection Diseases 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 230000006870 function Effects 0.000 claims description 6
- 230000009385 viral infection Effects 0.000 claims description 6
- 108010033276 Peptide Fragments Proteins 0.000 claims description 3
- 102000007079 Peptide Fragments Human genes 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 230000007502 viral entry Effects 0.000 claims description 3
- 230000029812 viral genome replication Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000009098 adjuvant therapy Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 37
- 239000012634 fragment Substances 0.000 abstract description 18
- 230000007246 mechanism Effects 0.000 abstract description 4
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 abstract description 3
- 230000009545 invasion Effects 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 68
- 239000003112 inhibitor Substances 0.000 description 57
- 235000018102 proteins Nutrition 0.000 description 54
- 230000000840 anti-viral effect Effects 0.000 description 47
- 108091028043 Nucleic acid sequence Proteins 0.000 description 40
- 108020001507 fusion proteins Proteins 0.000 description 39
- 102000037865 fusion proteins Human genes 0.000 description 39
- 241000713311 Simian immunodeficiency virus Species 0.000 description 31
- 230000005764 inhibitory process Effects 0.000 description 31
- 241001112090 Pseudovirus Species 0.000 description 28
- 210000000170 cell membrane Anatomy 0.000 description 26
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 23
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 19
- 239000013612 plasmid Substances 0.000 description 19
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 239000003814 drug Substances 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 17
- 208000015181 infectious disease Diseases 0.000 description 16
- 241000700159 Rattus Species 0.000 description 15
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 102000004961 Furin Human genes 0.000 description 13
- 108090001126 Furin Proteins 0.000 description 13
- 210000002966 serum Anatomy 0.000 description 13
- 208000030507 AIDS Diseases 0.000 description 12
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- -1 small molecule compounds Chemical class 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 239000006228 supernatant Substances 0.000 description 11
- 238000003556 assay Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 10
- 239000002773 nucleotide Substances 0.000 description 10
- 125000003729 nucleotide group Chemical group 0.000 description 10
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 102100034349 Integrase Human genes 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 9
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 9
- 108091093126 WHP Posttrascriptional Response Element Proteins 0.000 description 9
- 229910002091 carbon monoxide Inorganic materials 0.000 description 9
- 238000004113 cell culture Methods 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 101710091045 Envelope protein Proteins 0.000 description 8
- 241000713666 Lentivirus Species 0.000 description 8
- 101710188315 Protein X Proteins 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000013642 negative control Substances 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 238000012546 transfer Methods 0.000 description 8
- 238000010276 construction Methods 0.000 description 7
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 7
- 238000004806 packaging method and process Methods 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 229920002307 Dextran Polymers 0.000 description 6
- 206010059866 Drug resistance Diseases 0.000 description 6
- HRBYTAIBKPNZKQ-AVGNSLFASA-N Glu-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O HRBYTAIBKPNZKQ-AVGNSLFASA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 6
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 230000007910 cell fusion Effects 0.000 description 6
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 230000010415 tropism Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 5
- 102220493167 FGGY carbohydrate kinase domain-containing protein_N43K_mutation Human genes 0.000 description 5
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 5
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 108010076504 Protein Sorting Signals Proteins 0.000 description 5
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000012876 carrier material Substances 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 108010050848 glycylleucine Proteins 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 4
- 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 4
- XTQFHTHIAKKCTM-YFKPBYRVSA-N Gly-Glu-Gly Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O XTQFHTHIAKKCTM-YFKPBYRVSA-N 0.000 description 4
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 4
- 108010028921 Lipopeptides Proteins 0.000 description 4
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 4
- 108010019160 Pancreatin Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 4
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 4
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 108010020688 glycylhistidine Proteins 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 108010064235 lysylglycine Proteins 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- 229940055695 pancreatin Drugs 0.000 description 4
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108010029020 prolylglycine Proteins 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- XVZCXCTYGHPNEM-IHRRRGAJSA-N (2s)-1-[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O XVZCXCTYGHPNEM-IHRRRGAJSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 3
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 3
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 3
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 3
- VBVKSAFJPVXMFJ-CIUDSAMLSA-N Asp-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)O)N VBVKSAFJPVXMFJ-CIUDSAMLSA-N 0.000 description 3
- JUWZKMBALYLZCK-WHFBIAKZSA-N Asp-Gly-Asn Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O JUWZKMBALYLZCK-WHFBIAKZSA-N 0.000 description 3
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 102220500383 Cytosolic iron-sulfur assembly component 3_E49A_mutation Human genes 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 3
- QYPKJXSMLMREKF-BPUTZDHNSA-N Glu-Glu-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)N QYPKJXSMLMREKF-BPUTZDHNSA-N 0.000 description 3
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 3
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 3
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- PHIXPNQDGGILMP-YVNDNENWSA-N Ile-Glu-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N PHIXPNQDGGILMP-YVNDNENWSA-N 0.000 description 3
- KBDIBHQICWDGDL-PPCPHDFISA-N Ile-Thr-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N KBDIBHQICWDGDL-PPCPHDFISA-N 0.000 description 3
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 3
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 3
- XVZCXCTYGHPNEM-UHFFFAOYSA-N Leu-Leu-Pro Natural products CC(C)CC(N)C(=O)NC(CC(C)C)C(=O)N1CCCC1C(O)=O XVZCXCTYGHPNEM-UHFFFAOYSA-N 0.000 description 3
- LFXSPAIBSZSTEM-PMVMPFDFSA-N Leu-Trp-Phe Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)O)N LFXSPAIBSZSTEM-PMVMPFDFSA-N 0.000 description 3
- AZOFEHCPMBRNFD-BZSNNMDCSA-N Lys-Phe-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CC=CC=C1 AZOFEHCPMBRNFD-BZSNNMDCSA-N 0.000 description 3
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 3
- UFOWQBYMUILSRK-IHRRRGAJSA-N Met-Lys-His Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CNC=N1 UFOWQBYMUILSRK-IHRRRGAJSA-N 0.000 description 3
- XLTSAUGGDYRFLS-UMPQAUOISA-N Met-Thr-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCSC)N)O XLTSAUGGDYRFLS-UMPQAUOISA-N 0.000 description 3
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 3
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 3
- YTILBRIUASDGBL-BZSNNMDCSA-N Phe-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 YTILBRIUASDGBL-BZSNNMDCSA-N 0.000 description 3
- MWQXFDIQXIXPMS-UNQGMJICSA-N Phe-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC1=CC=CC=C1)N)O MWQXFDIQXIXPMS-UNQGMJICSA-N 0.000 description 3
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 3
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 3
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 3
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 3
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 3
- OQPNSDWGAMFJNU-QWRGUYRKSA-N Ser-Gly-Tyr Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OQPNSDWGAMFJNU-QWRGUYRKSA-N 0.000 description 3
- FZXOPYUEQGDGMS-ACZMJKKPSA-N Ser-Ser-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O FZXOPYUEQGDGMS-ACZMJKKPSA-N 0.000 description 3
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 3
- LLSLRQOEAFCZLW-NRPADANISA-N Ser-Val-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LLSLRQOEAFCZLW-NRPADANISA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 244000299461 Theobroma cacao Species 0.000 description 3
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 3
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 3
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 3
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 3
- KIMOCKLJBXHFIN-YLVFBTJISA-N Trp-Ile-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O)=CNC2=C1 KIMOCKLJBXHFIN-YLVFBTJISA-N 0.000 description 3
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 3
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 3
- VFOHXOLPLACADK-GVXVVHGQSA-N Val-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N VFOHXOLPLACADK-GVXVVHGQSA-N 0.000 description 3
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 3
- CXWJFWAZIVWBOS-XQQFMLRXSA-N Val-Lys-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N CXWJFWAZIVWBOS-XQQFMLRXSA-N 0.000 description 3
- QPPZEDOTPZOSEC-RCWTZXSCSA-N Val-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](C(C)C)N)O QPPZEDOTPZOSEC-RCWTZXSCSA-N 0.000 description 3
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 3
- 108010081404 acein-2 Proteins 0.000 description 3
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 3
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 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 3
- 235000014121 butter Nutrition 0.000 description 3
- 235000001046 cacaotero Nutrition 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 108010042598 glutamyl-aspartyl-glycine Proteins 0.000 description 3
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 3
- 108010072405 glycyl-aspartyl-glycine Proteins 0.000 description 3
- 108010010147 glycylglutamine Proteins 0.000 description 3
- 108010087823 glycyltyrosine Proteins 0.000 description 3
- 108010025306 histidylleucine Proteins 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 108010078274 isoleucylvaline Proteins 0.000 description 3
- 108010012988 lysyl-glutamyl-aspartyl-glycine Proteins 0.000 description 3
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 3
- 229960004710 maraviroc Drugs 0.000 description 3
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 150000003891 oxalate salts Chemical class 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 238000001742 protein purification Methods 0.000 description 3
- 229960000311 ritonavir Drugs 0.000 description 3
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 3
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 3
- 102200133710 rs879253827 Human genes 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 3
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 108700004896 tripeptide FEG Proteins 0.000 description 3
- 108010044292 tryptophyltyrosine Proteins 0.000 description 3
- IGXNPQWXIRIGBF-KEOOTSPTSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoic acid Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 IGXNPQWXIRIGBF-KEOOTSPTSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- LZRNYBIJOSKKRJ-XVYDVKMFSA-N Ala-Asp-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N LZRNYBIJOSKKRJ-XVYDVKMFSA-N 0.000 description 2
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 2
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 2
- ZJLORAAXDAJLDC-CQDKDKBSSA-N Ala-Tyr-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O ZJLORAAXDAJLDC-CQDKDKBSSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 description 2
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 2
- QCTOLCVIGRLMQS-HRCADAONSA-N Arg-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O QCTOLCVIGRLMQS-HRCADAONSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- MEFGKQUUYZOLHM-GMOBBJLQSA-N Asn-Arg-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MEFGKQUUYZOLHM-GMOBBJLQSA-N 0.000 description 2
- LJUOLNXOWSWGKF-ACZMJKKPSA-N Asn-Asn-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N LJUOLNXOWSWGKF-ACZMJKKPSA-N 0.000 description 2
- PBSQFBAJKPLRJY-BYULHYEWSA-N Asn-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N PBSQFBAJKPLRJY-BYULHYEWSA-N 0.000 description 2
- DOURAOODTFJRIC-CIUDSAMLSA-N Asn-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N DOURAOODTFJRIC-CIUDSAMLSA-N 0.000 description 2
- WUQXMTITJLFXAU-JIOCBJNQSA-N Asn-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)N)N)O WUQXMTITJLFXAU-JIOCBJNQSA-N 0.000 description 2
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 2
- CGYKCTPUGXFPMG-IHPCNDPISA-N Asn-Tyr-Trp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O CGYKCTPUGXFPMG-IHPCNDPISA-N 0.000 description 2
- HBUJSDCLZCXXCW-YDHLFZDLSA-N Asn-Val-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HBUJSDCLZCXXCW-YDHLFZDLSA-N 0.000 description 2
- LNENWJXDHCFVOF-DCAQKATOSA-N Asp-His-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC(=O)O)N LNENWJXDHCFVOF-DCAQKATOSA-N 0.000 description 2
- RTXQQDVBACBSCW-CFMVVWHZSA-N Asp-Ile-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RTXQQDVBACBSCW-CFMVVWHZSA-N 0.000 description 2
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 2
- UCHSVZYJKJLPHF-BZSNNMDCSA-N Asp-Phe-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O UCHSVZYJKJLPHF-BZSNNMDCSA-N 0.000 description 2
- BWJZSLQJNBSUPM-FXQIFTODSA-N Asp-Pro-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O BWJZSLQJNBSUPM-FXQIFTODSA-N 0.000 description 2
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 108010075254 C-Peptide Proteins 0.000 description 2
- 108010041397 CD4 Antigens Proteins 0.000 description 2
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 2
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 2
- ZGERHCJBLPQPGV-ACZMJKKPSA-N Cys-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N ZGERHCJBLPQPGV-ACZMJKKPSA-N 0.000 description 2
- 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 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- LPJVZYMINRLCQA-AVGNSLFASA-N Gln-Cys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)N)N LPJVZYMINRLCQA-AVGNSLFASA-N 0.000 description 2
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 2
- KUBFPYIMAGXGBT-ACZMJKKPSA-N Gln-Ser-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KUBFPYIMAGXGBT-ACZMJKKPSA-N 0.000 description 2
- SRZLHYPAOXBBSB-HJGDQZAQSA-N Glu-Arg-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SRZLHYPAOXBBSB-HJGDQZAQSA-N 0.000 description 2
- LXAUHIRMWXQRKI-XHNCKOQMSA-N Glu-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N)C(=O)O LXAUHIRMWXQRKI-XHNCKOQMSA-N 0.000 description 2
- DSPQRJXOIXHOHK-WDSKDSINSA-N Glu-Asp-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O DSPQRJXOIXHOHK-WDSKDSINSA-N 0.000 description 2
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 2
- PXXGVUVQWQGGIG-YUMQZZPRSA-N Glu-Gly-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N PXXGVUVQWQGGIG-YUMQZZPRSA-N 0.000 description 2
- MTAOBYXRYJZRGQ-WDSKDSINSA-N Glu-Gly-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MTAOBYXRYJZRGQ-WDSKDSINSA-N 0.000 description 2
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 2
- SJJHXJDSNQJMMW-SRVKXCTJSA-N Glu-Lys-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SJJHXJDSNQJMMW-SRVKXCTJSA-N 0.000 description 2
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 2
- TZOVVRJYUDETQG-RCOVLWMOSA-N Gly-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN TZOVVRJYUDETQG-RCOVLWMOSA-N 0.000 description 2
- BEQGFMIBZFNROK-JGVFFNPUSA-N Gly-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)CN)C(=O)O BEQGFMIBZFNROK-JGVFFNPUSA-N 0.000 description 2
- KMSGYZQRXPUKGI-BYPYZUCNSA-N Gly-Gly-Asn Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC(N)=O KMSGYZQRXPUKGI-BYPYZUCNSA-N 0.000 description 2
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 2
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 2
- UTYGDAHJBBDPBA-BYULHYEWSA-N Gly-Ile-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)CN UTYGDAHJBBDPBA-BYULHYEWSA-N 0.000 description 2
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 2
- ZZJVYSAQQMDIRD-UWVGGRQHSA-N Gly-Pro-His Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O ZZJVYSAQQMDIRD-UWVGGRQHSA-N 0.000 description 2
- BMWFDYIYBAFROD-WPRPVWTQSA-N Gly-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN BMWFDYIYBAFROD-WPRPVWTQSA-N 0.000 description 2
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 2
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 2
- IZVICCORZOSGPT-JSGCOSHPSA-N Gly-Val-Tyr Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IZVICCORZOSGPT-JSGCOSHPSA-N 0.000 description 2
- TVQGUFGDVODUIF-LSJOCFKGSA-N His-Arg-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CN=CN1)N TVQGUFGDVODUIF-LSJOCFKGSA-N 0.000 description 2
- UZZXGLOJRZKYEL-DJFWLOJKSA-N His-Asn-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UZZXGLOJRZKYEL-DJFWLOJKSA-N 0.000 description 2
- 108010093488 His-His-His-His-His-His Proteins 0.000 description 2
- IGBBXBFSLKRHJB-BZSNNMDCSA-N His-Lys-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 IGBBXBFSLKRHJB-BZSNNMDCSA-N 0.000 description 2
- WYSJPCTWSBJFCO-AVGNSLFASA-N His-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC1=CN=CN1)N WYSJPCTWSBJFCO-AVGNSLFASA-N 0.000 description 2
- DEMIXZCKUXVEBO-BWAGICSOSA-N His-Thr-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O DEMIXZCKUXVEBO-BWAGICSOSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- VQUCKIAECLVLAD-SVSWQMSJSA-N Ile-Cys-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N VQUCKIAECLVLAD-SVSWQMSJSA-N 0.000 description 2
- KFVUBLZRFSVDGO-BYULHYEWSA-N Ile-Gly-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O KFVUBLZRFSVDGO-BYULHYEWSA-N 0.000 description 2
- RWYCOSAAAJBJQL-KCTSRDHCSA-N Ile-Gly-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N RWYCOSAAAJBJQL-KCTSRDHCSA-N 0.000 description 2
- GLYJPWIRLBAIJH-UHFFFAOYSA-N Ile-Lys-Pro Natural products CCC(C)C(N)C(=O)NC(CCCCN)C(=O)N1CCCC1C(O)=O GLYJPWIRLBAIJH-UHFFFAOYSA-N 0.000 description 2
- CIDLJWVDMNDKPT-FIRPJDEBSA-N Ile-Phe-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N CIDLJWVDMNDKPT-FIRPJDEBSA-N 0.000 description 2
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- VBZOAGIPCULURB-QWRGUYRKSA-N Leu-Gly-His Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N VBZOAGIPCULURB-QWRGUYRKSA-N 0.000 description 2
- LKXANTUNFMVCNF-IHPCNDPISA-N Leu-His-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O LKXANTUNFMVCNF-IHPCNDPISA-N 0.000 description 2
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 2
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 2
- QNTJIDXQHWUBKC-BZSNNMDCSA-N Leu-Lys-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QNTJIDXQHWUBKC-BZSNNMDCSA-N 0.000 description 2
- OVZLLFONXILPDZ-VOAKCMCISA-N Leu-Lys-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OVZLLFONXILPDZ-VOAKCMCISA-N 0.000 description 2
- JDBQSGMJBMPNFT-AVGNSLFASA-N Leu-Pro-Val Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O JDBQSGMJBMPNFT-AVGNSLFASA-N 0.000 description 2
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 2
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 2
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 2
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 2
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 2
- BTEMNFBEAAOGBR-BZSNNMDCSA-N Leu-Tyr-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BTEMNFBEAAOGBR-BZSNNMDCSA-N 0.000 description 2
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 2
- QUYCUALODHJQLK-CIUDSAMLSA-N Lys-Asp-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUYCUALODHJQLK-CIUDSAMLSA-N 0.000 description 2
- LXNPMPIQDNSMTA-AVGNSLFASA-N Lys-Gln-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 LXNPMPIQDNSMTA-AVGNSLFASA-N 0.000 description 2
- QQUJSUFWEDZQQY-AVGNSLFASA-N Lys-Gln-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CCCCN QQUJSUFWEDZQQY-AVGNSLFASA-N 0.000 description 2
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 2
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 2
- HKXSZKJMDBHOTG-CIUDSAMLSA-N Lys-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN HKXSZKJMDBHOTG-CIUDSAMLSA-N 0.000 description 2
- MDDUIRLQCYVRDO-NHCYSSNCSA-N Lys-Val-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN MDDUIRLQCYVRDO-NHCYSSNCSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- VHGIWFGJIHTASW-FXQIFTODSA-N Met-Ala-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O VHGIWFGJIHTASW-FXQIFTODSA-N 0.000 description 2
- GODBLDDYHFTUAH-CIUDSAMLSA-N Met-Asp-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O GODBLDDYHFTUAH-CIUDSAMLSA-N 0.000 description 2
- XGIQKEAKUSPCBU-SRVKXCTJSA-N Met-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCSC)N XGIQKEAKUSPCBU-SRVKXCTJSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 2
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- FIRWJEJVFFGXSH-RYUDHWBXSA-N Phe-Glu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 FIRWJEJVFFGXSH-RYUDHWBXSA-N 0.000 description 2
- WLYPRKLMRIYGPP-JYJNAYRXSA-N Phe-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 WLYPRKLMRIYGPP-JYJNAYRXSA-N 0.000 description 2
- ZUQACJLOHYRVPJ-DKIMLUQUSA-N Phe-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 ZUQACJLOHYRVPJ-DKIMLUQUSA-N 0.000 description 2
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 2
- NMELOOXSGDRBRU-YUMQZZPRSA-N Pro-Glu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]1CCCN1 NMELOOXSGDRBRU-YUMQZZPRSA-N 0.000 description 2
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 2
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 2
- OBXVZEAMXFSGPU-FXQIFTODSA-N Ser-Asn-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)CN=C(N)N OBXVZEAMXFSGPU-FXQIFTODSA-N 0.000 description 2
- ICHZYBVODUVUKN-SRVKXCTJSA-N Ser-Asn-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ICHZYBVODUVUKN-SRVKXCTJSA-N 0.000 description 2
- BLPYXIXXCFVIIF-FXQIFTODSA-N Ser-Cys-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N)CN=C(N)N BLPYXIXXCFVIIF-FXQIFTODSA-N 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 2
- OWCVUSJMEBGMOK-YUMQZZPRSA-N Ser-Lys-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O OWCVUSJMEBGMOK-YUMQZZPRSA-N 0.000 description 2
- WNDUPCKKKGSKIQ-CIUDSAMLSA-N Ser-Pro-Gln Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O WNDUPCKKKGSKIQ-CIUDSAMLSA-N 0.000 description 2
- ILZAUMFXKSIUEF-SRVKXCTJSA-N Ser-Ser-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ILZAUMFXKSIUEF-SRVKXCTJSA-N 0.000 description 2
- QNBVFKZSSRYNFX-CUJWVEQBSA-N Ser-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N)O QNBVFKZSSRYNFX-CUJWVEQBSA-N 0.000 description 2
- FHXGMDRKJHKLKW-QWRGUYRKSA-N Ser-Tyr-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 FHXGMDRKJHKLKW-QWRGUYRKSA-N 0.000 description 2
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- CAGTXGDOIFXLPC-KZVJFYERSA-N Thr-Arg-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CCCN=C(N)N CAGTXGDOIFXLPC-KZVJFYERSA-N 0.000 description 2
- MPUMPERGHHJGRP-WEDXCCLWSA-N Thr-Gly-Lys Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)O)N)O MPUMPERGHHJGRP-WEDXCCLWSA-N 0.000 description 2
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 2
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 2
- 102220535565 Trace amine-associated receptor 6_I37T_mutation Human genes 0.000 description 2
- UEFHVUQBYNRNQC-SFJXLCSZSA-N Trp-Phe-Thr Chemical compound C([C@@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=CC=C1 UEFHVUQBYNRNQC-SFJXLCSZSA-N 0.000 description 2
- IKUMWSDCGQVGHC-UMPQAUOISA-N Trp-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC2=CNC3=CC=CC=C32)N)O IKUMWSDCGQVGHC-UMPQAUOISA-N 0.000 description 2
- 108010028230 Trp-Ser- His-Pro-Gln-Phe-Glu-Lys Proteins 0.000 description 2
- NSTPFWRAIDTNGH-BZSNNMDCSA-N Tyr-Asn-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NSTPFWRAIDTNGH-BZSNNMDCSA-N 0.000 description 2
- FQNUWOHNGJWNLM-QWRGUYRKSA-N Tyr-Cys-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)NCC(O)=O FQNUWOHNGJWNLM-QWRGUYRKSA-N 0.000 description 2
- UNUZEBFXGWVAOP-DZKIICNBSA-N Tyr-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UNUZEBFXGWVAOP-DZKIICNBSA-N 0.000 description 2
- CTDPLKMBVALCGN-JSGCOSHPSA-N Tyr-Gly-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O CTDPLKMBVALCGN-JSGCOSHPSA-N 0.000 description 2
- PJWCWGXAVIVXQC-STECZYCISA-N Tyr-Ile-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PJWCWGXAVIVXQC-STECZYCISA-N 0.000 description 2
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-N 0.000 description 2
- KLOZTPOXVVRVAQ-DZKIICNBSA-N Tyr-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 KLOZTPOXVVRVAQ-DZKIICNBSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- XGJLNBNZNMVJRS-NRPADANISA-N Val-Glu-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O XGJLNBNZNMVJRS-NRPADANISA-N 0.000 description 2
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 2
- LJSZPMSUYKKKCP-UBHSHLNASA-N Val-Phe-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=CC=C1 LJSZPMSUYKKKCP-UBHSHLNASA-N 0.000 description 2
- NHXZRXLFOBFMDM-AVGNSLFASA-N Val-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C NHXZRXLFOBFMDM-AVGNSLFASA-N 0.000 description 2
- DVLWZWNAQUBZBC-ZNSHCXBVSA-N Val-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N)O DVLWZWNAQUBZBC-ZNSHCXBVSA-N 0.000 description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 229960001830 amprenavir Drugs 0.000 description 2
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 210000000702 aorta abdominal Anatomy 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 2
- 102220395086 c.170T>G Human genes 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- PMDQGYMGQKTCSX-HQROKSDRSA-L calcium;[(2r,3s)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3s)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate Chemical compound [Ca+2].C([C@@H]([C@H](OP([O-])([O-])=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 PMDQGYMGQKTCSX-HQROKSDRSA-L 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 229960002023 chloroprocaine Drugs 0.000 description 2
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 108010016616 cysteinylglycine Proteins 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 108010054813 diprotin B Proteins 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229960002049 etravirine Drugs 0.000 description 2
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 2
- 229960002933 fosamprenavir calcium Drugs 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 235000012907 honey Nutrition 0.000 description 2
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 229960001936 indinavir Drugs 0.000 description 2
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 229940099584 lactobionate Drugs 0.000 description 2
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229940070765 laurate Drugs 0.000 description 2
- 108010057821 leucylproline Proteins 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000004779 membrane envelope Anatomy 0.000 description 2
- 230000034217 membrane fusion Effects 0.000 description 2
- 229940102396 methyl bromide Drugs 0.000 description 2
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 229960000884 nelfinavir Drugs 0.000 description 2
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 229960000689 nevirapine Drugs 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- 230000036963 noncompetitive effect Effects 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 108010051242 phenylalanylserine Proteins 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 2
- 108010070643 prolylglutamic acid Proteins 0.000 description 2
- 108010015796 prolylisoleucine Proteins 0.000 description 2
- 238000002331 protein detection Methods 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 102220244516 rs1479587262 Human genes 0.000 description 2
- 102200068774 rs200050206 Human genes 0.000 description 2
- 102200033030 rs587777513 Human genes 0.000 description 2
- 102220119628 rs886044790 Human genes 0.000 description 2
- 229960001860 salicylate Drugs 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 108010048106 sifuvirtide Proteins 0.000 description 2
- WIOOVJJJJQAZGJ-ISHQQBGZSA-N sifuvirtide Chemical compound C([C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CO)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=C(O)C=C1 WIOOVJJJJQAZGJ-ISHQQBGZSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- KIYMLWIZXQPEHU-UKELCRPCSA-N virip Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@H](C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=2C=CC=CC=2)C(O)=O)CCC1 KIYMLWIZXQPEHU-UKELCRPCSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- LXJOYRVJPWDJBZ-UHFFFAOYSA-N (2-acetamido-3-hydroxyphenyl)arsonic acid Chemical compound OC=1C(=C(C=CC1)[As](O)(O)=O)NC(C)=O LXJOYRVJPWDJBZ-UHFFFAOYSA-N 0.000 description 1
- FIGBOMZADOQJTB-RZVRUWJTSA-N (2S)-5-amino-2-(methylamino)-5-oxopentanoic acid Chemical compound CN[C@@H](CCC(N)=O)C(=O)O.CN[C@@H](CCC(N)=O)C(=O)O FIGBOMZADOQJTB-RZVRUWJTSA-N 0.000 description 1
- BRPMXFSTKXXNHF-IUCAKERBSA-N (2s)-1-[2-[[(2s)-pyrrolidine-2-carbonyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H]1NCCC1 BRPMXFSTKXXNHF-IUCAKERBSA-N 0.000 description 1
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- FNYAZSZTENLTRT-UHFFFAOYSA-N 7a-methyl-2,3,6,7-tetrahydroindene-1,5-dione Chemical compound C1CC(=O)C=C2CCC(=O)C21C FNYAZSZTENLTRT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- OMMDTNGURYRDAC-NRPADANISA-N Ala-Glu-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OMMDTNGURYRDAC-NRPADANISA-N 0.000 description 1
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- LDLSENBXQNDTPB-DCAQKATOSA-N Ala-Lys-Arg Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LDLSENBXQNDTPB-DCAQKATOSA-N 0.000 description 1
- DEWWPUNXRNGMQN-LPEHRKFASA-N Ala-Met-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@@H]1C(=O)O)N DEWWPUNXRNGMQN-LPEHRKFASA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- XKXAZPSREVUCRT-BPNCWPANSA-N Ala-Tyr-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=C(O)C=C1 XKXAZPSREVUCRT-BPNCWPANSA-N 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 102220478560 Apoptosis regulator Bcl-2_D36S_mutation Human genes 0.000 description 1
- YFBGNGASPGRWEM-DCAQKATOSA-N Arg-Asp-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YFBGNGASPGRWEM-DCAQKATOSA-N 0.000 description 1
- OBFTYSPXDRROQO-SRVKXCTJSA-N Arg-Gln-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCN=C(N)N OBFTYSPXDRROQO-SRVKXCTJSA-N 0.000 description 1
- OGUPCHKBOKJFMA-SRVKXCTJSA-N Arg-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N OGUPCHKBOKJFMA-SRVKXCTJSA-N 0.000 description 1
- WVNFNPGXYADPPO-BQBZGAKWSA-N Arg-Gly-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O WVNFNPGXYADPPO-BQBZGAKWSA-N 0.000 description 1
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- YQNBILXAUIAUCF-CIUDSAMLSA-N Asn-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N YQNBILXAUIAUCF-CIUDSAMLSA-N 0.000 description 1
- OLGCWMNDJTWQAG-GUBZILKMSA-N Asn-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(N)=O OLGCWMNDJTWQAG-GUBZILKMSA-N 0.000 description 1
- GQRDIVQPSMPQME-ZPFDUUQYSA-N Asn-Ile-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O GQRDIVQPSMPQME-ZPFDUUQYSA-N 0.000 description 1
- RVHGJNGNKGDCPX-KKUMJFAQSA-N Asn-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N RVHGJNGNKGDCPX-KKUMJFAQSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- JPPLRQVZMZFOSX-UWJYBYFXSA-N Asn-Tyr-Ala Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 JPPLRQVZMZFOSX-UWJYBYFXSA-N 0.000 description 1
- KVMPVNGOKHTUHZ-GCJQMDKQSA-N Asp-Ala-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KVMPVNGOKHTUHZ-GCJQMDKQSA-N 0.000 description 1
- POTCZYQVVNXUIG-BQBZGAKWSA-N Asp-Gly-Pro Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O POTCZYQVVNXUIG-BQBZGAKWSA-N 0.000 description 1
- SWTQDYFZVOJVLL-KKUMJFAQSA-N Asp-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)O)N)O SWTQDYFZVOJVLL-KKUMJFAQSA-N 0.000 description 1
- QNIACYURSSCLRP-GUBZILKMSA-N Asp-Lys-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O QNIACYURSSCLRP-GUBZILKMSA-N 0.000 description 1
- JUWISGAGWSDGDH-KKUMJFAQSA-N Asp-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=CC=C1 JUWISGAGWSDGDH-KKUMJFAQSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- QSFHZPQUAAQHAQ-CIUDSAMLSA-N Asp-Ser-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O QSFHZPQUAAQHAQ-CIUDSAMLSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004364 Benzylated hydrocarbon Substances 0.000 description 1
- 108010017088 CCR5 Receptors Proteins 0.000 description 1
- 102000004274 CCR5 Receptors Human genes 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 241000222356 Coriolus Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- GUKYYUFHWYRMEU-WHFBIAKZSA-N Cys-Gly-Asp Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O GUKYYUFHWYRMEU-WHFBIAKZSA-N 0.000 description 1
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- 101710121417 Envelope glycoprotein Proteins 0.000 description 1
- XZWYTXMRWQJBGX-VXBMVYAYSA-N FLAG peptide Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=C(O)C=C1 XZWYTXMRWQJBGX-VXBMVYAYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101710114816 Gene 41 protein Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- CITDWMLWXNUQKD-FXQIFTODSA-N Gln-Gln-Asn Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CITDWMLWXNUQKD-FXQIFTODSA-N 0.000 description 1
- BLOXULLYFRGYKZ-GUBZILKMSA-N Gln-Glu-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BLOXULLYFRGYKZ-GUBZILKMSA-N 0.000 description 1
- HYPVLWGNBIYTNA-GUBZILKMSA-N Gln-Leu-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HYPVLWGNBIYTNA-GUBZILKMSA-N 0.000 description 1
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 1
- HPBKQFJXDUVNQV-FHWLQOOXSA-N Gln-Tyr-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O HPBKQFJXDUVNQV-FHWLQOOXSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 1
- FBEJIDRSQCGFJI-GUBZILKMSA-N Glu-Leu-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O FBEJIDRSQCGFJI-GUBZILKMSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- UCZXXMREFIETQW-AVGNSLFASA-N Glu-Tyr-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O UCZXXMREFIETQW-AVGNSLFASA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- LJPIRKICOISLKN-WHFBIAKZSA-N Gly-Ala-Ser Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O LJPIRKICOISLKN-WHFBIAKZSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- PMNHJLASAAWELO-FOHZUACHSA-N Gly-Asp-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PMNHJLASAAWELO-FOHZUACHSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- DHDOADIPGZTAHT-YUMQZZPRSA-N Gly-Glu-Arg Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DHDOADIPGZTAHT-YUMQZZPRSA-N 0.000 description 1
- SOEATRRYCIPEHA-BQBZGAKWSA-N Gly-Glu-Glu Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SOEATRRYCIPEHA-BQBZGAKWSA-N 0.000 description 1
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 1
- CQIIXEHDSZUSAG-QWRGUYRKSA-N Gly-His-His Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 CQIIXEHDSZUSAG-QWRGUYRKSA-N 0.000 description 1
- YTSVAIMKVLZUDU-YUMQZZPRSA-N Gly-Leu-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YTSVAIMKVLZUDU-YUMQZZPRSA-N 0.000 description 1
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 1
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 1
- WDEHMRNSGHVNOH-VHSXEESVSA-N Gly-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)CN)C(=O)O WDEHMRNSGHVNOH-VHSXEESVSA-N 0.000 description 1
- OJNZVYSGVYLQIN-BQBZGAKWSA-N Gly-Met-Asp Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O OJNZVYSGVYLQIN-BQBZGAKWSA-N 0.000 description 1
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 1
- CSMYMGFCEJWALV-WDSKDSINSA-N Gly-Ser-Gln Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O CSMYMGFCEJWALV-WDSKDSINSA-N 0.000 description 1
- ZLCLYFGMKFCDCN-XPUUQOCRSA-N Gly-Ser-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CO)NC(=O)CN)C(O)=O ZLCLYFGMKFCDCN-XPUUQOCRSA-N 0.000 description 1
- DUAWRXXTOQOECJ-JSGCOSHPSA-N Gly-Tyr-Val Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O DUAWRXXTOQOECJ-JSGCOSHPSA-N 0.000 description 1
- 241000941423 Grom virus Species 0.000 description 1
- MDBYBTWRMOAJAY-NHCYSSNCSA-N His-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MDBYBTWRMOAJAY-NHCYSSNCSA-N 0.000 description 1
- WGVPDSNCHDEDBP-KKUMJFAQSA-N His-Asp-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WGVPDSNCHDEDBP-KKUMJFAQSA-N 0.000 description 1
- CSTNMMIHMYJGFR-IHRRRGAJSA-N His-His-Arg Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CN=CN1 CSTNMMIHMYJGFR-IHRRRGAJSA-N 0.000 description 1
- UXSATKFPUVZVDK-KKUMJFAQSA-N His-Lys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CN=CN1)N UXSATKFPUVZVDK-KKUMJFAQSA-N 0.000 description 1
- KQJBFMJFUXAYPK-AVGNSLFASA-N His-Met-Met Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N KQJBFMJFUXAYPK-AVGNSLFASA-N 0.000 description 1
- DGLAHESNTJWGDO-SRVKXCTJSA-N His-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N DGLAHESNTJWGDO-SRVKXCTJSA-N 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000740205 Homo sapiens Sal-like protein 1 Proteins 0.000 description 1
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 1
- LVQDUPQUJZWKSU-PYJNHQTQSA-N Ile-Arg-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N LVQDUPQUJZWKSU-PYJNHQTQSA-N 0.000 description 1
- KIMHKBDJQQYLHU-PEFMBERDSA-N Ile-Glu-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KIMHKBDJQQYLHU-PEFMBERDSA-N 0.000 description 1
- LPXHYGGZJOCAFR-MNXVOIDGSA-N Ile-Glu-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N LPXHYGGZJOCAFR-MNXVOIDGSA-N 0.000 description 1
- GTSAALPQZASLPW-KJYZGMDISA-N Ile-His-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N GTSAALPQZASLPW-KJYZGMDISA-N 0.000 description 1
- UDBPXJNOEWDBDF-XUXIUFHCSA-N Ile-Lys-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)O)N UDBPXJNOEWDBDF-XUXIUFHCSA-N 0.000 description 1
- JERJIYYCOGBAIJ-OBAATPRFSA-N Ile-Tyr-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JERJIYYCOGBAIJ-OBAATPRFSA-N 0.000 description 1
- 206010069803 Injury associated with device Diseases 0.000 description 1
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 1
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 1
- YWKNKRAKOCLOLH-OEAJRASXSA-N Leu-Phe-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=CC=C1 YWKNKRAKOCLOLH-OEAJRASXSA-N 0.000 description 1
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 1
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 1
- XZNJZXJZBMBGGS-NHCYSSNCSA-N Leu-Val-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XZNJZXJZBMBGGS-NHCYSSNCSA-N 0.000 description 1
- HQVDJTYKCMIWJP-YUMQZZPRSA-N Lys-Asn-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O HQVDJTYKCMIWJP-YUMQZZPRSA-N 0.000 description 1
- PXHCFKXNSBJSTQ-KKUMJFAQSA-N Lys-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)O PXHCFKXNSBJSTQ-KKUMJFAQSA-N 0.000 description 1
- YEIYAQQKADPIBJ-GARJFASQSA-N Lys-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCCCN)N)C(=O)O YEIYAQQKADPIBJ-GARJFASQSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- ISHNZELVUVPCHY-ZETCQYMHSA-N Lys-Gly-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O ISHNZELVUVPCHY-ZETCQYMHSA-N 0.000 description 1
- DTUZCYRNEJDKSR-NHCYSSNCSA-N Lys-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN DTUZCYRNEJDKSR-NHCYSSNCSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- YPLVCBKEPJPBDQ-MELADBBJSA-N Lys-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N YPLVCBKEPJPBDQ-MELADBBJSA-N 0.000 description 1
- ZJSZPXISKMDJKQ-JYJNAYRXSA-N Lys-Phe-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(O)=O)CC1=CC=CC=C1 ZJSZPXISKMDJKQ-JYJNAYRXSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- TVHCDSBMFQYPNA-RHYQMDGZSA-N Lys-Thr-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TVHCDSBMFQYPNA-RHYQMDGZSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- MSSJHBAKDDIRMJ-SRVKXCTJSA-N Met-Lys-Gln Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O MSSJHBAKDDIRMJ-SRVKXCTJSA-N 0.000 description 1
- 102220494379 Methylmalonyl-CoA mutase, mitochondrial_N42T_mutation Human genes 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241000199919 Phaeophyceae Species 0.000 description 1
- CDNPIRSCAFMMBE-SRVKXCTJSA-N Phe-Asn-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CDNPIRSCAFMMBE-SRVKXCTJSA-N 0.000 description 1
- RGZYXNFHYRFNNS-MXAVVETBSA-N Phe-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N RGZYXNFHYRFNNS-MXAVVETBSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- OQTDZEJJWWAGJT-KKUMJFAQSA-N Phe-Lys-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O OQTDZEJJWWAGJT-KKUMJFAQSA-N 0.000 description 1
- SCKXGHWQPPURGT-KKUMJFAQSA-N Phe-Lys-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O SCKXGHWQPPURGT-KKUMJFAQSA-N 0.000 description 1
- WEDZFLRYSIDIRX-IHRRRGAJSA-N Phe-Ser-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 WEDZFLRYSIDIRX-IHRRRGAJSA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- MVIJMIZJPHQGEN-IHRRRGAJSA-N Phe-Ser-Val Chemical compound CC(C)[C@@H](C([O-])=O)NC(=O)[C@H](CO)NC(=O)[C@@H]([NH3+])CC1=CC=CC=C1 MVIJMIZJPHQGEN-IHRRRGAJSA-N 0.000 description 1
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 1
- KIGGUSRFHJCIEJ-DCAQKATOSA-N Pro-Asp-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O KIGGUSRFHJCIEJ-DCAQKATOSA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 1
- XYHMFGGWNOFUOU-QXEWZRGKSA-N Pro-Ile-Gly Chemical compound OC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1 XYHMFGGWNOFUOU-QXEWZRGKSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 1
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 1
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 1
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 231100000645 Reed–Muench method Toxicity 0.000 description 1
- 241001068263 Replication competent viruses Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 102100037204 Sal-like protein 1 Human genes 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- MIJWOJAXARLEHA-WDSKDSINSA-N Ser-Gly-Glu Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O MIJWOJAXARLEHA-WDSKDSINSA-N 0.000 description 1
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 1
- FGBLCMLXHRPVOF-IHRRRGAJSA-N Ser-Tyr-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FGBLCMLXHRPVOF-IHRRRGAJSA-N 0.000 description 1
- HAYADTTXNZFUDM-IHRRRGAJSA-N Ser-Tyr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O HAYADTTXNZFUDM-IHRRRGAJSA-N 0.000 description 1
- YEDSOSIKVUMIJE-DCAQKATOSA-N Ser-Val-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O YEDSOSIKVUMIJE-DCAQKATOSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- JHBHMCMKSPXRHV-NUMRIWBASA-N Thr-Asn-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O JHBHMCMKSPXRHV-NUMRIWBASA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 1
- SLUWOCTZVGMURC-BFHQHQDPSA-N Thr-Gly-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O SLUWOCTZVGMURC-BFHQHQDPSA-N 0.000 description 1
- UYTYTDMCDBPDSC-URLPEUOOSA-N Thr-Ile-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N UYTYTDMCDBPDSC-URLPEUOOSA-N 0.000 description 1
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-N 0.000 description 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- RVMNUBQWPVOUKH-HEIBUPTGSA-N Thr-Ser-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RVMNUBQWPVOUKH-HEIBUPTGSA-N 0.000 description 1
- UQCNIMDPYICBTR-KYNKHSRBSA-N Thr-Thr-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O UQCNIMDPYICBTR-KYNKHSRBSA-N 0.000 description 1
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- PELIQFPESHBTMA-WLTAIBSBSA-N Thr-Tyr-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 PELIQFPESHBTMA-WLTAIBSBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 1
- BGWSLEYVITZIQP-DCPHZVHLSA-N Trp-Phe-Ala Chemical compound C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(O)=O BGWSLEYVITZIQP-DCPHZVHLSA-N 0.000 description 1
- OEVJGIHPQOXYFE-SRVKXCTJSA-N Tyr-Asn-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O OEVJGIHPQOXYFE-SRVKXCTJSA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- YGKVNUAKYPGORG-AVGNSLFASA-N Tyr-Asp-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O YGKVNUAKYPGORG-AVGNSLFASA-N 0.000 description 1
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- JKUZFODWJGEQAP-KBPBESRZSA-N Tyr-Gly-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)O)N)O JKUZFODWJGEQAP-KBPBESRZSA-N 0.000 description 1
- NXRGXTBPMOGFID-CFMVVWHZSA-N Tyr-Ile-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O NXRGXTBPMOGFID-CFMVVWHZSA-N 0.000 description 1
- HFJJDMOFTCQGEI-STECZYCISA-N Tyr-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N HFJJDMOFTCQGEI-STECZYCISA-N 0.000 description 1
- NSGZILIDHCIZAM-KKUMJFAQSA-N Tyr-Leu-Ser Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NSGZILIDHCIZAM-KKUMJFAQSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- LMSBRIVOCYOKMU-NRPADANISA-N Val-Gln-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N LMSBRIVOCYOKMU-NRPADANISA-N 0.000 description 1
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 1
- SZTTYWIUCGSURQ-AUTRQRHGSA-N Val-Glu-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SZTTYWIUCGSURQ-AUTRQRHGSA-N 0.000 description 1
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- IEBGHUMBJXIXHM-AVGNSLFASA-N Val-Lys-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)O)N IEBGHUMBJXIXHM-AVGNSLFASA-N 0.000 description 1
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 1
- NSUUANXHLKKHQB-BZSNNMDCSA-N Val-Pro-Trp Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 NSUUANXHLKKHQB-BZSNNMDCSA-N 0.000 description 1
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 1
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 1
- QTPQHINADBYBNA-DCAQKATOSA-N Val-Ser-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN QTPQHINADBYBNA-DCAQKATOSA-N 0.000 description 1
- USXYVSTVPHELAF-RCWTZXSCSA-N Val-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N)O USXYVSTVPHELAF-RCWTZXSCSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 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
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 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
- 239000002253 acid Substances 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124411 anti-hiv antiviral agent Drugs 0.000 description 1
- 238000011225 antiretroviral therapy Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- XHRPOTDGOASDJS-UHFFFAOYSA-N cholesterol n-octadecanoate Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCCCCCC)C2 XHRPOTDGOASDJS-UHFFFAOYSA-N 0.000 description 1
- XHRPOTDGOASDJS-XNTGVSEISA-N cholesteryl stearate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCCCC)C1 XHRPOTDGOASDJS-XNTGVSEISA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- VDALIBWXVQVFGZ-UHFFFAOYSA-N dimethyl-[[4-[[3-(4-methylphenyl)-8,9-dihydro-7h-benzo[7]annulene-6-carbonyl]amino]phenyl]methyl]-(oxan-4-yl)azanium;chloride Chemical compound [Cl-].C1=CC(C)=CC=C1C1=CC=C(CCCC(=C2)C(=O)NC=3C=CC(C[N+](C)(C)C4CCOCC4)=CC=3)C2=C1 VDALIBWXVQVFGZ-UHFFFAOYSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229960002542 dolutegravir Drugs 0.000 description 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 229940048820 edetates Drugs 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 125000005313 fatty acid group Chemical group 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940125777 fusion inhibitor Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 150000004676 glycans Chemical group 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002941 microtiter virus yield reduction assay Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940068586 prezista Drugs 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000007026 protein scission Effects 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 108010043277 recombinant soluble CD4 Proteins 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229940107904 reyataz Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 102220259303 rs1041843537 Human genes 0.000 description 1
- 102200065432 rs193929337 Human genes 0.000 description 1
- 102220076182 rs749750052 Human genes 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000003239 susceptibility assay Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010084932 tryptophyl-proline Proteins 0.000 description 1
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 108010009962 valyltyrosine Proteins 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- C07K16/1036—Retroviridae, e.g. leukemia viruses
- C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
-
- 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
- C12N15/86—Viral vectors
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0684—Cells of the urinary tract or kidneys
- C12N5/0686—Kidney cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- 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
- C12N2510/00—Genetically modified cells
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
- C12N2740/15041—Use of virus, viral particle or viral elements as a vector
- C12N2740/15043—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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16022—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
- C12N2800/00—Nucleic acids vectors
- C12N2800/10—Plasmid DNA
- C12N2800/106—Plasmid DNA for vertebrates
- C12N2800/107—Plasmid DNA for vertebrates for mammalian
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- AIDS & HIV (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Tropical Medicine & Parasitology (AREA)
- Cell Biology (AREA)
- Physics & Mathematics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Plant Pathology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了强效双功能HIV进入抑制剂及其应用。本发明公开的强效双功能HIV进入抑制剂为A1)或A2):A1)由多肽2P23与抑制HIV进入的单克隆抗体ibalizumab或PRO140的单链形式连接得到的蛋白质;A2)由多肽2P23、所述抑制HIV进入的单克隆抗体ibalizumab或PRO 140的单链形式与IgG4‑Fc段或其突变肽段连接得到的蛋白质。本发明中的强效双功能HIV进入抑制剂,是针对HIV入侵靶细胞的机制而设计,不但具有极强的活性,而且具有更好的广谱性,从而达到提高疗效、减少给药剂量、降低病毒逃逸的目的,为抗HIV药物研发提供新的思路。
Description
技术领域
本发明涉及生物医药领域中,强效双功能HIV进入抑制剂及其应用。
背景技术
人免疫缺陷病毒(HIV)是获得性免疫缺陷综合征(AIDS)即艾滋病的病原体,分为HIV-1型和HIV-2型两种,以HIV-1流行为主。由于HIV的高度变异和可逃避宿主免疫系统识别的特性,迄今尚无安全有效的疫苗。自1996年以来,多种药物联合使用的高效抗逆转录病毒疗法(HAART)依然是可有效抑制HIV复制,大大降低与AIDS相关的发病率和死亡率以及HIV传播风险的治疗手段。该方案的不足之处是无法清除病毒储存库,一旦停药,患者体内病毒很快出现反弹,然而长期服药易引起毒副作用和耐药性(1)。因此,艾滋病治愈仍面临巨大挑战和难题。
HIV进入靶细胞的过程,由病毒包膜蛋白(Env)介导。其中,表面亚基gp120与细胞受体CD4和辅助受体CCR5或CXCR4结合,从而引起病毒包膜复合体发生构象变化(2)。跨膜亚基gp41通过将融合肽插入细胞膜,进而折叠形成6-螺旋束结构参与病毒-细胞融合,从而实现HIV的入侵细胞过程(3)。
因可在早期阻断病毒感染,基于入侵过程的HIV进入抑制剂成为人们研究的热点。目前,有多种进入抑制剂被广泛报道,包括蛋白质、多肽以及小分子化合物等。根据其作用靶点的不同,主要分为两大类,靶向结合病毒Env上不同表位,如广谱中和抗体VRC01、10-1074、3BNC117、N6、10E8与多肽恩夫韦肽(T-20)、艾博卫泰(ABT)等,和靶向结合宿主细胞表面受体或辅助受体的单克隆抗体或小分子物质,如ibalizumab(iMab)、马拉维若(maraviroc)等。
迄今,有四个HIV进入抑制剂批准用于临床治疗,包括靶向CD4的iMab(4),CCR5变构拮抗剂maraviroc(5),以及融合抑制剂T-20和ABT(6,7)。其中,maraviroc仅选择性针对CCR5嗜性病毒有效,对CXCR4嗜性毒株无效;T-20需要静脉给药,局部可出现不良反应,作为患者出现耐药后的二线用药;ABT作为全球首个长效HIV融合抑制剂,与克立芝或其他抗病毒药物联合使用,适用于耐药后的二线治疗。iMab作为首个获批用于HIV治疗的单克隆抗体,与其他药物联合应用于治疗HIV成人多重耐药感染(8)。iMab是一种人源化IgG4单克隆抗体,通过与人CD4受体的第二结构域结合,以非竞争方式阻断HIV进入,同时不影响主要组织相容性复合体II类(MHCII)受体的结合以及病毒gp120的附着(9)。2009年临床试验1b期发现,在14例接受iMab方案治疗9周的患者中,13例出现了耐药毒株,对iMab的敏感性较刚入组时变差,主要表现为iMab对上述毒株的最大抑制率降低(10)。进一步对其进行分析研究发现,gp120 V5区域N端聚糖(PNGS)的缺失是导致HIV-1对iMab产生耐药性的主要原因,并且V2环的长度影响其耐药程度,当V5区域PNGS缺失或数量减少,V2环越长,其对iMab敏感性越低(11)。在靶向宿主细胞的单克隆抗体中,PRO140,同样是一种人源化IgG4单克隆抗体,可有效阻断HIV的感染(12)。其中,PRO 140表位位于CCR5的N端和胞外环第二结构域,通过阻断CCR5和HIV gp120的附着进而干扰病毒与宿主细胞膜的结合(13)。同其他CCR5拮抗剂一样,PRO 140使用前需进行病毒嗜性分析。
近年来,人们对膜融合的分子机制研究越来越深入。本发明人实验室一直致力于开发强效HIV融合抑制剂,设计出一系列多肽,通过阻断融合蛋白gp41的HR1和HR2功能区形成六螺旋束而阻止病毒与靶细胞膜的融合。其中,通过引入M-T钩子结构、HIV-2序列和形成“盐桥”残基设计出HR2衍生短肽2P23,具有极强的靶序列结合能力和更高的基因耐药屏障,能有效抑制HIV-1、HIV-2、猴免疫缺陷病毒(SIV)和T20耐药株(14)。同时发现,基于2P23的棕榈酸修饰脂肽LP-19具有更高的抗病毒活性和成药性,其稳定性和生物半衰期都得到显著改善(15)。究其原因,考虑是脂肽LP-19可通过脂肪酸基团结合至细胞膜脂阀结构,从而提高了细胞膜局部的抑制剂浓度,这与六螺旋束结构以及病毒膜融合的机制相一致。
单链抗体(scFv)是由抗体重链可变区与轻链可变区在一段肽链的连接下构成的小分子,是具有抗体活性的最小功能结构单位。由于其具有分子质量小,穿透力强,免疫原性低等特点,在疾病临床诊断、治疗、预防等方面具有重要作用和广阔的应用前景。2019年,研究者将靶向HIV进入过程中的不同广谱中和抗体,通过以单链抗体的形式进行表达,并与其全分子抗体的活性进行比较,除外对含有特殊突变的HIV-1毒株,两种形式的抗体抗病毒活性接近(16)。
由于HIV的高突变特性,针对HIV包膜不同表位或进入步骤的双功能或多功能抑制剂被广泛开发(17,18)。通常情况下,靶向病毒自身包膜蛋白的抑制剂比靶向宿主细胞的易于诱导出病毒耐药突变。如果一种抑制剂靶向较为保守的表位,则不易产生耐药。所以,设计双靶点或多靶点抑制剂,可提高其耐药屏障。
发明内容
本发明所要解决的技术问题是如何强效抑制HIV。
为了解决以上技术问题,本发明提供了强效HIV进入抑制剂。本发明所提供的强效HIV进入抑制剂,是针对HIV入侵靶细胞的机制而设计,不但具有极强活性和广谱性,而且耐药屏障高,从而达到提高疗效、减少给药剂量、降低病毒逃逸的目的。该抑制剂为下述A1)-A4)中的任一种蛋白质:
A1)由多肽2P23与HIV单克隆抗体的单链抗体形式连接得到的蛋白质;
A2)由多肽2P23、所述HIV单克隆抗体的单链抗体形式与IgG4-Fc段或其突变肽段(如IgG4-Fc-LS段,即将IgG4-Fc进行突变得到的肽段)连接得到的蛋白质;
A3)在A1)或A2)中经过一个或几个氨基酸残基的取代和/或缺失和/或添加且具有相同功能的蛋白质;
A4)在A1)或A2)或A3)的N端或/和C端连接标签得到的蛋白质。
为了使A1)或A2)中的蛋白质便于纯化,可在A1)或A2)的蛋白质的氨基末端或羧基末端连接上如下表所示的标签。
表:标签的序列
标签 | 残基 | 序列 |
Poly-Arg | 5-6(通常为5个) | RRRRR |
Poly-His | 2-10(通常为6个) | HHHHHH |
FLAG | 8 | DYKDDDDK |
Strep-tag II | 8 | WSHPQFEK |
c-myc | 10 | EQKLISEEDL |
上述A3)中的蛋白质,为与A1)或A2)的蛋白质的氨基酸序列具有75%或75%以上同一性且具有相同功能的蛋白质。所述具有75%或75%以上同一性为具有75%、具有80%、具有85%、具有90%、具有95%、具有96%、具有97%、具有98%或具有99%的同一性。
上述A3)中蛋白质可人工合成,也可先合成其编码基因,再进行生物表达得到。
上述蛋白质中,所述多肽2P23的序列可为序列表中SEQ ID No.2的第22-44位。
所述单克隆抗体可为ibalizumab或PRO 140。
所述IgG4-Fc-LS段的序列可为序列表中SEQ ID No.6的第314-530位。
上述蛋白质中,所述单克隆抗体可为单链抗体。
上述蛋白质中,所述单克隆抗体的单链抗体序列可为序列表中SEQ ID No.2的第60-308位或SEQ ID No.4的第60-308位。
上述蛋白质中,A1)所述蛋白质的序列可为序列表中SEQ ID No.2的第22-308位或SEQ ID No.4的第22-308位。
本发明还提供了与所述蛋白质相关的生物材料,所述生物材料为下述B1)至B5)中的任一种:
B1)编码所述蛋白质的核酸分子;
B2)含有B1)所述核酸分子的表达盒;
B3)含有B1)所述核酸分子的重组载体、或含有B2)所述表达盒的重组载体;
B4)含有B1)所述核酸分子的重组微生物、或含有B2)所述表达盒的重组微生物、或含有B3)所述重组载体的重组微生物;
B5)含有B1)所述核酸分子的细胞系、或含有B2)所述表达盒的细胞系。
上述生物材料中,B1)所述核酸分子可为如下b11)-b15)中任一种:
b11)序列表中SEQ ID No.1的第73-933位所示的DNA分子;
b12)序列表中SEQ ID No.3的第73-933位所示的DNA分子;
b13)序列表中SEQ ID No.5的第73-1599位所示的DNA分子;
b14)与b11)-b13)中任一种限定的核苷酸序列具有75%或75%以上同一性,且编码所述蛋白质的DNA分子;
b15)在严格条件下与b11)-b14)中任一种限定的核苷酸序列杂交,且编码所述蛋白质的DNA分子。
其中,所述核酸分子可以是DNA,如cDNA、基因组DNA或重组DNA;所述核酸分子也可以是RNA,如mRNA或hnRNA等。
本领域普通技术人员可以很容易地采用已知的方法,例如定向进化和点突变的方法,对编码本发明的蛋白质的核苷酸序列进行突变。那些经过人工修饰的,具有与本发明分离的核苷酸序列75%或者更高同一性的核苷酸,只要编码本发明的蛋白质且具有本发明的蛋白质的功能,均是衍生于本发明的核苷酸序列并且等同于本发明的序列。
这里使用的术语“同一性”指与天然核酸序列的序列相似性。“同一性”包括与本发明的编码本发明的蛋白质的核苷酸序列具有75%或更高,或85%或更高,或90%或更高,或95%或更高同一性的核苷酸序列。同一性可以用肉眼或计算机软件进行评价。使用计算机软件,两个或多个序列之间的同一性可以用百分比(%)表示,其可以用来评价相关序列之间的同一性。
上述75%或75%以上同一性,可为80%、85%、90%或95%以上的同一性。
上述应用中,B2)所述的含有编码所述蛋白质的核酸分子的表达盒,是指能够在宿主细胞中表达所述蛋白质的DNA,该DNA不但可包括启动所述蛋白质编码基因转录的启动子,还可包括终止所述蛋白质编码基因转录的终止子。进一步,所述表达盒还可包括增强子序列。
可用现有的表达载体构建含有所述蛋白质编码基因表达盒的重组载体。
上述应用中,所述载体可为质粒、黏粒、噬菌体或病毒载体。所述病毒载体具体可为pRRLSIN.cPPT.PGK-GFP.WPRE载体。
B3)所述重组载体具体可为p-2P23-PRO140-EGFP、p-2P23-iMab-EGFP或p-2P23-PRO140-Fc-EGFP。所述p-2P23-PRO140-EGFP为将慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI识别位点间的DNA片段替换为SEQ ID No.1的第7-1758位所示的DNA片段,保持其他序列不变得到的重组载体。所述p-2P23-iMab-EGFP为将慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI识别序列间的DNA片段替换为SEQ ID No.3的第7-1758位所示的DNA片段,保持其他序列不变得到的重组载体。所述p-2P23-PRO140-Fc-EGFP为将慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI识别序列间的DNA片段替换为SEQ ID No.5的第7-2424位所示的DNA片段,保持其他序列不变得到的重组载体。
上述应用中,所述微生物可为酵母、细菌、藻或真菌。
上述应用中,所述细胞系不包括繁殖材料。
本发明还提供了所述蛋白质的药用盐或衍生物。
本发明的蛋白质药用盐和多肽药用盐,包括醋酸盐(acetate)、乳糖醛酸盐(lactobionate)、苯磺酸盐(benzenesulfonate)、月桂酸酯(laurate)、安息香酸盐(benzoate)、苹果酸盐(malate)、重碳酸盐(bicarbonate)、马来酸盐(maleate)、硫酸氢盐(bisulfate)、扁桃酸盐(mandelate)、酒石酸氢盐(bitartrate)、甲磺酸盐(mesylate)、硼酸盐(borate)、溴甲烷(methylbromide)、溴化物(bromide)、硝酸甲酯(methylnitrate)、依地酸钙(calcium edetate)、甲基硫酸盐(methylsulfate)、右旋樟脑磺酸(camsylate)、粘酸盐(mucate)、碳酸盐(carbonate)、萘磺酸盐(napsylate)、氯化物(chloride)、硝酸盐(nitrate)、棒酸盐(clavulanate)、N-甲葡糖胺(N-methylglucamine)、柠檬酸盐(citrate)、铵盐(ammonium salt)、二氢氯化物(dihydrochloride)、油酸盐(oleate)、乙二胺四乙酸盐(edetate)、草酸盐(oxalate)、乙二磺酸盐(edisylate)、扑酸盐(pamoate)、(双羟萘酸盐embonate)、丙酸酯月桂硫酸酯(estolate)、棕榈酸盐(palmitate)、乙磺酸酯(esylate)、泛酸盐(pantothenate)、延胡索酸盐(fumarate)、磷酸盐/二磷酸(phosphate/diphosphate)、葡庚糖酸盐(gluceptate)、聚半乳糖醛酸盐(polygalacturonate)、葡(萄)糖酸盐(gluconate)、水杨酸盐(salicylate)、谷氨酸盐(glutamate)、硬脂酸盐(stearate)、对羟乙酰氨基苯胂酸(glycollylarsanilate)、硫酸盐(sulfate)、羟基苯甲酸盐(hexylresorcinate)、碱式乙酸盐(subacetate)、海巴(hydrabamine)、琥珀酸盐(succinate)、氢溴酸盐(hydrobromide)、丹宁酸盐(tannate)、氢氯化物(hydrochloride)、酒石酸盐(tartrate)、羟萘酸盐(hydroxynaphthoate)、8-氯茶碱盐(teoclate)、碘化物(iodide)、甲苯磺酸盐(tosylate)、三乙基碘(triethiodide)、乳酸(lactate)、戊酸盐(valerate)等。取决于用途,药用盐可以由阳离子如钠(sodium)、钾(potassium)、铝(aluminum)、钙(calcium)、锂(lithium)、锰(magnesium)和锌(zinc)、铋(bismuth)等所形成,也可由碱如氨、乙二胺(ethylenediamine)、N-甲基-谷氨酰胺(N-methyl-glutamine)、赖氨酸(lysine)、精氨酸(arginine)、鸟氨酸(ornithine)、胆碱(choline)、N,N'-二苄基乙二胺(N,N'-dibenzylethylene-diamine)、氯普鲁卡因(chloroprocaine),二乙醇氨(diethanolamine),普鲁卡因(procaine)、二乙胺(diethylamine)、哌嗪(piperazine)、三羟甲基氨基甲烷(tris(hydroxymethyl)aminomethane)和羟化四甲铵(tetramethylammonium hydroxide)等所形成。这些盐可以采用标准方法制备,例如通过游离酸与有机或无机碱的反应。在一个碱性基团如氨基存在的情况下,酸性盐如氢氯化物(hydrochloride)、氢溴化物(hydrobromide)、醋酸盐(acetate)、扑酸盐(pamoate)等等可用作剂型;在一个酸性基团(如-COOH)或醇基存在的情况下,可药用的酯如醋酸酯(acetate)、马来酸酯(maleate)、三甲基乙酸氯甲酯(pivaloyloxymethyl)等、以及文献中公知的用于改善可溶性和水解性的酯可以用作持续释放和前体药制剂。
本发明还提供了一种组合物,所述组合物由所述蛋白质、其衍生物或其可药用盐与药学上可接受的载体或辅料组成。
所述组合物具有如下任一用途:
E1)抗病毒;
E2)治疗和/或预防和/或辅助治疗病毒感染所致疾病;
E3)抑制病毒与细胞进行融合;
E4)抑制病毒侵入细胞;
E5)抑制病毒复制;
所述E1)-E5)中,所述病毒为下述v1-v7中的任一:
v1、HIV-1、HIV-2和SIV;
v2、HIV-1和HIV-2;
v3、HIV-1和SIV;
v4、HIV-2和SIV;
v5、HIV-1;
v6、HIV-2;
v7、SIV。
本发明还提供了所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物在制备具有E1)-E5)中至少一种功能产品中的应用:
E1)抗病毒(如HIV或SIV);
E2)治疗和/或预防和/或辅助治疗病毒感染所致疾病,如药物或疫苗;
E3)抑制病毒与细胞进行融合;
E4)抑制病毒侵入细胞;
E5)抑制病毒复制;
所述E1)-E5)中,所述病毒为下述v1-v7中的任一:
v1、HIV-1、HIV-2和SIV;
v2、HIV-1和HIV-2;
v3、HIV-1和SIV;
v4、HIV-2和SIV;
v5、HIV-1;
v6、HIV-2;
v7、SIV。
HIV-1毒株可包括NL4-3、398-F1_F6_20、TRO.11、X2278_C2_B6、PVO、SC422661.8、JRFL、SF162、CNE4、CNE6、CNE9、CNE11、CNE14、CNE57、43-22、B01、CAP45.2.00.G3、Du156、CE703010217_B6、CE1176_A3、HIV_25710-2.43、X1632-S2-B10、246_F3_C10_2、AE03、CNE8、CNE55、CNE107、CH119.10、BJOX002000.03、CH64.20、CH70.1、CH110、CH120.6、CNE49。HIVNL4-3诱导突变株包括:L57R、L57R/E136G、E49K、E49A、E136G、N43K/E49A、E49K/N126K、Q39R/N43K/N126K、N43K/E49A/N126K、Q52R、I37T、V38A、V38M、Q40H、N43K、D36S/V38M、V38A/N42T、I37T/N43K。
本发明所提供的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物,可以用于HIV(HIV-1和/或HIV-2)和/或SIV感染的治疗,包括HIV和/或SIV感染的各个阶段,例如艾滋病发病期(AIDS)、有症状期和无症状期。本发明所提供的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物,也可以用于HIV(HIV-1和/或HIV-2)和/或SIV感染的预防,包括暴露前或可疑暴露后,例如输血、器官移植、体液交换、咬伤、意外针刺或手术中暴露于病人血液等。
在实际应用中,可以将本发明的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物作为药物直接给予病人、或者与适宜的载体或赋形剂混合后给予病人,以达到治疗和/或预防HIV感染的目的。这里的载体材料包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋酸纤维素酞酸酯和羧甲乙纤维素等)。其中优选的是水溶性载体材料。使用这些材料可以制成多种剂型,包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。其中,栓剂可为阴道栓剂,也可以是阴道环,也可以是适于阴道应用的药膏、乳霜或凝胶。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。为了将单位给药剂型制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将单位给药剂型制成栓剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将单位给药剂型制成注射用制剂,如溶液剂、乳剂、冻干粉针剂和混悬剂,可以使用本领域常用的所有稀释剂,例如,水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
使用上述剂型可以经注射给药,包括皮下注射、静脉注射、肌肉注射和腹腔注射、脑池内注射或灌输等;腔道给药,如经直肠、阴道和舌下;呼吸道给药,如经鼻腔;粘膜给药。上述给药途径优选的是注射给药,优选的注射途径是皮下注射。
本发明的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重及个体反应,所用的具体活性成分,给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药。
对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体活性成分的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体活性成分的给药时间、给药途径和排泄率;治疗持续时间;与所采用的具体活性成分组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,活性成分的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。一般说来,本发明的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物用于哺乳动物特别是人的剂量可以介于0.001-1000mg/kg体重/天,例如介于0.01-100mg/kg体重/天,又例如介于0.1-10mg/kg体重/天。给药频率可以为每天1-2次、1次/2天、1次/3天、1次/4天、1次/5天、1次/6天或1次/7天,优选的可以是1次/1-2天或1-2次/周。
本发明的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物可以直接单独用于HIV感染者的治疗和预防,也可以与一种或多种抗HIV药物联合使用,可以同时使用,也可以间隔使用,以达到提高整体治疗效果的目的。这些抗HIV药物包括但不限于逆转录酶抑制剂、蛋白酶抑制剂、侵入抑制剂、整合抑制剂和成熟抑制剂等。上述的逆转录酶抑制剂可以是核苷类逆转录酶抑制剂,如齐多夫定(AZT)、拉米夫定(3TC)、去羟肌苷(ddI)、扎西他滨(ddC)、司他夫定(d4T)、替诺福韦(TDF)、阿巴卡韦(ABC)、恩曲他滨(FTC),也可以是非核苷类逆转录酶抑制剂,如奈韦拉平(NVP)、依非韦伦(EFV)、地拉夫定(DLV)、依曲韦林(ETR)等的一种或几种;上述的蛋白酶抑制剂可以是沙奎那韦(SQV-HGC)、茚地那韦(IDV)、利托那韦(RTV)、安瑞那韦(APV)、克力芝(LPV/RTV)、奈非那韦(NFV)、福沙那伟钙(FPV)、Reyataz(ATV)和Prezista等的一种或几种;上述的整合抑制剂可以是Raltegravir、Dolutegravir和Elvitegravi等的一种或几种;上述的侵入抑制剂可以是Maraviroc、T-20、TAK-779、T2635、VIRIP(VIR-576)、西夫韦肽、艾博韦肽、可溶性CD4蛋白及其类似物、针对辅助受体CCR5的抗体(如PRO 140)、针对gp120/gp41的单克隆抗体(如VRC01和10E8)和针对受体CD4的单克隆抗体(如TNX-355)等的一种或几种。
本发明所提供的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物,可以用于HIV(HIV-1和/或HIV-2)和/或SIV感染的治疗和/或预防。在实际应用中,可以将本发明的所述蛋白质,所述生物材料,所述药用盐或衍生物,或所述组合物作为药物直接给予病人、或者与适宜的载体或赋形剂混合后给予病人,以达到治疗和/或预防HIV感染的目的。
本发明人从HIV进入环节着手,设计双功能抑制剂,以期从阻断病毒gp120与受体CD4或辅助受体CCR5的结合以及病毒包膜和细胞膜融合两个阶段来实现抑制病毒的进入。其中,阻断病毒gp120与CD4或CCR5的结合,可以理解为把病毒进入细胞的“门把手”给封闭上;而阻断病毒包膜和细胞膜的融合,进而切断病毒进入细胞阶段中的“最后环节”。本发明将靶向gp41、细胞CD4受体或CCR5辅助受体等位点的强效分子(膜融合抑制剂2P23、iMab、PRO 140的单链抗体),通过融合蛋白形式,表达基于HIV进入过程不同结合靶点的强效双功能抑制剂2P23-PRO140和2P23-iMab,实现抗病毒活性更强、更广谱、耐药屏障更高、拦截病毒更早期的目标。在此基础上,进一步将强效双功能抑制剂,通过融合表达IgG4-Fc段(含M428L/N434S双突变)的长效双功能HIV进入抑制剂,具有更好的稳定性、更长的半衰期和更强的体外抗病毒活性。本发明为抗HIV药物研发提供新的思路。
附图说明
图1为双功能进入抑制剂的慢病毒载体构建模式图和表达鉴定。A)双功能进入抑制剂的慢病毒载体构建模式图;B)双功能进入抑制剂的SDS-PAGE图和Western blot鉴定,marker表示蛋白分子量标准。
图2双功能进入抑制剂通过细胞膜表面CCR5或CD4与细胞膜结合。A)2P23-PRO140通过CCR5与细胞膜结合;B)2P23-iMab通过CD4与细胞膜结合。
图3为双功能进入抑制剂通过靶向结合细胞膜发挥抗病毒作用。
图4为双功能进入抑制剂对不同亚型HIV-1假病毒的抑制作用。
图5为双功能进入抑制剂对HIV-1包膜蛋白介导的细胞融合的抑制作用。
图6为双功能进入抑制剂对HIV-1耐药突变株假病毒的抑制作用。
图7为双功能进入抑制剂对HIV-2可复制病毒和SIV假病毒的抑制作用。
图8为2P23-PRO140-Fc的SDS-PAGE和Western blot鉴定。marker表示蛋白分子量标准。
图9为2P23-PRO140-Fc对HIV-1国际代表性毒株假病毒的抑制作用。
图10为2P23-PRO140-Fc表现出更好的稳定性。
图11为2P23-PRO140-Fc在大鼠血清中表现出更长的半衰期和更强的体外抗病毒活性。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南,并不以任何方式构成对本发明的限制。
实施例1为重组蛋白的构建与表达;实施例2为双功能分子通过CCR5或CD4与细胞膜结合;实施例3为双功能分子通过结合细胞膜发挥强效抗病毒作用;实施例4为双功能分子的抗病毒效果评价;实施例5为长效化改造双功能分子的构建与表达;实施例6为2P23-PRO140-Fc对HIV-1国际代表性毒株假病毒的抑制作用;实施例7为2P23-PRO140-Fc表现出更好的稳定性;实施例8为2P23-PRO140-Fc大鼠血清的体外抗病毒活性。
下述实施例中的实验方法,如无特殊说明,均为常规方法,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。下述实施例中所用的材料、试剂、仪器等,如无特殊说明,均可从商业途径得到。实施例中的定量试验,均设置三次重复实验,每次实验三复孔,结果取三次实验平均值±标准差。下述实施例中,如无特殊说明,序列表中各核苷酸序列的第1位均为相应DNA/RNA的5′末端核苷酸,末位均为相应DNA/RNA的3′末端核苷酸。
下述实施例中的病毒,公众按照国家生物安全的有关规定可从申请人获得,各病毒只为重复本发明的相关实验所用,不可作为其它用途使用。
pRRLSIN.cPPT.PGK-GFP.WPRE、编码Gag/Pol/Rev的包装质粒Δ8.9、编码VSV-G包膜的质粒记载在文献(Jin,H.,et al.,Generation of HIV-resistant cells with asingle-domain antibody:implications for HIV-1gene therapy.Cell Mol Immunol,2021.18(3):p.660-674.)和(Tang,X.,et al.,AMembrane-Anchored Short-PeptideFusion Inhibitor Fully Protects Target Cells from Infections of HumanImmunodeficiency Virus Type 1(HIV-1),HIV-2,and Simian ImmunodeficiencyVirus.J Virol,2019.93(22).)中,公众可从申请人处获得,只为重复本发明的相关实验所用,不可作为其它用途使用。
实施例1.重组蛋白的构建与表达
1.1重组载体的构建
本实施例将多肽2P23分别与PRO 140单链抗体(记为PRO140SC)和ibalizumab单链抗体(记为iMabSC)通过柔性肽连接,将得到的融合蛋白分别记为2P23-PRO140和2P23-iMab,构建可融合表达EGFP的强效双功能进入抑制剂的慢病毒载体。首先,通过在双功能进入抑制剂基因和EGFP之间加上弗林蛋白酶(furin)和2A肽(T2A)编码序列,实现蛋白表达后二者之间的切割分离。其次在双功能进入抑制剂基因N端添加IgG3前导(leader)分泌肽序列,促进蛋白合成后分泌至细胞外,以及C端添加6×His标签序列,用以蛋白的纯化和检测。最后,将连接双功能进入抑制剂和EGFP的融合基因,连接在慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI位点之间(见图1.A)。进一步将所得载体进行病毒包装蛋白表达,得到与6×His标签的融合蛋白,分别记为2P23-PRO140、2P23-iMab。具体如下:
合成序列表中SEQ ID No.1所示的DNA分子,将慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI识别序列间的DNA片段替换为SEQ ID No.1的第7-1758位所示的DNA片段(记为2P23-PRO140-EGFP融合基因),保持其他序列不变,将得到的重组载体记为p-2P23-PRO140-EGFP。p-2P23-PRO140-EGFP能表达序列表中SEQ ID No.2所示的2P23-PRO140和EGFP的融合蛋白,将该融合蛋白记为2P23-PRO140-EGFP。该融合蛋白在表达后经furin、T2A的自我切割后,融合蛋白成为2P23-PRO140和EGFP。其中,2P23-PRO140在分泌信号肽的作用下,分泌至细胞外。
SEQ ID No.1中,第1-6位为BamHI的识别序列,第4-12位为Kozak的DNA序列,第10-66位为IgG3的先导DNA序列,第67-72位为XbaI的识别序列,第73-141位为2P23的DNA序列,第142-186位为柔性连接肽的DNA序列,第187-933位为PRO140的DNA序列,第934-939位为XmaI的识别序列,第940-957位为6xHis的DNA序列,第958-969位为furin的DNA序列,第970-978位为GSG的DNA序列,第979-1032位为T2A的DNA序列,第1033-1038位为NdeI的识别序列,第1039-1755位为EGFP的DNA序列,第1756-1758位为终止密码子的DNA序列,第1759-1764位为SalI的识别序列。其中,第73-933位为2P23-PRO140的DNA序列。
SEQ ID No.2中,第1-19位为IgG3 leader的序列,第22-44位为2P23的序列,第45-59位为柔性连接肽的序列,第60-308位为PRO140SC的序列,第311-316位为6xHis的序列,第317-320位为furin的序列,第321-323位为GSG的序列,第324-341位为T2A的序列,第344-582位为EGFP的序列。其中,第22-308位为2P23-PRO140的序列。
合成序列表中SEQ ID No.1的第187-933位所示的PRO140SC基因,将p-2P23-PRO140SC-EGFP的XbaI和XmaI识别序列间的DNA片段替换为PRO140SC基因,保持其他序列不变,将得到的重组载体记为p-PRO140SC-EGFP。p-PRO140SC-EGFP能表达PRO140SC和EGFP的融合蛋白,将该融合蛋白记为PRO140SC-EGFP。该融合蛋白在表达后经furin、T2A的自我切割后,融合蛋白成为PRO140SC和EGFP。其中,PRO140SC在分泌信号肽的作用下,分泌至细胞外。
合成序列表中SEQ ID No.3所示的DNA分子,将第三代慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI识别序列间的DNA片段替换为SEQ ID No.3的第7-1758位所示的DNA片段(记为2P23-iMab-EGFP融合基因),保持其他序列不变,将得到的重组载体记为p-2P23-iMab-EGFP。p-2P23-iMab-EGFP能表达序列表中SEQ ID No.4所示的2P23-iMab和EGFP的融合蛋白,将该融合蛋白记为2P23-iMab-EGFP。该融合蛋白经furin、T2A的自我切割后,融合蛋白成为2P23-iMab和EGFP。其中,2P23-iMab在分泌信号肽的作用下,分泌至细胞外。
SEQ ID No.3中,第1-6位为BamHI的识别序列,第4-12位为Kozak的DNA序列,第10-66位为IgG3 leader的DNA序列,第67-72位为XbaI的识别序列,第73-141位为2P23的DNA序列,第142-186位为柔性肽的DNA序列,第187-933位为iMabSC的DNA序列,第934-939位为XmaI的识别序列,第940-957位为6xHis的DNA序列,第958-969位为furin的DNA序列,第970-978位为GSG的DNA序列,第979-1032位为T2A的DNA序列,第1033-1038位为NdeI的识别序列,第1039-1755位为EGFP的DNA序列,第1756-1758位为终止密码子的DNA序列,第1759-1764位为SalI的识别序列。其中,第73-933位为2P23-iMab的DNA序列。
SEQ ID No.4中,第1-19位为IgG3 leader的序列,第22-44位为2P23的序列,第45-59位为柔性肽的序列,第60-308位为iMabSC的序列,第311-316位为6xHis的序列,第317-320位为furin的序列,第321-323位为GSG的序列,第324-341位为T2A的序列,第344-582位为EGFP的序列。其中,第22-308位为2P23-iMab的序列。
合成序列表中SEQ ID No.3的第187-933位所示的iMabSC基因,将p-2P23-iMab-EGFP的Xba I和Xma I识别序列间的DNA片段替换为iMabSC基因,保持其他序列不变,将得到的重组载体记为p-iMabSC-EGFP。p-iMabSC-EGFP能表达iMabSC和EGFP等的融合蛋白,将该融合蛋白记为iMabSC-EGFP。该融合蛋白经furin、T2A的自我切割后,融合蛋白成为iMabSC和EGFP。其中,iMabSC在分泌信号肽的作用下,分泌至细胞外。
1.2蛋白的表达与纯化
将步骤1得到的重组慢病毒载体p-2P23-PRO140-EGFP、p-PRO140SC-EGFP、p-2P23-iMab-EGFP、p-iMabSC-EGFP分别与编码Gag/Pol/Rev的包装质粒Δ8.9、编码VSV-G包膜的质粒在HEK293T细胞中进行包装,并转导HEK293T细胞,表达融合蛋白,收取上清液,运用Ni离子亲和层析进行蛋白纯化,通过SDS-PAGE检测融合蛋白的纯度;通过Western blot,采用抗-His单克隆抗体(Sigma,SAB4200620)检测融合蛋白的特异性。
由p-2P23-PRO140-EGFP、p-PRO140SC-EGFP、p-2P23-iMab-EGFP、p-iMabSC-EGFP分别成功得到SEQ ID No.2的第22-316位所示的融合蛋白2P23-PRO140-His,SEQ ID No.2的第60-316位所示的PRO140SC与6xHis的融合蛋白PRO140SC-His,SEQ ID No.4的第22-316位所示的融合蛋白2P23-iMab-His,SEQ ID No.4的第60-316位所示的iMabSC与6xHis的融合蛋白iMabSC-His。注:2P23-PRO140-His、PRO140SC-His、2P23-iMab-His、iMabSC-His下文分别简称2P23-PRO140、PRO140SC、2P23-iMab、iMabSC。
结果见图1.B,SDS-PAGE结果显示所得各目的融合蛋白较纯,Western blot结果显示所得融合蛋白特异性强。
将所得各蛋白作为病毒抑制剂进行下述实验。
实施例2.双功能分子通过CCR5或CD4与细胞膜结合
为分析双功能分子的作用机制,发明人采用流式细胞术分析双功能分子是否通过CCR5或CD4与靶细胞膜结合而发挥抗病毒活性。实验的操作如下:将TZM-bl细胞进行消化并计数,1x106/每组,向每组细胞分别对应加入饱和浓度的抑制剂,于4℃孵育1小时。用FACS缓冲液(含0.5%牛血清白蛋白和2mM EDTA的磷酸盐缓冲液)彻底洗涤细胞两次,加入鼠抗His单克隆抗体(Sigma),4℃进行孵育1小时。然后,用FACS缓冲液洗涤两次,加入AlexaFluor 488标记的兔抗小鼠IgG抗体(Invitrogen,A27023),放入4℃孵育1小时。再次,细胞经彻底洗涤后,分别与用APC标记的小鼠抗人CD195抗体(BD BioSciences,556903)或APC标记的小鼠抗人CD4抗体(BD BioSciences,300514)在4℃下孵育1小时。洗涤两次后,加入含4%甲醛的FACS缓冲液对细胞进行重悬固定。最后,采用FACSCanto II仪器(Becton,Dickinson,Mountain View,CA)进行分析双功能分子与细胞膜的结合情况。如图2.A所示,抗His和抗CCR5双阳性细胞比例为100%,提示2P23-PRO140和PRO140SC均可通过CCR5结合到细胞膜上。同样,抗His和抗CD4双阳性细胞比例为99.9%,提示2P23-iMab和iMabSC通过CD4结合到细胞膜上(见图2.B)。上述结果表明,双功能分子2P23-PRO140、2P23-iMab确实可以通过CCR5辅助受体或CD4受体与细胞膜表面结合。
实施例3.双功能分子通过结合细胞膜发挥强效抗病毒作用
在明确了双功能分子确实可以通过CCR5受体或CD4辅助受体与细胞膜表面结合,发明人进一步检测膜结合分子的抗病毒活性。实验操作如下:将TZM-bl细胞用胰酶消化并计数,用DMEM完全培养基稀释至105/mL,加入96孔板,每孔100μL,置于37℃、5%CO2细胞培养箱培养过夜。将饱和浓度抑制剂加入96孔板细胞中,体积为50μL,各3复孔,于37℃、5%CO2细胞培养箱培养1小时。然后吸弃上清并用DMEM完全培养基洗涤3次,以去除未结合的抑制剂,并加入150μL DMEM完全培养基(洗涤组)。同时,设置不经洗涤步骤的对照组(未洗组)。最后,两组分别加入50μL含有DEAE-dextran(终浓度为15μg/mL)的HIV-1假病毒(相当于100TCID50)。阴性对照细胞孔加入50μL DMEM培养基。将96孔板置于37℃、5%CO2细胞培养箱培养。48小时后,取出96孔板,吸弃每孔中上清,加入30μL荧光素酶细胞培养裂解试剂(Promega,E1531),室温放置15分钟后,加入50μL荧光素酶检测底物试剂(Promega,E1501)。用移液器从每孔中吸取50μL液体,加入对应96孔白板中,放入微孔板光度计读取每孔的相对荧光单位(RLU)。
结果如图3.A所示,对于两种HIV-1假病毒,2P23-PRO140与靶细胞孵育后经充分洗涤,仍可保持强效的活性。对于JRFL,2P23-PRO140未洗组抑制率为98.53%,洗涤组的抑制率为82.64%;对于NL4-3,2P23-PRO140未洗组抑制率为98.47%,洗涤组的抑制率为62.79%。对照组2P23,对JRFL和NL4-3,未洗组抑制率分别为100.42%和99.34%,但洗涤组经洗涤后抑制率分别降至3.95%和12.47%。此外,对照组PRO140SC,对于NL4-3,未洗组与洗涤组均无法抑制;对于JRFL,与未洗组可完全抑制相比,经充分洗涤后抑制率降至5.40%。此部分结果与上述流式结果综合表明,2P23-PRO140经PRO140SC结合至细胞膜表面,充分洗涤并不能完全去除2P23-PRO140的结合,仍可发挥强效抗病毒作用。
如图3.B所示,对于四种HIV-1假病毒,2P23-iMab与靶细胞孵育后经充分洗涤,仍可保持强效的活性。其中,与未洗组可完全抑制JRFL和NL4-3相比,2P23组经洗涤后活性几乎完全丧失。而对于JRFL,iMabSC自身并不能完全抑制,未洗组抑制率为48.43%,经充分洗涤后抑制率降至2.67%。而2P23-iMab未洗组抑制率为96.24%,洗涤组的抑制率仍为47.03%。此部分结果与上述流式结果综合表明,2P23-iMab经iMabSC结合至细胞膜表面,充分洗涤并不能完全去除2P23-iMab的结合,仍可发挥强效抗病毒作用。与iMabSC相比,同样可结合细胞膜,但2P23-iMab可通过iMabSC提高靶细胞从而提高细胞周围2P23的局部浓度,进一步发挥强效多肽2P23的作用。因此,双功能分子2P23-PRO140、2P23-iMab可通过靶向结合细胞膜发挥强效抗病毒作用。
实施例4.双功能分子的抗病毒效果评价
艾滋病主要是由HIV-1引起,由于病毒变异产生了诸多亚型。其中,A、B、C亚型是引起世界范围内艾滋病流行的主要病毒,而在中国主要以A/E、B/C重组毒株为主。HIV-2主要在西非等地局限性流行,且已传播至世界不同地区。本实施例中制备了不同亚型HIV-1假病毒、HIV-2可复制毒株(ROD与ST)和SIV假病毒(SIVpbj与SIV239),用以评价双功能分子的抗病毒效果。
4.1双功能分子对不同亚型HIV-1假病毒的抑制活性评价
为评价双功能分子的抗病毒活性,发明人制备了包括HIV-1国际代表性毒株等在内的33株HIV-1假病毒。其中有A亚型1株、B亚型6株、B’亚型8株、C亚型5株、G亚型1株、A和C重组型即A/C亚型1株、A和E重组型即A/E亚型4株,B和C重组型即B/C亚型7株。这些毒株涵盖了CCR5、CXCR4以及R5/X4三种嗜性的病毒。实验中,以多肽2P23和单链抗体(PRO140SC、iMabSC)作为对照进行平行检测。
表达HIV-1各亚型包膜蛋白的质粒包括:
HIV-1国际代表性毒株(398-F1_F6_20、TRO.11、X2278_C2_B6、CE703010217_B6、CE1176_A3、HIV_25710-2.43、X1632-S2-B10、246_F3_C10_2、CNE8、CNE55、CH119.10、BJOX002000.03)由美国NIH艾滋病试剂和参照物项目提供,目录号为12670;
CRF07_BC(CH64.20、CH70.1、CH110、CH119.10、CH120.6):中国疾病控制中心邵一鸣教授惠赠,记载在文献(Yao,X.,et al.,Broad Antiviral Activity and CrystalStructure of HIV-1Fusion Inhibitor Sifuvirtide.Journal of BiologicalChemistry,2012.287(9):p.6788-6796.)中;
B′(B01、43-22),CRF01_AE(AE03):中国食品药品检定研究院王佑春教授惠赠,记载在文献(Yao,X.,et al.,Broad Antiviral Activity and Crystal Structure of HIV-1Fusion Inhibitor Sifuvirtide.Journal of Biological Chemistry,2012.287(9):p.6788-6796.)中。
B′(CNE4、CNE6、CNE9、CNE11、CNE14、CNE57),CRF01_AE(CNE107),CRF07_BC(CNE49):清华大学艾滋病综合研究中心张琳琦教授惠赠。
4.1.1制备HIV-1假病毒:
(1)HIV-1假病毒的制备:参见参考文献14中材料与方法中的“Single-cycleinfection assay”部分。采用细胞转染试剂将表达上述33株HIV-1毒株包膜蛋白(Env)的重组表达质粒和HIV-1骨架质粒pSG3Δenv(由美国NIH艾滋病试剂和参照物项目提供,目录号为11051)共转染293T细胞,于37℃、5%CO2细胞培养箱中孵育6小时后换液,然后继续孵育48小时。用移液器吸取含有假病毒颗粒的细胞培养上清液,经0.45μm滤器过滤收取上清,加入胎牛血清(FBS)(使FBS最终体积比例为20%)后转移至聚丙烯管中,于-80℃保存备用或直接进行病毒滴定;(2)HIV-1假病毒的滴定:将病毒在96孔板中做3倍稀释,设置3个复孔9个梯度,终体积为100μL。将TZM-bl细胞用胰酶消化并计数,用DMEM完全培养基将细胞稀释至1×105个/ml,每孔加100μL细胞(含15μg/mL DEAE-dextran),于37℃、5%CO2培养48小时。然后从细胞培养箱中取出96孔板,从上样孔中吸弃上清,加入30μL荧光素酶细胞培养裂解试剂,放置10分钟后加入50μL荧光素酶检测底物试剂。用移液器从每孔中吸出50μL液体,加于对应的96孔白板中,于微孔板光度计读取发光值放入微孔板光度计读取每孔的相对荧光单位(RLU)。用Reed-Muench法计算病毒滴度。
4.1.2抗病毒活性检测结果:
所用抑制剂为实施例1得到的2P23-PRO140、2P23-iMab,并利用实施例1得到的PRO140SC、iMabSC及实验室留存的2P23多肽作为对照,操作步骤如下:
将2P23-PRO140、2P23-iMab、PRO140SC、iMabSC、2P23倍比稀释(3倍)得到稀释液,将得到的各稀释液分别加入96孔板实验孔,设置3个复孔9个梯度,终体积为50μL。阴性对照孔和阳性对照孔加入50μL DMEM培养基。除阴性对照外,所有孔(实验孔与阳性对照孔)分别加入50μL已制备的病毒,每孔加入量相当于100TCID50。向所有孔中加入100μL TZM-bl细胞(105/mL),而后向所有孔中加入DEAE-dextran,使DEAE-dextran的终浓度为15μg/mL。将所得反应体系于37℃、5%CO2细胞培养箱培养48小时后,取出96孔板,吸弃上清,加入30μL细胞裂解液,室温放置15分钟后,加入50μL荧光素酶检测试剂。用移液器从每孔中吸取50μL液体,加入对应96孔白板中,放入微孔板光度计读取每孔的相对荧光单位(RLU)。
抑制剂抗HIV-1的数据分析:半数抑制剂量是指抑制率为50%时所对应的抑制剂的浓度,用IC50表示。抑制剂抗HIV实验中得到的数据为相对荧光单位(RLU)数值,可用来定量分析药物半数抑制剂量(IC50),所有抑制剂浓度均转化为log10浓度值,每一浓度样品孔计算出平均RLU值,计算每一浓度样品的荧光抑制率,计算公式:
数据分析利用GraphPad Prism software 8.0.1软件,采用非线性回归分析中参数S型剂量方程分析每种抑制剂的%抑制率和IC50。
结果如图4所示,2P23-PRO140对上述不同亚型的假病毒,都表现出极高的活性,显著高于对照2P23和单链抗体PRO140SC。其中,2P23-PRO140的抗病毒活性IC50为0.06nM,比2P23活性(IC50=3.38nM)强约56倍;比PRO140SC活性(IC50=15.00nM)强250倍。其中,对于作为代表性毒株的12株HIV-1国际代表性毒株(398-F1_F6_20、TRO.11、X2278_C2_B6、CE703010217_B6、CE1176_A3、HIV_25710-2.43、X1632-S2-B10、246_F3_C10_2、CNE8、CNE55、CH119.10、BJOX002000.03),抗病毒结果显示,2P23-PRO140的抗病毒的IC50为0.04nM,比2P23的活性(IC50=3.23nM)强81倍;比PRO140SC的活性(IC50=18.33nM)强458倍。同时,比本实验室报道的脂肽LP-19(2P23脂肪酸修饰后多肽)活性(IC50=0.41nM)强10倍。可见,2P23-PRO140具有极强的抗病毒活性。
对上述33株不同亚型的HIV-1假病毒,2P23-iMab抗病毒IC50为0.39nM,比2P23活性强约9倍。其中,对于12株HIV-1国际代表性毒株假病毒,如图4所示,2P23-iMab的抗病毒IC50为0.56nM(0.0174μg/mL),比2P23的活性(IC50=3.23nM)强6倍;比iMabSC的活性(IC50>605.28nM)强至少1081倍。值得注意的是,有4/12株病毒(HIV_25710-2.43,X1632-S2-B10,CNE55,CH119.10)对iMabSC不敏感,表现为即使当iMabSC浓度提高为1812.97nM(50μg/mL),依然无法抑制50%的病毒。与iMabSC相比,2P23-iMab则表现出很好的广谱性,对上述所有毒株,均可达到完全抑制效果。
4.2双功能分子对HIV-1包膜介导的细胞融合的抑制活性
发明人基于DSP系统的细胞-细胞融合抑制实验检测了双功能分子2P23-PRO140、2P23-iMab及其模板PRO140SC、iMabSC对HIV-1包膜蛋白介导的细胞融合的抑制活性,具体实验方法参见参考文献14中的“Cell-cell fusion assay”部分。具体操作为:将HEK293T细胞(效应细胞)消化并计数,取100μL(1.5x105/mL)接种于96孔板,于37℃、5%CO2细胞培养箱孵育过夜。以表达HIV-1包膜蛋白的质粒和表达DSP1-7的质粒(此实验中,表达HIV-1包膜蛋白,所用质粒同抗病毒实验)共转染(实验孔和阳性对照孔),37℃培养24小时。将抑制剂倍比稀释(3倍)加入96孔板,终体积为50μL,同时取50μL DMEM培养基代替抑制剂加入阴性对照孔和阳性对照孔。将稳定表达CXCR4/CCR5和DSP8-11的293FT细胞(靶细胞)消化重悬,加入EnduRen活细胞底物(Promega,E648B),在37℃孵育30分钟。然后将靶细胞加入效应细胞中(3x104/孔),400g离心3分钟。在37℃孵育2小时后,放入微孔板光度计读取每孔的相对荧光单位(RLU),分析数值并计算其IC50。
结果如图5所示,与对照组2P23(IC50=3.66nM)相比,2P23-PRO140抑制HIV-1毒株融合的活性强10.5倍(IC50=0.35nM)。与PRO140SC相比,2P23-PRO140可完全抑制不同嗜性HIV-1毒株包膜蛋白与靶细胞的融合。同样,作为非竞争性抑制剂iMabSC对上述毒株的抑制表现出不完全抑制,而2P23的引入使得2P23-iMab具有极强的抑制融合活性(IC50=0.36nM)。上述结果提示,双功能分子可有效抑制HIV-1包膜介导的细胞融合。
4.3双功能分子对HIV-1耐药突变毒株假病毒的抑制活性评价
为进一步评价所用抑制剂为实施例1得到的2P23-PRO140、2P23-iMab的抗病毒活性,发明人采用图7中的两套HIV gp41诱导突变株检测2P23-PRO140对病毒感染的抑制作用,假病毒包装和抗病毒实验步骤同步骤4.1.1和4.1.2,并利用实施例1得到的PRO140SC、iMabSC、2P23作为对照。这两套突变株分别为T-20耐药株和2P23耐药株。表达HIV-1NL4-3野毒株Env及T-20耐药株Env的质粒由本发明人实验室制备保存,参见发表的文献14;表达2P23耐药株Env的质粒由本发明人实验室制备保存,参见发表的文献(Su,Y.,et al.,Genetic Pathway of HIV-1Resistance to Novel Fusion Inhibitors Targeting theGp41 Pocket.Journal of Virology,2015.89(24):p.12467-12479;Su,Y.,et al.,Mechanism of HIV-1Resistance to Short-Peptide Fusion Inhibitors Targeting theGp41 Pocket.Journal of Virology,2015.89(11):p.5801-5811;Yu,D.,et al.,Molecular mechanism of HIV-1resistance to sifuvirtide,a clinical trial-approved membrane fusion inhibitor.J Biol Chem,2018.293(33):p.12703-12718;Wu,X.,et al.,Mechanism of HIV-1Resistance to an Electronically Constrainedα-Helical Peptide Membrane Fusion Inhibitor.Journal of Virology,2018.92(7))。
结果如图6所示,与HIV-1NL4-3野毒株(IC50=0.75nM)相比,2P23对T-20耐药株仍可有效抑制(IC50=0.67nM),而对2P23耐药株活性下降(IC50=21.00nM)。与之对比,2P23-PRO140抑制HIV-1NL4-3野毒株感染的IC50为0.01nM,对T-20耐药株和2P23耐药株仍具有极高的抑制活性,其IC50分别为0.02nM和0.03nM。其中,与2P23相比,2P23-PRO140对T-20耐药株和2P23耐药株的活性强34倍和700倍。此部分结果表明,PRO140SC显著提高了2P23的抗病毒活性,并且,上述gp41诱导突变对2P23-PRO140的抗病毒活性无影响。此外,与PRO140SC因具有病毒嗜性选择,仅对CCR5嗜性毒株有效相比,2P23-PRO140对CXCR4嗜性毒株表现出的极强活性,进一步体现了其广谱性。2P23-iMab对HIV-1NL4-3野毒株的抗病毒IC50为0.09nM,比2P23活性强约8.4倍。对于上述两套T-20耐药株和2P23耐药株,iMabSC对大部分毒株仍表现出不完全抑制,而2P23-iMab的IC50分别为0.09nM和0.55nM,活性是2P23的7.4倍和38倍。这说明2P23-iMab也具有很好的广谱性和很强的抗病毒活性。
4.4双功能分子对HIV-2和SIV的抑制活性评价
为评估本发明双功能分子的抗病毒优势,本实验进一步检测了其对HIV-2和SIV的抑制活性。HIV-2毒株的分子克隆质粒HIV-2ROD和HIV-2ST质粒由美国NIH艾滋病试剂和参照物项目获得;表达SIV毒株SIVpbj和SIV239包膜蛋白的质粒(分别为pSIVpbj-Env和pSIV239-Env)由复旦大学徐建青教授惠赠。感染性HIV-2毒株的制备方法:采用PEI转染试剂将HIV-2ROD或HIV-2ST质粒转染至HEK293T细胞,放入37℃、5%CO2的细胞培养箱培养6小时。换液后于细胞培养箱中继续培养48小时,收取上清,1,000g离心10min,并经0.45μm滤器过滤。加入胎牛血清使其终体积比例为20%,直接使用或分装储存于-80℃备用或进行病毒滴度测定。SIVpbj和SIV239假病毒的制备与上述4.1.1中方法相同。
结果如图7所示,与2P23(IC50=6.94nM)和PRO140SC(IC50=10.21nM)相比,2P23-PRO140(IC50=0.19nM)对HIV-2ST的活性分别提高了约37倍和54倍。而对SIVpbj和SIV239假病毒,相比PRO140SC,2P23-PRO140的活性分别提高了2452倍和2628倍。此外,与iMabSC无法抑制上述HIV-2ROD与SIVpbj和SIV239毒株相比,2P23-iMab的活性均大有改善。综上结果,2P23-PRO140与2P23-iMab对HIV-2和SIV均具有很强的抑制作用。因此,本发明的2P23-PRO140和2P23-iMab对各种亚型HIV-1、T-20耐药株和2P23耐药株,以及HIV-2ST和SIV239均具有很强的抗病毒活性。
实施例5.长效化改造双功能分子2P23-PRO140-Fc的构建与表达
基于上述双功能分子的活性与机制,发明人对2P23-PRO140进行长效化改造。长效化改造双功能分子的构建与表达,载体和表达盒同上述双功能分子。将2P23-PRO140与IgG4-Fc(含M428L和N434S双突变,记为IgG4-Fc-LS)通过柔性肽(G4S)连接,将得到的融合蛋白记为2P23-PRO140-Fc,构建可融合表达EGFP的强效双功能进入抑制剂的慢病毒载体(见图1.A)。首先,通过在双功能进入抑制剂基因和EGFP之间加上furin蛋白剪切位点和T2A蛋白编码序列,实现蛋白表达后二者之间的切割分离。其次在双功能进入抑制剂基因N端添加IgG3 leader分泌肽序列,促进蛋白合成后分泌至细胞外,以及C端添加6xHis序列,用于蛋白的纯化和检测。最后,将连接双功能进入抑制剂和EGFP的融合基因,连接在慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI位点之间。具体如下:
合成序列表中SEQ ID No.5所示的DNA分子,将慢病毒转移载体pRRLSIN.cPPT.PGK-GFP.WPRE的BamHI和SalI识别序列间的DNA片段替换为SEQ ID No.5的第7-2424位所示的DNA片段(记为2P23-PRO140-Fc-EGFP融合基因),保持其他序列不变,将得到的重组载体记为p-2P23-PRO140-Fc-EGFP。p-2P23-PRO140-Fc-EGFP能表达序列表中SEQ ID No.6所示的2P23-PRO140-Fc和EGFP等的融合蛋白,将该融合蛋白记为2P23-PRO140-Fc-EGFP。该融合蛋白经furin、T2A的自我切割后,融合蛋白成为2P23-PRO140-Fc和EGFP。其中,2P23-PRO140-Fc在分泌信号肽的作用下,分泌至细胞外。
SEQ ID No.5中,第1-6位为BamHI的识别序列,第4-12位为Kozak的DNA序列,第10-66位为IgG3 leader的DNA序列,第67-72位为XbaI的识别序列,第73-141位为2P23的DNA序列,第142-186位为柔性肽的DNA序列,第187-933位为PRO140SC的DNA序列,第934-948位为G4S的DNA序列,第949-1599位为IgG4-Fc-LS的DNA序列,第1600-1605位为XmaI的识别序列,第1606-1623位为6xHis的DNA序列,第1624-1635位为furin的DNA序列,第1636-1644位为GSG的DNA序列,第1645-1698位为T2A的DNA序列,第1699-1704位为NdeI的识别序列,第1705-2421位为EGFP的DNA序列,第2422-2424位为终止密码子的DNA序列,第2425-2430位为SalI的识别序列。其中,第73-1599位为2P23-PRO140-Fc的DNA序列。
SEQ ID No.6中,第1-19位为IgG3 leader的序列,第22-44位为2P23的序列,第45-59位为柔性肽的序列,第60-308位为PRO140SC的序列,第309-313位为G4S的序列,第314-530位为IgG4-Fc-LS的序列,第533-538位为6xHis的序列,第539-542位为furin的序列,第543-545位为GSG的序列,第546-563位为T2A的序列,第566-804位为EGFP的序列。其中,第22-530位为2P23-PRO140-Fc的序列。
将重组慢病毒质粒p-2P23-PRO140-Fc-EGFP与编码Gag/Pol/Rev的包装质粒Δ8.9、编码VSV-G包膜的质粒在HEK293T细胞中进行包装,并转导HEK293T细胞,表达融合蛋白,收取上清,运用Ni离子亲和层析进行蛋白纯化,得到SEQ ID No.6的第22-538位所示的融合蛋白2P23-PRO140-Fc,通过SDS-PAGE检测融合蛋白的纯度;通过Western blot,采用抗-His单克隆抗体检测发现所得融合蛋白的特异性。结果显示,蛋白较纯,特异性强(见图8)。
实施例6. 2P23-PRO140-Fc对HIV-1国际代表性毒株假病毒的抑制作用
发明人采用上述具有代表性的12株国际代表性毒株,检测实施例5的长效化改造的双功能分子2P23-PRO140-Fc对HIV-1的抑制活性。
操作步骤:将抑制剂2P23-PRO140-Fc倍比稀释(3倍)稀释加入96孔板实验孔,终体积为50μL,阴性对照孔和阳性对照孔加入50μL DMEM培养基。除阴性对照孔外,实验孔和阳性对照孔均加入50μL已制备的病毒,每孔加入量相当于100TCID50。向所有孔中加入100μLTZM-blL细胞(105/mL),加入DEAE-dextran,使其终浓度为15μg/mL。将所得反应体系于37℃、5%CO2细胞培养箱培养48小时后,取出96孔板,吸弃上清,加入30μL细胞裂解液,室温放置15分钟后,加入50μL荧光素酶检测试剂。用移液器从每孔中吸取50μL液体,加入对应96孔白板中,放入微孔板光度计读取每孔的相对荧光单位(RLU)。所用病毒按照上文实施例4中4.1.1的方法制备。
结果如图9所示,对12株不同亚型的HIV-1国际代表性毒株,2P23-PRO140-Fc的抗病毒活性IC50为0.24nM,与2P23-PRO140(IC50为0.04nM)相比,活性下降约6倍;但比2P23活性(IC50=3.23nM)强13倍;比PRO140SC活性(IC50=18.33nM)强76倍。可见,长效化改造分子2P23-PRO140-Fc仍具有很强的抗病毒活性。
实施例7. 2P23-PRO140-Fc表现出更好的稳定性
为比较抑制剂长效化改造前后的稳定性,发明人检测了2P23-PRO140与2P23-PRO140-Fc经胰酶或血清处理或置于37℃环境中储存对其活性影响的实验。
7.1胰酶敏感性实验,操作步骤:将抑制剂2P23-PRO140与2P23-PRO140-Fc采用PBS稀释至一定浓度,加入胰酶(Sigma,T4799-10G)(胰酶与蛋白质质量比为1:20),混合均匀,进行分装,置于37℃孵育。在不同时间点(0、15、30、60、90、120、240min)收集样品,放入-20℃保存。通过对假病毒HIV-1NL4-3单轮感染抑制实验,检测每个时间点样品的剩余抗病毒活性。
7.2大鼠血清敏感性实验,操作步骤:将重组蛋白采用PBS稀释至一定浓度,加入大鼠血清(血清与蛋白质体积比为1:20),混合均匀,进行分装,置于37℃孵育。在不同时间点(0、15、30、60、90、120、180、240min)收集样品,放入-20℃保存。通过对假病毒HIV-1NL4-3单轮感染抑制实验,检测每个时间点样品的剩余抗病毒活性。
7.3 37℃热稳定性实验,操作步骤:将重组蛋白采用PBS稀释至一定浓度并进行分装,置于37℃孵育。在不同时间点(0、4、8、12、24、48、96、120、168、240h)收集样品,放入-20℃保存。通过对假病毒HIV-1NL4-3单轮感染抑制实验检测每个时间点样品的剩余抗病毒活性。
结果如图10.A所示,与2P23-PRO140活性几乎完全丧失相比,2P23-PRO140-Fc在相同条件下经胰酶处理240min,对HIV-1NL4-3的感染仍可保留约41.89%的抑制率。同样,采用大鼠血清处理240min,二者均可有效保持其抗病毒作用(图10.B)。上述两种处理结果,综合提示,2P23-PRO140-Fc比2P23-PRO140有更好的代谢稳定性。
为比较二者的热稳定性,通过收集2P23-PRO140-Fc与2P23-PRO140在37℃储存168h过程中不同时间点的样本,检测其抗病毒活性。结果如图10.C所示,在37℃储存1h、12h、168h,2P23-PRO140的活性分别降低11倍、41倍和80倍,而2P23-PRO140-Fc的活性分别降低1.2倍、2.5倍和2.2倍,提示通过Fc-LS改造,可有效提高2P23-PRO140的热稳定性。
实施例8. 2P23-PRO140-Fc大鼠血清的体外抗病毒活性
为进一步探究双功能抑制剂改造前后在大鼠血清中的ex vivo抗病毒活性,检测了2P23-PRO140与2P23-PRO140-Fc大鼠血清对假病毒HIV-1NL4-3单轮感染的抑制活性。
操作步骤:
8.1蛋白样品的准备:
用6mL PBS(pH7.2)将两种重组蛋白2P23-PRO140、2P23-PRO140-Fc分别稀释至600μg/mL,以备用于对照组与实验组的蛋白注射。
8.2大鼠皮下注射:
将200g左右雄性SD大鼠随机分组为对照组与实验组,其中对照组与实验组各5只,采用耳号进行标记。
对照组:使用1mL注射器抽取重组蛋白2P23-PRO140,根据每只大鼠体重,按3mg/kg剂量在大鼠背部皮肤经皮下注射给药。
实验组:采用相同的方法,按3mg/kg剂量,将2P23-PRO140-Fc在大鼠背部皮肤经皮下注射给药。
8.3采血:
采血途径:眼眶静脉丛采血,腹主动脉采血。
采血时间:给药前(0h),给药后(1h,4h,8h,12h,24h,2d,4d,5d,7d)
采血量:每次约0.5~1.0mL,试验终点时(7d)动物完全麻醉后,腹主动脉采集全部血液。
血样处理方法:全血室温静置1h使血液凝固,4℃3,000rpm离心15分钟,离心后取上清即可(同之前处理)。血清标本保存于-80℃。
8.4假病毒HIV-1NL4-3单轮感染抑制实验:
1)在96孔板中,将大鼠血清稀释倍数按1:10起始,3倍倍比稀释,分别设置3个复孔,共9个梯度,体积为50μL。阴性对照孔和阳性对照孔加入50μL DMEM培养基。
2)除阴性对照外,所有孔(实验孔与阳性对照孔)分别加入50μL已制备的HIV-1NL4-3假病毒,每孔加入量相当于100TCID50。
3)向所有孔中加入100μL TZM-bl细胞(105/mL),含有DEAE-dextran,终浓度为15μg/mL。
4)将所得反应体系于37℃、5%CO2培养箱中,培养48h后,取出96孔板,吸弃上清。向每孔中加入30μL细胞裂解试剂,室温裂解15min后,加入50μL Bright-Glo Luciferase检测试剂。混匀后,用移液器从每孔中吸取50μL加入对应96孔白板中,放入微孔板光度计读取每孔的相对荧光单位(RLU)。计算当抑制率为50%时的血清稀释倍数来表征血清的抗病毒活性。
结果如图11所示,2P23-PRO140的血浆浓度在给药后4h达峰,抑制病毒感染IC50为465.8倍的稀释倍数。与之相比,2P23-PRO140-Fc的血浆浓度在给药后24h达峰,抑制病毒感染IC50为1025倍稀释倍数。随后,2P23-PRO140的血浆浓度在给药后24h下降至检测不到的水平,而2P23-PRO140-Fc在给药后直到120h下降至检测不到。此ex vivo抗病毒活性提示,2P23-PRO140-Fc在大鼠血清的体外抗病毒活性更强,以及半衰期得到有效延长。
以上对本发明进行了详述。对于本领域技术人员来说,在不脱离本发明的宗旨和范围,以及无需进行不必要的实验情况下,可在等同参数、浓度和条件下,在较宽范围内实施本发明。虽然本发明给出了特殊的实施例,应该理解为,可以对本发明作进一步的改进。总之,按本发明的原理,本申请欲包括任何变更、用途或对本发明的改进,包括脱离了本申请中已公开范围,而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围,可以进行一些基本特征的应用。
参考文献:
1.Collier DA,Monit C,Gupta RK.2019.The Impact of HIV-1Drug Escape onthe Global Treatment Landscape.Cell Host Microbe 26:48-60.
2.Checkley MA,Luttge BG,Freed EO.2011.HIV-1envelope glycoproteinbiosynthesis,trafficking,and incorporation.J Mol Biol 410:582-608.
3.Eckert DM,Kim PS.2001.Mechanisms of viral membrane fusion and itsinhibition.Annu Rev Biochem 70:777-810.
4.Moore JP,Sattentau QJ,Klasse PJ,Burkly LC.1992.A monoclonalantibody to CD4 domain 2 blocks soluble CD4-induced conformational changes inthe envelope glycoproteins of human immunodeficiency virus type 1(HIV-1)andHIV-1 infection of CD4+cells.J Virol 66:4784-93.
5.Dorr P,Westby M,Dobbs S,Griffin P,Irvine B,Macartney M,Mori J,Rickett G,Smith-Burchnell C,Napier C,Webster R,Armour D,Price D,Stammen B,Wood A,Perros M.2005.Maraviroc(UK-427,857),a potent,orally bioavailable,andselective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.Antimicrob AgentsChemother 49:4721-32.
6.Wild CG,Teresa;Matthews,Thomas.1993.A Synthetic Peptide from HIV-1gp41 Is a Potent Inhibitor of Virus-Mediated Cell—Cell Fusion.AIDS Res HumRetroviruses 9:1051-1053.
7.Chong H,Yao X,Zhang C,Cai L,Cui S,Wang Y,He Y.2012.Biophysicalproperty and broad anti-HIV activity of albuvirtide,a 3-maleimimidopropionicacid-modified peptide fusion inhibitor.PLoS One 7:e32599.
8.Emu B,Fessel J,Schrader S,Kumar P,Richmond G,Win S,Weinheimer S,Marsolais C,Lewis S.2018.Phase 3 Study of Ibalizumab for Multidrug-ResistantHIV-1.N Engl J Med 379:645-654.
9.Freeman MM,Seaman MS,Rits-Volloch S,Hong X,Kao CY,Ho DD,ChenB.2010.Crystal structure of HIV-1 primary receptor CD4 in complex with apotent antiviral antibody.Structure 18:1632-41.
10.Jacobson JM,Kuritzkes DR,Godofsky E,DeJesus E,Larson JA,WeinheimerSP,Lewis ST.2009.Safety,pharmacokinetics,and antiretroviral activity ofmultiple doses of ibalizumab(formerly TNX-355),an anti-CD4 monoclonalantibody,in human immunodeficiency virus type 1-infected adults.AntimicrobAgents Chemother 53:450-7.
11.Toma J,Weinheimer SP,Stawiski E,Whitcomb JM,Lewis ST,PetropoulosCJ,Huang W.2011.Loss of asparagine-linked glycosylation sites in variableregion 5 of human immunodeficiency virus type 1 envelope is associated withresistance to CD4 antibody ibalizumab.J Virol 85:3872-80.
12.Trkola A,Ketas TJ,Nagashima KA,Zhao L,Cilliers T,Morris L,MooreJP,Maddon PJ,Olson WC.2001.Potent,broad-spectrum inhibition of humanimmunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140.J Virol75:579-88.
13.Olson WC,Rabut GE,Nagashima KA,Tran DN,Anselma DJ,Monard SP,SegalJP,Thompson DA,Kajumo F,Guo Y,Moore JP,Maddon PJ,Dragic T.1999.Differentialinhibition of human immunodeficiency virus type 1 fusion,gp120 binding,andCC-chemokine activity by monoclonal antibodies to CCR5.J Virol 73:4145-55.
14.Xiong S,Borrego P,Ding X,Zhu Y,Martins A,Chong H,Taveira N,HeY.2017.A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activityagainst Human Immunodeficiency Virus Type 1(HIV-1),HIV-2,and SimianImmunodeficiency Virus.J Virol 91:e01839-16.
15.Chong H,Xue J,Xiong S,Cong Z,Ding X,Zhu Y,Liu Z,Chen T,Feng Y,HeL,Guo Y,Wei Q,Zhou Y,Qin C,He Y.2017.A Lipopeptide HIV-1/2 Fusion Inhibitorwith Highly Potent In Vitro,Ex Vivo,and In Vivo Antiviral Activity.J Virol91:e00288-17.
16.van Dorsten RT,Lambson BE,Wibmer CK,Weinberg MS,Moore PL,MorrisL.2020.Neutralization Breadth and Potency of Single-Chain Variable FragmentsDerived from Broadly Neutralizing Antibodies Targeting Multiple Epitopes onthe HIV-1 Envelope.J Virol 94:e01533-19.
17.Davis-Gardner ME,Alfant B,Weber JA,Gardner MR,Farzan M.2020.ABispecific Antibody That Simultaneously Recognizes the V2-and V3-GlycanEpitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent thanIts Parental Antibodies.Mbio 11:e03080-19.
18.Moshoette T,Ali SA,Papathanasopoulos MA,KillickMA.2019.Engineering and characterising a novel,highly potent bispecificantibody iMab-CAP256 that targets HIV-1.Retrovirology 16:31.
序列表
<110> 中国医学科学院病原生物学研究所
<120> 强效双功能HIV进入抑制剂及其应用
<160> 6
<170> PatentIn version 3.5
<210> 1
<211> 1764
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 1
ggatccacca tgaaacatct gtggttcttc ctcctcctag tggcagctcc cagatgggtc 60
ctgtcctcta gagagatgac ctgggaggag tgggagaaga aggtggagga gctggagaag 120
aagatcgagg agctgctgaa gggcggaggc ggaagcggcg gaggcggaag cggcggaggc 180
ggaagcgagg tgcagctggt ggagtctggt ggaggcttgg taaagcctgg aggttccctt 240
agactctcct gtgcagcctc tggttacact ttcagtaact attggatcgg atgggtccgc 300
caggctccag gcaaagggct ggagtggatt ggcgatatct accctggagg gaactacatc 360
aggaacaatg agaagttcaa ggacaagacc accctgtcag cagatacttc caagaacaca 420
gcctatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtggaagc 480
agcttcggta gtaactacgt gttcgcctgg tttacttact ggggccaagg gactctggtc 540
acagtctcct caggcggagg cggaagcggc ggaggcggaa gcggcggagg cggaagcgat 600
attgtgatga cccaatctcc actctccctg cctgtcactc ctggagagcc agcctccatc 660
tcttgcagat ctagtcagcg ccttctgagc agttatggac atacctattt acattggtac 720
ctacagaagc caggccagtc tccacagctc ctgatctacg aagtttccaa ccgattttct 780
ggggtcccag acaggttcag tggcagtggg tcagggacag atttcacact taagatcagt 840
agagtggagg ctgaggatgt gggagtttat tactgctctc aaagtacaca tgttcctctc 900
acgttcggac aggggaccaa ggtggaaata aaacccgggc accatcacca tcaccataga 960
gccaagaggg gcagcggaga gggcagagga agcctgctga cctgcggcga cgtggaggag 1020
aaccccggcc ctcatatgat ggtgagcaag ggcgaggagc tgttcaccgg ggtggtgccc 1080
atcctggtcg agctggacgg cgacgtaaac ggccacaagt tcagcgtgtc cggcgagggc 1140
gagggcgatg ccacctacgg caagctgacc ctgaagttca tctgcaccac cggcaagctg 1200
cccgtgccct ggcccaccct cgtgaccacc ctgacctacg gcgtgcagtg cttcagccgc 1260
taccccgacc acatgaagca gcacgacttc ttcaagtccg ccatgcccga aggctacgtc 1320
caggagcgca ccatcttctt caaggacgac ggcaactaca agacccgcgc cgaggtgaag 1380
ttcgagggcg acaccctggt gaaccgcatc gagctgaagg gcatcgactt caaggaggac 1440
ggcaacatcc tggggcacaa gctggagtac aactacaaca gccacaacgt ctatatcatg 1500
gccgacaagc agaagaacgg catcaaggtg aacttcaaga tccgccacaa catcgaggac 1560
ggcagcgtgc agctcgccga ccactaccag cagaacaccc ccatcggcga cggccccgtg 1620
ctgctgcccg acaaccacta cctgagcacc cagtccgccc tgagcaaaga ccccaacgag 1680
aagcgcgatc acatggtcct gctggagttc gtgaccgccg ccgggatcac tctcggcatg 1740
gacgagctgt acaagtaagt cgac 1764
<210> 2
<211> 582
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 2
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Ser Arg Glu Met Thr Trp Glu Glu Trp Glu Lys Lys Val
20 25 30
Glu Glu Leu Glu Lys Lys Ile Glu Glu Leu Leu Lys Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
50 55 60
Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser
65 70 75 80
Cys Ala Ala Ser Gly Tyr Thr Phe Ser Asn Tyr Trp Ile Gly Trp Val
85 90 95
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asp Ile Tyr Pro
100 105 110
Gly Gly Asn Tyr Ile Arg Asn Asn Glu Lys Phe Lys Asp Lys Thr Thr
115 120 125
Leu Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
130 135 140
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Gly Ser Ser Phe Gly
145 150 155 160
Ser Asn Tyr Val Phe Ala Trp Phe Thr Tyr Trp Gly Gln Gly Thr Leu
165 170 175
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
180 185 190
Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro
195 200 205
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Arg
210 215 220
Leu Leu Ser Ser Tyr Gly His Thr Tyr Leu His Trp Tyr Leu Gln Lys
225 230 235 240
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe
245 250 255
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
260 265 270
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
275 280 285
Cys Ser Gln Ser Thr His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys
290 295 300
Val Glu Ile Lys Pro Gly His His His His His His Arg Ala Lys Arg
305 310 315 320
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
325 330 335
Glu Asn Pro Gly Pro His Met Met Val Ser Lys Gly Glu Glu Leu Phe
340 345 350
Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly
355 360 365
His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly
370 375 380
Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro
385 390 395 400
Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser
405 410 415
Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met
420 425 430
Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly
435 440 445
Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val
450 455 460
Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile
465 470 475 480
Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile
485 490 495
Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg
500 505 510
His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln
515 520 525
Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr
530 535 540
Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp
545 550 555 560
His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly
565 570 575
Met Asp Glu Leu Tyr Lys
580
<210> 3
<211> 1764
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 3
ggatccacca tgaaacatct gtggttcttc ctcctcctag tggcagctcc cagatgggtc 60
ctgtcctcta gagagatgac ctgggaggag tgggagaaga aggtggagga gctggagaag 120
aagatcgagg agctgctgaa gggcggaggc ggaagcggcg gaggcggaag cggcggaggc 180
ggaagccagg tgcagctgca gcagagcggc cccgaggtgg tgaagcccgg cgccagcgtg 240
aagatgagct gcaaggccag cggctacacc ttcaccagct acgtgatcca ctgggtgaga 300
cagaagcccg gccagggcct ggactggatc ggctacatca acccctacaa cgacggcacc 360
gactacgacg agaagttcaa gggcaaggcc accctgacca gcgacaccag caccagcacc 420
gcctacatgg agctgagcag cctgagaagc gaggacaccg ccgtgtacta ctgcgccaga 480
gagaaggaca actacgccac cggcgcctgg ttcgcctact ggggccaggg caccctggtg 540
accgtgagca gcggcggagg cggaagcggc ggaggcggaa gcggcggagg cggaagcgac 600
atcgtgatga cccagagccc cgacagcctg gccgtgagcc tgggcgagag agtgaccatg 660
aactgcaaga gcagccagag cctgctgtac agcaccaacc agaagaacta cctggcctgg 720
taccagcaga agcccggcca gagccccaag ctgctgatct actgggccag caccagagag 780
agcggcgtgc ccgacagatt cagcggcagc ggcagcggca ccgacttcac cctgaccatc 840
agcagcgtgc aggccgagga cgtggctgtg tactactgcc agcagtacta cagctacaga 900
accttcggcg gcggcaccaa gctggagatc aagcccgggc accatcacca tcaccataga 960
gccaagaggg gcagcggaga gggcagagga agcctgctga cctgcggcga cgtggaggag 1020
aaccccggcc ctcatatgat ggtgagcaag ggcgaggagc tgttcaccgg ggtggtgccc 1080
atcctggtcg agctggacgg cgacgtaaac ggccacaagt tcagcgtgtc cggcgagggc 1140
gagggcgatg ccacctacgg caagctgacc ctgaagttca tctgcaccac cggcaagctg 1200
cccgtgccct ggcccaccct cgtgaccacc ctgacctacg gcgtgcagtg cttcagccgc 1260
taccccgacc acatgaagca gcacgacttc ttcaagtccg ccatgcccga aggctacgtc 1320
caggagcgca ccatcttctt caaggacgac ggcaactaca agacccgcgc cgaggtgaag 1380
ttcgagggcg acaccctggt gaaccgcatc gagctgaagg gcatcgactt caaggaggac 1440
ggcaacatcc tggggcacaa gctggagtac aactacaaca gccacaacgt ctatatcatg 1500
gccgacaagc agaagaacgg catcaaggtg aacttcaaga tccgccacaa catcgaggac 1560
ggcagcgtgc agctcgccga ccactaccag cagaacaccc ccatcggcga cggccccgtg 1620
ctgctgcccg acaaccacta cctgagcacc cagtccgccc tgagcaaaga ccccaacgag 1680
aagcgcgatc acatggtcct gctggagttc gtgaccgccg ccgggatcac tctcggcatg 1740
gacgagctgt acaagtaagt cgac 1764
<210> 4
<211> 582
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 4
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Ser Arg Glu Met Thr Trp Glu Glu Trp Glu Lys Lys Val
20 25 30
Glu Glu Leu Glu Lys Lys Ile Glu Glu Leu Leu Lys Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln
50 55 60
Gln Ser Gly Pro Glu Val Val Lys Pro Gly Ala Ser Val Lys Met Ser
65 70 75 80
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val Ile His Trp Val
85 90 95
Arg Gln Lys Pro Gly Gln Gly Leu Asp Trp Ile Gly Tyr Ile Asn Pro
100 105 110
Tyr Asn Asp Gly Thr Asp Tyr Asp Glu Lys Phe Lys Gly Lys Ala Thr
115 120 125
Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser
130 135 140
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Lys Asp
145 150 155 160
Asn Tyr Ala Thr Gly Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu
165 170 175
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
180 185 190
Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala
195 200 205
Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gln Ser
210 215 220
Leu Leu Tyr Ser Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
225 230 235 240
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
245 250 255
Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
260 265 270
Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val Tyr
275 280 285
Tyr Cys Gln Gln Tyr Tyr Ser Tyr Arg Thr Phe Gly Gly Gly Thr Lys
290 295 300
Leu Glu Ile Lys Pro Gly His His His His His His Arg Ala Lys Arg
305 310 315 320
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
325 330 335
Glu Asn Pro Gly Pro His Met Met Val Ser Lys Gly Glu Glu Leu Phe
340 345 350
Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly
355 360 365
His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly
370 375 380
Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro
385 390 395 400
Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser
405 410 415
Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met
420 425 430
Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly
435 440 445
Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val
450 455 460
Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile
465 470 475 480
Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile
485 490 495
Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg
500 505 510
His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln
515 520 525
Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr
530 535 540
Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp
545 550 555 560
His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly
565 570 575
Met Asp Glu Leu Tyr Lys
580
<210> 5
<211> 2430
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 5
ggatccacca tgaaacatct gtggttcttc ctcctcctag tggcagctcc cagatgggtc 60
ctgtcctcta gagagatgac ctgggaggag tgggagaaga aggtggagga gctggagaag 120
aagatcgagg agctgctgaa gggcggaggc ggaagcggcg gaggcggaag cggcggaggc 180
ggaagcgagg tgcagctggt ggagtctggt ggaggcttgg taaagcctgg aggttccctt 240
agactctcct gtgcagcctc tggttacact ttcagtaact attggatcgg atgggtccgc 300
caggctccag gcaaagggct ggagtggatt ggcgatatct accctggagg gaactacatc 360
aggaacaatg agaagttcaa ggacaagacc accctgtcag cagatacttc caagaacaca 420
gcctatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtggaagc 480
agcttcggta gtaactacgt gttcgcctgg tttacttact ggggccaagg gactctggtc 540
acagtctcct caggcggagg cggaagcggc ggaggcggaa gcggcggagg cggaagcgat 600
attgtgatga cccaatctcc actctccctg cctgtcactc ctggagagcc agcctccatc 660
tcttgcagat ctagtcagcg ccttctgagc agttatggac atacctattt acattggtac 720
ctacagaagc caggccagtc tccacagctc ctgatctacg aagtttccaa ccgattttct 780
ggggtcccag acaggttcag tggcagtggg tcagggacag atttcacact taagatcagt 840
agagtggagg ctgaggatgt gggagtttat tactgctctc aaagtacaca tgttcctctc 900
acgttcggac aggggaccaa ggtggaaata aaaggcggag gcggaagcgc tcctgagttt 960
ctgggaggac ctagcgtgtt cctgttccct cccaagccca aggacaccct gatgatcagc 1020
cggaccccag aagtcacctg cgtggtggtg gacgtgtctc aggaagaccc cgaggtgcag 1080
ttcaattggt acgtggacgg cgtggaggtg cacaacgcta agaccaagcc cagggaggag 1140
cagttcaaca gcacctacag ggtggtgtcc gtgctgacag tgctgcatca ggattggctg 1200
aacggcaagg agtacaagtg caaggtgtcc aacaagggcc tgcctagcag catcgagaag 1260
accatcagca aggccaaggg ccagcctaga gagcctcagg tgtacacact gcccccttct 1320
caggaggaga tgaccaagaa ccaggtgtcc ctgacttgcc tcgtgaaggg cttctacccc 1380
agcgatattg ccgtggagtg ggagtctaac ggccagcccg agaacaacta caagaccacc 1440
cctcccgtgc tggatagcga cggctctttc ttcctgtaca gccggctgac agtggacaaa 1500
agtcgctggc aggagggcaa cgtgttcagt tgcagcgtgc tgcacgaggc tctgcacagc 1560
cactacaccc agaagagcct gagcctgagc ctgggaaagc ccgggcacca tcaccatcac 1620
catagagcca agaggggcag cggagagggc agaggaagcc tgctgacctg cggcgacgtg 1680
gaggagaacc ccggccctca tatgatggtg agcaagggcg aggagctgtt caccggggtg 1740
gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1800
gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1860
aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1920
agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1980
tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 2040
gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 2100
gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 2160
atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 2220
gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 2280
cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 2340
aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 2400
ggcatggacg agctgtacaa gtaagtcgac 2430
<210> 6
<211> 804
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 6
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Ser Arg Glu Met Thr Trp Glu Glu Trp Glu Lys Lys Val
20 25 30
Glu Glu Leu Glu Lys Lys Ile Glu Glu Leu Leu Lys Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
50 55 60
Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser
65 70 75 80
Cys Ala Ala Ser Gly Tyr Thr Phe Ser Asn Tyr Trp Ile Gly Trp Val
85 90 95
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asp Ile Tyr Pro
100 105 110
Gly Gly Asn Tyr Ile Arg Asn Asn Glu Lys Phe Lys Asp Lys Thr Thr
115 120 125
Leu Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
130 135 140
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Gly Ser Ser Phe Gly
145 150 155 160
Ser Asn Tyr Val Phe Ala Trp Phe Thr Tyr Trp Gly Gln Gly Thr Leu
165 170 175
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
180 185 190
Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro
195 200 205
Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Arg
210 215 220
Leu Leu Ser Ser Tyr Gly His Thr Tyr Leu His Trp Tyr Leu Gln Lys
225 230 235 240
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe
245 250 255
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
260 265 270
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
275 280 285
Cys Ser Gln Ser Thr His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys
290 295 300
Val Glu Ile Lys Gly Gly Gly Gly Ser Ala Pro Glu Phe Leu Gly Gly
305 310 315 320
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
325 330 335
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
340 345 350
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
355 360 365
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
370 375 380
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
385 390 395 400
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
405 410 415
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
420 425 430
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
435 440 445
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
450 455 460
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
465 470 475 480
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
485 490 495
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His
500 505 510
Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
515 520 525
Gly Lys Pro Gly His His His His His His Arg Ala Lys Arg Gly Ser
530 535 540
Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn
545 550 555 560
Pro Gly Pro His Met Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly
565 570 575
Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys
580 585 590
Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu
595 600 605
Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro
610 615 620
Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr
625 630 635 640
Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu
645 650 655
Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr
660 665 670
Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg
675 680 685
Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly
690 695 700
His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala
705 710 715 720
Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn
725 730 735
Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr
740 745 750
Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser
755 760 765
Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met
770 775 780
Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp
785 790 795 800
Glu Leu Tyr Lys
Claims (8)
1.蛋白质,为下述A1)-A3)中的任一种:
A1)从N端至C端由多肽2P23与HIV单克隆抗体的单链抗体依次连接得到的蛋白质;
A2)从N端至C端由多肽2P23、所述HIV单克隆抗体的单链抗体与IgG4-Fc段或其突变肽段依次连接得到的蛋白质;
A3)在A1)或A2)的N端或/和C端连接标签得到的蛋白质;
其中,所述单克隆抗体为ibalizumab或PRO 140;
所述IgG4-Fc突变肽段的序列为序列表中SEQ ID No.6的第314-530位;
所述多肽2P23的序列为序列表中SEQ ID No.2的第22-44位;
所述单克隆抗体PRO 140的序列为序列表中SEQ ID No.2的第60-308位;
所述单克隆抗体ibalizumab的序列为序列表中SEQ ID No.4的第60-308位。
2.根据权利要求1所述的蛋白质,其特征在于:所述单克隆抗体为单链抗体。
3.根据权利要求1或2所述的蛋白质,其特征在于:A1)所述蛋白质的序列为序列表中SEQ ID No.2的第22-308位或SEQ ID No.4的第22-308位。
4.与权利要求1-3中任一所述的蛋白质相关的生物材料,为下述B1)至B5)中的任一种:
B1)编码权利要求1-3中任一所述蛋白质的核酸分子;
B2)含有B1)所述核酸分子的表达盒;
B3)含有B1)所述核酸分子的重组载体、或含有B2)所述表达盒的重组载体;
B4)含有B1)所述核酸分子的重组微生物、或含有B2)所述表达盒的重组微生物、或含有B3)所述重组载体的重组微生物;
B5)含有B1)所述核酸分子的细胞系、或含有B2)所述表达盒的细胞系;所述细胞系不包括繁殖材料。
5.根据权利要求4所述的生物材料,其特征在于:B1)所述核酸分子为如下b11)-b13)中任一种:
b11)序列表中SEQ ID No.1的第73-933位所示的DNA分子;
b12)序列表中SEQ ID No.3的第73-933位所示的DNA分子;
b13)序列表中SEQ ID No.5的第73-1599位所示的DNA分子。
6.权利要求1-3中任一所述蛋白质的药用盐。
7.一种组合物,由权利要求1-3中任一所述蛋白质或其药用盐与药学上可接受的载体或辅料组成。
8.权利要求1-3中任一所述蛋白质,权利要求4或5所述的生物材料,权利要求6所述的药用盐,或权利要求7所述的组合物在制备具有E1)- E5)中至少一种功能产品中的应用:
E1)抗病毒;
E2)治疗和/或预防和/或辅助治疗病毒感染所致疾病;
E3)抑制病毒与细胞进行融合;
E4)抑制病毒侵入细胞;
E5)抑制病毒复制;
所述E1)- E5)中,所述病毒为下述v1-v7中的任一:
v1、HIV-1、HIV-2和SIV;
v2、HIV-1和HIV-2;
v3、HIV-1和SIV;
v4、HIV-2和SIV;
v5、HIV-1;
v6、HIV-2;
v7、SIV。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210438141.6A CN114907490B (zh) | 2022-04-25 | 2022-04-25 | 强效双功能hiv进入抑制剂及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210438141.6A CN114907490B (zh) | 2022-04-25 | 2022-04-25 | 强效双功能hiv进入抑制剂及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114907490A CN114907490A (zh) | 2022-08-16 |
CN114907490B true CN114907490B (zh) | 2022-12-09 |
Family
ID=82764720
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210438141.6A Active CN114907490B (zh) | 2022-04-25 | 2022-04-25 | 强效双功能hiv进入抑制剂及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114907490B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106543273A (zh) * | 2015-09-20 | 2017-03-29 | 复旦大学 | 用于抑制hiv感染的多肽及其药物用途 |
CN111944025A (zh) * | 2017-04-18 | 2020-11-17 | 中国医学科学院病原生物学研究所 | 艾滋病病毒膜融合抑制剂脂肽及药物用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008134076A1 (en) * | 2007-04-30 | 2008-11-06 | Progenics Pharmaceuticals, Inc. | Methods for reducing viral load in hiv-1-infected patients |
WO2012006437A2 (en) * | 2010-07-07 | 2012-01-12 | University Of Louisville Research Foundation, Inc. | Polypeptides having antiviral activity and methods for use thereof |
-
2022
- 2022-04-25 CN CN202210438141.6A patent/CN114907490B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106543273A (zh) * | 2015-09-20 | 2017-03-29 | 复旦大学 | 用于抑制hiv感染的多肽及其药物用途 |
CN111944025A (zh) * | 2017-04-18 | 2020-11-17 | 中国医学科学院病原生物学研究所 | 艾滋病病毒膜融合抑制剂脂肽及药物用途 |
Non-Patent Citations (3)
Title |
---|
A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus;Shengwen Xiong等;《Journal of Virology》;20161216;第91卷(第1期);1-15 * |
A Membrane-Anchored Short-Peptide Fusion Inhibitor Fully Protects Target Cells from Infections of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus;Xiaoran Tang等;《Journal of Virology》;20191029;第93卷(第22期);1-21 * |
基于GPI锚定双功能HIV进入抑制剂的基因治疗策略;靳红亮;《中国博士学位论文全文数据库》;20210515(第5期);第11页第1.1.2节,第25页第1段,第27页第2段,第29页最后一段,第48页图3-1,第52页第1段、第70页第1段至第71页第2段、图4-1,第72页最后一段 * |
Also Published As
Publication number | Publication date |
---|---|
CN114907490A (zh) | 2022-08-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3365366B1 (en) | Trispecific and/or trivalent binding proteins for prevention or treatment of hiv infection | |
US7939083B2 (en) | Soluble, stabilized, proteolytically cleaved, trimeric HIV-1 gp140 proteins comprising modifications in the N-terminus of the gp41 ectodomain | |
MXPA02006379A (es) | Mejoriasen o relacionadas con la respuesta inmune a vih. | |
JPH10506008A (ja) | HIV−1 Vpr 融合分子に基づいたHIVビリオン中へのタンパク質ターゲッティング | |
Lagenaur et al. | sCD4-17b bifunctional protein: extremely broad and potent neutralization of HIV-1 Env pseudotyped viruses from genetically diverse primary isolates | |
CN108727475B (zh) | 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 | |
JP2004509601A (ja) | 非感染性hiv様粒子の組換え発現 | |
AU2017410525B2 (en) | Potent HIV inhibiting lipopeptide, derivative thereof, pharmaceutical composition thereof and use thereof | |
JP2004522401A (ja) | ワクチンおよび治療薬としてのcd4非依存性のhivエンベロープタンパク質 | |
JP2002538814A (ja) | Hiv感染の予防および治療のための新規キメラタンパク質 | |
CN114907490B (zh) | 强效双功能hiv进入抑制剂及其应用 | |
US7115262B1 (en) | Chimeric protein for prevention and treatment of HIV infection | |
CN115160435A (zh) | 一种双特异性抗hiv-1抗体 | |
Tan et al. | The membrane-proximal region of C–C chemokine receptor type 5 participates in the infection of HIV-1 | |
CN114106191A (zh) | 一种中和冠状病毒的双特异性抗体 | |
EP4351647A1 (en) | Antibody-cd4 conjugates and methods of using the same | |
EP3104884B1 (en) | A new non-hiv vaccine antigen from the vaginal microbiota capable of inducing a mucosal neutralizing protective antibody response against hiv infection | |
アラムムンタシル | Effect of HIV-1 fusion inhibitor resistant gp41 mutations on the sensitivity to neutralizing antibodies | |
Alam | Effect of HIV-1 fusion inhibitor resistant gp41 | |
KR20230112691A (ko) | 바이러스 감염을 치료하기 위한 방법 및 조성물 | |
OA19487A (en) | Potent HIV inhibiting lipopeptide, derivative thereof, pharmaceutical composition thereof and use thereof. | |
CN117980465A (zh) | 一种用于艾滋病病毒感染基因治疗的基因序列构建体 | |
Couto | Synthetic antibodies targeting HIV-1 infectivity | |
EP0879884A2 (en) | Novel CD4 derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |