WO2018191858A1 - 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 - Google Patents
强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 Download PDFInfo
- Publication number
- WO2018191858A1 WO2018191858A1 PCT/CN2017/080860 CN2017080860W WO2018191858A1 WO 2018191858 A1 WO2018191858 A1 WO 2018191858A1 CN 2017080860 W CN2017080860 W CN 2017080860W WO 2018191858 A1 WO2018191858 A1 WO 2018191858A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hiv
- polypeptide
- sequence
- lipopeptide
- linked
- Prior art date
Links
- 108010028921 Lipopeptides Proteins 0.000 title claims abstract description 230
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 46
- 230000003389 potentiating effect Effects 0.000 title abstract description 55
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 206
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 195
- 229920001184 polypeptide Polymers 0.000 claims abstract description 183
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims abstract description 92
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 89
- 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 claims abstract description 74
- 125000006239 protecting group Chemical group 0.000 claims abstract description 51
- 150000002634 lipophilic molecules Chemical class 0.000 claims abstract description 38
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 19
- 208000031886 HIV Infections Diseases 0.000 claims description 137
- 241000713340 Human immunodeficiency virus 2 Species 0.000 claims description 60
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 58
- 210000004899 c-terminal region Anatomy 0.000 claims description 49
- 241000700605 Viruses Species 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 45
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 40
- 210000004027 cell Anatomy 0.000 claims description 38
- 235000021314 Palmitic acid Nutrition 0.000 claims description 28
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 28
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 21
- 235000012000 cholesterol Nutrition 0.000 claims description 20
- 230000007910 cell fusion Effects 0.000 claims description 19
- 235000021355 Stearic acid Nutrition 0.000 claims description 18
- OTKJDMGTUTTYMP-UHFFFAOYSA-N dihydrosphingosine Natural products CCCCCCCCCCCCCCCC(O)C(N)CO OTKJDMGTUTTYMP-UHFFFAOYSA-N 0.000 claims description 18
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 18
- 239000008117 stearic acid Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 230000004048 modification Effects 0.000 claims description 14
- 238000012986 modification Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 229930003427 Vitamin E Natural products 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 11
- 230000029812 viral genome replication Effects 0.000 claims description 11
- 229940046009 vitamin E Drugs 0.000 claims description 11
- 235000019165 vitamin E Nutrition 0.000 claims description 11
- 239000011709 vitamin E Substances 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- 230000009385 viral infection Effects 0.000 claims description 10
- 208000036142 Viral infection Diseases 0.000 claims description 9
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 9
- 239000000194 fatty acid Substances 0.000 claims description 9
- 229930195729 fatty acid Natural products 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 150000004665 fatty acids Chemical class 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 8
- 235000018102 proteins Nutrition 0.000 claims description 7
- 108010038807 Oligopeptides Proteins 0.000 claims description 6
- 102000015636 Oligopeptides Human genes 0.000 claims description 6
- 238000009098 adjuvant therapy Methods 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 230000002155 anti-virotic effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- OTKJDMGTUTTYMP-ROUUACIJSA-N Safingol ( L-threo-sphinganine) Chemical compound CCCCCCCCCCCCCCC[C@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ROUUACIJSA-N 0.000 claims 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 2
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 57
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 56
- 230000000694 effects Effects 0.000 abstract description 53
- 101800001690 Transmembrane protein gp41 Proteins 0.000 abstract description 17
- 230000036436 anti-hiv Effects 0.000 abstract description 15
- 235000001014 amino acid Nutrition 0.000 description 64
- 229940024606 amino acid Drugs 0.000 description 63
- 239000003112 inhibitor Substances 0.000 description 61
- 241000713311 Simian immunodeficiency virus Species 0.000 description 51
- 230000034217 membrane fusion Effects 0.000 description 38
- 230000005764 inhibitory process Effects 0.000 description 31
- 235000002639 sodium chloride Nutrition 0.000 description 31
- -1 SC35EK Chemical compound 0.000 description 30
- 241001112090 Pseudovirus Species 0.000 description 25
- 239000003814 drug Substances 0.000 description 22
- 210000002966 serum Anatomy 0.000 description 22
- 241000282693 Cercopithecidae Species 0.000 description 21
- 229940079593 drug Drugs 0.000 description 20
- 238000002347 injection Methods 0.000 description 19
- 239000007924 injection Substances 0.000 description 19
- 230000003612 virological effect Effects 0.000 description 19
- 238000002474 experimental method Methods 0.000 description 18
- 208000030507 AIDS Diseases 0.000 description 16
- 230000003247 decreasing effect Effects 0.000 description 16
- OTKJDMGTUTTYMP-ZWKOTPCHSA-N sphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ZWKOTPCHSA-N 0.000 description 16
- 238000002983 circular dichroism Methods 0.000 description 15
- 229940125777 fusion inhibitor Drugs 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 208000015181 infectious disease Diseases 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 230000004927 fusion Effects 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 210000000170 cell membrane Anatomy 0.000 description 11
- 230000001404 mediated effect Effects 0.000 description 11
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000013461 design Methods 0.000 description 10
- 238000010254 subcutaneous injection Methods 0.000 description 10
- 239000007929 subcutaneous injection Substances 0.000 description 10
- OTKXCALUHMPIGM-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 OTKXCALUHMPIGM-FQEVSTJZSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 230000003993 interaction Effects 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 7
- 102100034349 Integrase Human genes 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 208000037357 HIV infectious disease Diseases 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 101710091045 Envelope protein Proteins 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- 241000282553 Macaca Species 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 101710188315 Protein X Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 5
- 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 5
- 108010048106 sifuvirtide Proteins 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 229960005486 vaccine Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CBPJQFCAFFNICX-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 CBPJQFCAFFNICX-IBGZPJMESA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 108010032976 Enfuvirtide Proteins 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000012876 carrier material Substances 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
- 238000001514 detection method Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002609 medium Substances 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
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 230000008685 targeting Effects 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
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 3
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 3
- 229920002307 Dextran Polymers 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
- 108010010803 Gelatin Proteins 0.000 description 3
- 101000999322 Homo sapiens Putative insulin-like growth factor 2 antisense gene protein Proteins 0.000 description 3
- 102100036485 Putative insulin-like growth factor 2 antisense gene protein Human genes 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 238000013459 approach Methods 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
- 102220358754 c.107A>G Human genes 0.000 description 3
- 239000006143 cell culture medium Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 229940110456 cocoa butter Drugs 0.000 description 3
- 235000019868 cocoa butter Nutrition 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 3
- 229960002062 enfuvirtide Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000013613 expression plasmid Substances 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
- 230000036541 health Effects 0.000 description 3
- 239000002835 hiv fusion inhibitor Substances 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 229960002446 octanoic acid Drugs 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000006187 pill Substances 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
- 238000000746 purification Methods 0.000 description 3
- 108020003175 receptors Proteins 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
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- PSVXZQVXSXSQRO-UHFFFAOYSA-N undecaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO PSVXZQVXSXSQRO-UHFFFAOYSA-N 0.000 description 3
- WDGICUODAOGOMO-DHUJRADRSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(tritylamino)pentanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)CC(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WDGICUODAOGOMO-DHUJRADRSA-N 0.000 description 2
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- HXMVNCMPQGPRLN-UHFFFAOYSA-N 2-hydroxyputrescine Chemical compound NCCC(O)CN HXMVNCMPQGPRLN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JDDWRLPTKIOUOF-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-[[4-[2-[bis(4-methylphenyl)methylamino]-2-oxoethoxy]phenyl]-(2,4-dimethoxyphenyl)methyl]carbamate Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(=O)NC(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JDDWRLPTKIOUOF-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 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
- 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
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 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
- 101710121417 Envelope glycoprotein Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 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
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 241000282560 Macaca mulatta Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 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
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-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
- 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
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 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
- 239000012491 analyte Substances 0.000 description 2
- 238000004873 anchoring Methods 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 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
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000010835 comparative analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 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
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 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
- 238000007499 fusion processing Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 2
- 235000012907 honey Nutrition 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000009545 invasion Effects 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
- 239000008101 lactose Substances 0.000 description 2
- 150000004668 long chain fatty acids Chemical class 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229960004710 maraviroc Drugs 0.000 description 2
- 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 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 239000013642 negative control Substances 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
- 229960000689 nevirapine Drugs 0.000 description 2
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 2
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 2
- GLZWNFNQMJAZGY-UHFFFAOYSA-N octaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCO GLZWNFNQMJAZGY-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 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
- 238000011191 terminal modification Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- ZFEAMMNVDPDEGE-LGRGJMMZSA-N tifuvirtide Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(C)=O)[C@@H](C)CC)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)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](CCC(O)=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)C1=CC=C(O)C=C1 ZFEAMMNVDPDEGE-LGRGJMMZSA-N 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 239000013638 trimer Substances 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
- 230000007502 viral entry Effects 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
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 238000005303 weighing Methods 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
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ADOHASQZJSJZBT-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-SANMLTNESA-N 0.000 description 1
- KJYAFJQCGPUXJY-UMSFTDKQSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(tritylamino)butanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KJYAFJQCGPUXJY-UMSFTDKQSA-N 0.000 description 1
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 1
- QXVFEIPAZSXRGM-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 QXVFEIPAZSXRGM-DJJJIMSYSA-N 0.000 description 1
- WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-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
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000000349 (Z)-3-carboxyprop-2-enoyl group Chemical group O=C([*])/C([H])=C([H])\C(O[H])=O 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 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
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- NUHRPLKTAAVHCZ-UHFFFAOYSA-N 3-[2-[2-[2-[2-(9h-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)NCCOCCOCCOCCOCCC(=O)O)C3=CC=CC=C3C2=C1 NUHRPLKTAAVHCZ-UHFFFAOYSA-N 0.000 description 1
- JYNHRDJTWNEGJE-UHFFFAOYSA-N 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(9h-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)O)C3=CC=CC=C3C2=C1 JYNHRDJTWNEGJE-UHFFFAOYSA-N 0.000 description 1
- 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 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
- UPJMWRYBLNHWQS-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;toluene Chemical compound CC1=CC=CC=C1.CC1=CC=C(S(O)(=O)=O)C=C1 UPJMWRYBLNHWQS-UHFFFAOYSA-N 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- 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 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229940124718 AIDS vaccine Drugs 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 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 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
- 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 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101100450244 Dictyostelium discoideum hbx2 gene Proteins 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
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101710114816 Gene 41 protein Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010083930 HIV Receptors Proteins 0.000 description 1
- 102000006481 HIV Receptors Human genes 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- ONXPDKGXOOORHB-BYPYZUCNSA-N N(5)-methyl-L-glutamine Chemical compound CNC(=O)CC[C@H](N)C(O)=O ONXPDKGXOOORHB-BYPYZUCNSA-N 0.000 description 1
- CYZKJBZEIFWZSR-LURJTMIESA-N N(alpha)-methyl-L-histidine Chemical compound CN[C@H](C(O)=O)CC1=CNC=N1 CYZKJBZEIFWZSR-LURJTMIESA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 241000199919 Phaeophyceae Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 231100000645 Reed–Muench method Toxicity 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 241001529934 Simian T-lymphotropic virus 3 Species 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 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
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 229940118555 Viral entry inhibitor Drugs 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010011303 albuvirtide Proteins 0.000 description 1
- QNWVQSLLLTZQPH-VIIPOJRNSA-N albuvirtide Chemical compound C([C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCNC(=O)COCCOCCNC(=O)CCN1C(C=CC1=O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(O)=O)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)=O)C1=CC=C(O)C=C1 QNWVQSLLLTZQPH-VIIPOJRNSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000002832 anti-viral assay Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function 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
- 229940077388 benzenesulfonate Drugs 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
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 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
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 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
- 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
- 239000013592 cell lysate Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 210000003793 centrosome Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003067 chemokine receptor CCR5 antagonist Substances 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 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
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal 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
- 230000007547 defect Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction 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
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- AYXBAIULRDEVAS-UHFFFAOYSA-N dimethyl-[[4-[[3-(4-methylphenyl)-8,9-dihydro-7h-benzo[7]annulene-6-carbonyl]amino]phenyl]methyl]-(oxan-4-yl)azanium;iodide Chemical compound [I-].C1=CC(C)=CC=C1C1=CC=C(CCCC(=C2)C(=O)NC=3C=CC(C[N+](C)(C)C4CCOCC4)=CC=3)C2=C1 AYXBAIULRDEVAS-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
- 238000009826 distribution Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 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
- 238000009509 drug development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229960003692 gamma aminobutyric acid 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
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 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 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- BICAGYDGRXJYGD-UHFFFAOYSA-N hydrobromide;hydrochloride Chemical compound Cl.Br BICAGYDGRXJYGD-UHFFFAOYSA-N 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
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229950010245 ibalizumab Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 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 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
- 229940070765 laurate Drugs 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
- 239000002502 liposome Substances 0.000 description 1
- 235000020094 liqueur Nutrition 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 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
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000013521 mastic Substances 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 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
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- CZIOQBGIMPWRFL-MWOCQOIESA-N mt-sc22ek Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)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](N)CCSC)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)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](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O)C1=CC=C(O)C=C1 CZIOQBGIMPWRFL-MWOCQOIESA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 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
- 229940049964 oleate Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000007935 oral tablet Substances 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
- 229940039748 oxalate Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000026792 palmitoylation Effects 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
- 239000006072 paste Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002688 persistence 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
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940068586 prezista Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification 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
- 230000035484 reaction time Effects 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 108010043277 recombinant soluble CD4 Proteins 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940107904 reyataz Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 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
- ZPBBRCQSQDYDSV-FVYZORJTSA-N sc29ek Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)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](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=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](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1 ZPBBRCQSQDYDSV-FVYZORJTSA-N 0.000 description 1
- 230000007017 scission Effects 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
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 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
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000001356 surgical procedure 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
- 229920002258 tannic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 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
- 238000012546 transfer Methods 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940044953 vaginal ring Drugs 0.000 description 1
- 239000006213 vaginal ring Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- C07K14/08—RNA viruses
- C07K14/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus human T-cell leukaemia-lymphoma virus
- C07K14/155—Lentiviridae, e.g. human immunodeficiency virus [HIV], visna-maedi virus or equine infectious anaemia virus
- C07K14/16—HIV-1 ; HIV-2
- C07K14/162—HIV-1 ; HIV-2 env, e.g. gp160, gp110/120, gp41, V3, peptid T, CD4-Binding site
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/55—IL-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/21—Retroviridae, e.g. equine infectious anemia virus
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/54—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 organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- 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
- A61K47/54—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 organic compound
- A61K47/545—Heterocyclic compounds
-
- 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
- A61K47/54—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 organic compound
- A61K47/554—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 organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
-
- 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
-
- 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
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to lipopeptides, derivatives thereof, pharmaceutical compositions thereof and uses thereof for potently inhibiting HIV in the field of biomedicine.
- AIDS is an important infectious disease that currently seriously harms human health and social development.
- Human immunodeficiency virus that causes AIDS is divided into two types, HIV-1 and HIV-2.
- HIV-1 is the main pathogen (www.unaids.org).
- HIV-1 is the main pathogen (www.unaids.org).
- Current clinical therapeutic drugs mainly include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, viral entry inhibitors, and integrase inhibitors (www.fda.gov).
- a highly effective antiviral treatment regimen widely used clinically the so-called "cocktail” therapy consists mainly of 3-4 reverse transcriptase inhibitors and protease inhibitors. Due to the persistence of HIV infection, patients need long-term administration, so it is easy to lead to drug resistance, which seriously affects the clinical treatment effect [1]. Therefore, the development of new anti-HIV drugs has always been an important strategy to prevent and control AIDS.
- HIV entry inhibitors act on the early stages of viral replication and act by blocking the virus from entering the target cells, as if “rejecting the enemy outside the country”, so there is a clear treatment and prevention.
- HIV membrane fusion inhibitor enfuvirtide also known as T-20
- T-20 HIV membrane fusion inhibitor enfuvirtide
- the 36 amino acid polypeptide drug the second is the co-receptor CCR5 antagonist Maraviroc.
- T-20 requires high doses per day (90mg subcutaneous injection twice a day) due to its relatively low activity, and it is easy to cause drug resistance. Malawi is selective against CCR5 tropic virus and is ineffective against CRCR4 tropic virus [2].
- HIV entry into the target cell is mediated by its surface envelope glycoprotein (Env), which is formed by the surface subunit gp120 and the transmembrane subunit gp41 by non-covalent bonds, and is a trimer structure in its native state [ 3].
- Env surface envelope glycoprotein
- gp120 binds to the cellular receptor CD4 and co-receptors (such as CCR5 or CXCR4), resulting in a dramatic conformational change in gp120, thereby exposing and activating the membrane fusion function of gp41.
- Gp41 is structurally divided into three parts: the extramembranous region, the transmembrane region (TM) and the intramembrane region.
- the extramembranous region includes several important functional regions such as N-terminal hydrophobic fusion peptide (FP), N-terminal helical repeat (NHR), C-terminal helical repeat (CHR), and membrane proximal region (MPER). figure 1).
- FP N-terminal hydrophobic fusion peptide
- NHR N-terminal helical repeat
- CHR C-terminal helical repeat
- MPER membrane proximal region
- the amino acid interaction with the d position forms a centrally located helical trimer with amino acids at the e and g positions exposed to the periphery of the centrosome and interacting with the amino acids at the a and d positions of the three CHR helices [4].
- the three CHR spirals are combined in an anti-parallel manner in the grooves formed by the three NHR spirals, respectively. It looks like three stacking cards.
- the mechanism of HIV membrane fusion has a deeper understanding. First, the exposed gp41 fusion peptide is inserted into the target cell membrane, followed by the reverse binding of CHR to NHR, and the virus is formed by the formation of stable 6-HB.
- the membrane approaches the target cell membrane and causes fusion, and eventually the HIV genetic material enters the target cell.
- the 6-HB structure also revealed that the C-terminal portion of the NHR helix forms a distinct hydrophobic deep pocket pocket, while the N-terminal of the CHR, the three amino acids of the so-called pocket binding region (PBD), is inserted into the NHR hydrophobic pocket, with each other
- PBD pocket binding region
- the role plays an important role in stabilizing the 6-HB structure and is therefore essential for HIV infection.
- the hydrophobic pocket structure of NHR has long been considered an important target for anti-HIV drugs, and the PBD motif of CHR is the key to designing anti-HIV peptide inhibitors [5,6].
- polypeptides derived from gp41NHR and CHR have significant anti-HIV activity, mainly by competitively blocking the formation of the virus itself 6-HB by binding to the corresponding NHR or CHR, thereby blocking the virus-cell membrane. Fusion process [6].
- the antiviral activity of the prototype CHR polypeptide is significantly higher than the prototype NHR polypeptide.
- the drug T-20 belongs to the CHR polypeptide, and its sequence is shown in Figure 1, which corresponds to the amino acid sequence of positions 127 to 162 of the HIV-1 strain HXB2gp41.
- T-20 in its sequence structure is that its C-terminus is a tryptophan-rich hydrophobic motif (TRM: WASLWNWF), but its N-terminus does not include the PBD sequence (WMEWDREI). It has been found that T-20 TRM mediates the binding of peptides to cellular lipid membranes and is therefore considered to be the lipid membrane binding domain (LBD), a property that is important for the antiviral activity of T-20.
- LBD lipid membrane binding domain
- C34 is first used for the resolution of the 6-HB structure, and the corresponding amino acid sequence of the gp41 sequence is considered to be the CHR core sequence; 2) the N-terminus of C34 contains an important PBD sequence, compared to T- 20 has strong NHR binding ability and antiviral activity; 3) C34 has significantly enhanced inhibitory activity against T-20 resistant virus strain.
- Newly developed HIV membrane fusion inhibitors such as T2635, SC35EK, SC29EK, Sifuvirtide (SFT), Abbott (ABT), C34-Chol, etc. are all obtained by sequence optimization and/or modification of C34. [6,7], they also have better inhibitory activity and stability than T-20.
- the M-T hook structure also makes it possible to design short peptides targeting NHR hydrophobic pockets, such as MT-SC22EK with a length of 24 amino acids and HP23 and 2P23 with a length of 23 amino acids [13-15]. These short peptides have higher antiviral activity and target sequence binding ability than other long sequence polypeptides. 2P23 is not only effective against HIV-1 and its T-20 resistant strains, but also very effective against HIV-2 and simian immunodeficiency virus (SIV), and is a broad-spectrum viral membrane fusion inhibitor [13].
- SIV simian immunodeficiency virus
- the lipid raft is rich in cholesterol (cholesterol) and sphingomyelin, as well as many transmembrane proteins and receptors (such as the HIV receptor CD4), which play an important role in virus entry and infection;
- the enveloped viral lipid bilayer membrane structure derived from cell membranes is also rich in cholesterol and sphingomyelin, and is involved in maintaining the normal structure and function of viral envelope proteins [16,17]. HIV is invading the target During the process of the cell, the lipid raft structure and the lipids (such as cholesterol and sphingomyelin) provide a suitable platform for the interaction between the viral gp120 and the cellular receptor CD4/co-receptor.
- T-20 on the cell membrane surface by recombinant construction techniques can also significantly increase its inhibitory viral activity [25,26].
- lipopeptide by chemical modification of peptides, the so-called "lipopeptide", the cell membrane targeting and antiviral activity of the polypeptide can be improved, while at the same time significantly improving the stability and biological properties of the polypeptide.
- Half-life [18-20,27].
- Studies on HIV membrane fusion inhibitors have shown that when the activity of CHR polypeptides is increased depending on the C-terminal modification, the NHR polypeptide is suitable for N-terminal modification, which is consistent with the structure of 6-HB and the mechanism of viral membrane fusion.
- the CHR polypeptide is beneficial for its binding to the viral NHR by C-terminal anchoring, whereas the NHR polypeptide is the opposite, and its N-terminus is anchored to the cell membrane to facilitate its binding to the viral CHR [19, 28, 29].
- the design of lipopeptide HIV membrane fusion inhibitors has focused on C34 containing PBD as a template.
- a representative example is the lipopeptide C34-Chol (see Figure 1) designed by Ingallinella et al. in 2009, which links cholesterol to the C-terminus of C34 via a flexible tether and cysteine, based on its antiviral results.
- the inventors' laboratory used palmitic acid (C16), cholesterol and dihydrosphingosine three lipid compounds to modify the short peptides HP23 and HP23L targeting NHR pockets respectively, and prepared a group of high activities. Lipopeptides, in which the stability of LP-11 is also greatly improved [18]. Recently, the inventors' laboratory has designed a palmitic acid-modified lipopeptide LP-19 based on a broad-spectrum anti-HIV short peptide 2P23, which has higher antiviral activity and drug-forming properties [30]. These research advances have laid a solid theoretical foundation and technical route for the design of new HIV membrane fusion inhibitors.
- HIV fusion inhibitor peptide T-1249 is able to insert or adsorb to lipidic bilayers. Putative correlation with improved efficiency. J Am Chem Soc 2004, 126: 14758- 14763.
- the technical problem to be solved by the present invention is how to effectively suppress HIV.
- the present invention provides a potent HIV membrane fusion inhibitor.
- the potent HIV membrane fusion inhibitor provided by the present invention is a lipopeptide having a strong inhibitory activity against HIV, a pharmaceutically acceptable salt thereof, or a derivative thereof, wherein the lipopeptide is the following a) or b):
- the lipopeptide is linked by a polypeptide having antiviral activity and a lipophilic compound linked to the carboxy terminus of the polypeptide;
- the lipopeptide is linked by a polypeptide having antiviral activity, a terminal protecting group and a lipophilic compound linked to the carboxy terminus of the polypeptide;
- the terminal protecting group is an amino terminal protecting group and/or a carboxy terminal protecting group base;
- polypeptide is any one of P1 to P5:
- X 1 to X 28 are each an amino acid residue, said X 1 is W, L or Y, said X 2 is E or T, said X 3 is Q, A or S, and said X 4 is K , N or L, X 5 is I or L, X 6 is E, D, K, R or A, X 7 is E, D, K, R or A, X 8 is L or I, X 9 is L or I, X 10 is K, R, E, D or A, X 11 is K, R, E, D or A, X 12 is A or S, and X 13 is E, D, K, R or A, X 14 Is E, D, K, R or A, X 15 is Q, X 16 is Q, X 17 is K, R, E, D or A, X 18 is K, R, E, D or A, X 19 is N, X 20 is E or D, X 21 is E, D, K, R or A, X 22 is E, D, K
- the P2 is 1 to 4 amino acid residues deleted from the amino terminus of the P1 (ie, 1 to 4 amino acid residues of the four amino acid residues X 1 , X 2 , X 3 and X 4 in the formula I)
- the resulting polypeptide is 1 to 4 amino acid residues deleted from the amino terminus of the P1 (ie, 1 to 4 amino acid residues of the four amino acid residues X 1 , X 2 , X 3 and X 4 in the formula I)
- the resulting polypeptide is 1 to 4 amino acid residues deleted from the amino terminus of the P1 (ie, 1 to 4 amino acid residues of the four amino acid residues X 1 , X 2 , X 3 and X 4 in the formula I)
- the P3 is obtained by deleting 1 to 3 amino acid residues of the carboxy terminus of the P1 (ie, 1 to 3 amino acid residues of the three amino acid residues X 26 , X 27 and X 28 in the formula I) Polypeptide
- the P4 is a polypeptide obtained by adding a cysteine residue to the carboxy terminus of the P1;
- the virus is any of the following v1-v7: v1, HIV-1, HIV-2 and SIV; v2, HIV-1 and HIV-2; v3, HIV-1 and SIV; v4, HIV-2 and SIV; v5, HIV-1; v6, HIV-2; v7, SIV.
- P5 is the core sequence of the lipopeptide of the present invention.
- Add at the N-terminus of the core sequence 1 to 4 amino acid residues and/or 1-3 amino acid residues at the C-terminus thereof are effective for increasing their antiviral activity.
- the lipopeptide has higher antiviral activity than LP-19 and/or T-20 and/or C34-Chol.
- the sequence of P1 is X 1 X 2 X 3 X 4 IEELX 9 KKX 12 EEQQKKNEEELKKLEK;
- the P2 is P2-1, P2-2, P2-3 or P2-4,
- the sequence of P2-1 is X 2 X 3 X 4 IEELX 9 KKX 12 EEQQKKNEEELKKLEK;
- the sequence of the P2-2 is X 3 X 4 IEELX 9 KKX 12 EEQQKKNEEELKKLEK;
- the sequence of the P2-3 is X 4 IEELX 9 KKX 12 EEQQKKNEEELKKLEK;
- the sequence of the P2-4 is IEELX 9 KKX 12 EEQQKKNEEELKKLEK;
- the sequence of P3 is X 1 X 2 X 3 X 4 IEELX 9 KKX 12 EEQQKKNEEELKK;
- the sequence of the P4 is X 1 X 2 X 3 X 4 IEELX 9 KKX 12 EEQQKKNEEELKKLEKC;
- X 1 , X 2 , X 3 , X 4 , X 9 and X 12 have the same definitions (Formula I).
- X n (n is a natural number in any of 1 to 28) in the sequence of the polypeptide, each of the capital letters is an abbreviation of an amino acid, and an amino acid.
- Abbreviations have the meanings well-known in the art, for example: Y is tyrosine, T is threonine, S is serine, L is leucine, I is isoleucine, E is glutamic acid, K is lysine The acid, Q is glutamine, N is asparagine, A is alanine, and W is tryptophan.
- All of the amino acids in the polypeptide sequence may be L-form amino acids, and one or more (eg, 2-5, 2-4, or 2-3) amino acids may also be modified with a conformationally D-type amino acid.
- the amino acid, rare amino acids present in nature, etc. are replaced to increase the bioavailability, stability and/or antiviral activity of the polypeptide.
- the D-type amino acid refers to an amino acid corresponding to the L-form amino acid constituting the protein
- the artificially modified amino acid refers to a common L-type amino acid which constitutes a protein modified by methylation, phosphorylation or the like
- a rare amino acid existing in nature includes a constituent protein.
- Unusual amino acids and amino acids that do not constitute proteins such as 5-hydroxylysine, methylhistidine, gamma aminobutyric acid, homoserine, and the like.
- the P1 is P-80/84/85/52, P-87/51 or P50; the P-80/84/85/52 is in the order a polypeptide represented by SEQ ID NO: 1 in the list (i.e., a polypeptide represented by amino acid residues 1 to 28 of LP-80, LP-84, LP-85 and LP-52 in Fig. 2), said P-87/51
- the polypeptide represented by the sequence 2 in the sequence table ie, the polypeptide represented by amino acid residues 1 to 28 of LP-87 and LP-51 in FIG. 2
- the P50 is the polypeptide represented by the sequence 3 in the sequence listing.
- the P2-1 is P-88/62
- the P-88/62 is represented by the sequence 4 in the sequence listing.
- a polypeptide i.e., a polypeptide represented by amino acid residues 1 to 27 of LP-88 and LP-62 in Figure 2
- said P2-2 being P63 or P60, said P63 being represented by sequence 5 in the sequence listing a polypeptide (i.e., a polypeptide represented by amino acid residues 1-26 of LP-63 in Figure 2)
- said P60 being a polypeptide represented by SEQ ID NO:6 in the sequence listing (i.e., the first of LP-60 in Figure 2) a polypeptide represented by amino acid residue 26);
- said P2-3 is P-89/64
- said P-89/64 is a polypeptide represented by SEQ ID NO: 7 in the sequence listing (ie, LP-89 and LP in Fig.
- polypeptide represented by amino acid residues 1 to 25 of -64 Said P2-4 as P-90/65 or P61, the P-90/65 is a polypeptide represented by SEQ ID NO: 8 in the Sequence Listing (i.e., the polypeptide represented by amino acid residues 1 to 24 of LP-90 and LP-65 in Figure 2), and the P61 is in the sequence listing.
- a polypeptide represented by SEQ ID NO: 9 i.e., a polypeptide represented by amino acid residues 1 to 24 of LP-61 in Fig.
- said P3 is P-91/55, and said P-91/55 is in the sequence listing a polypeptide represented by SEQ ID NO: 10 (i.e., a polypeptide represented by amino acid residues 1 to 25 of LP-91 and LP-55 in Fig. 2); said P4 is P83 or P86, and said P83 is a sequence 11 in the sequence listing.
- the polypeptide shown ie, the polypeptide represented by amino acid residues 1-29 of LP-83 in Figure 2
- the P86 is the polypeptide shown by SEQ ID NO: 12 in the sequence listing (ie, the number of LP-86 in Figure 2) a polypeptide represented by amino acid residues 1-29).
- the lipophilic compound may be a fatty acid having 8 to 20 carbon atoms, cholesterol (cholesterol, Chol), dihydro (neuro) sphingosine Alcohol (dihydrosphingosine, DHS) or vitamin E (tocopherol, Toc) and the like.
- the fatty acid having 8 to 20 carbon atoms may be palmitic acid (also known as palmitic acid) (C16) or stearic acid (C18).
- the lipophilic compound may be attached to the side chain of the terminal amino acid or may be directly linked to the peptide chain.
- the modification of the fatty acid, dihydrosphingosine and vitamin E in the C-terminally linked lipophilic compound can be achieved by amidation reaction with the amino group of the lysine (Lys) side chain at the end of the polypeptide; the modification of cholesterol can be passed
- the thiol group of the cysteine (Cys) side chain at the end of the polypeptide is grafted onto the polypeptide chain by a highly chemically selective thioether reaction.
- the lipopeptide may be LP-80/84/85/52, LP-90/65, LP-87/5, LP-88/62, LP -50, any of the 12 lipopeptides of LP-83, LP-91/55, LP-86, LP-63, LP-89/64, LP-60 and LP-61;
- the LP-80/84/85/52 is LP-80/84/85/52a or LP-80/84/85/52b; the LP-80/84/85/52a is from the P-80/ 84/85/52 and a lipophilic compound linked to the carboxy terminus of the P-80/84/85/52; the LP-80/84/85/52b is from the LP-80/84/ 85/52a is formed by linking the terminal protecting group; in the LP-80/84/85/52a and LP-80/84/85/52b, the lipophilic compound is stearic acid, dihydrosphingosine Alcohol, vitamin E or palmitic acid;
- the LP-90/65 is LP-90/65a or LP-90/65b, and the LP-90/65a is derived from the P-90/65 and the procarboxy terminus of the P-90/65 a lipid compound is linked; the LP-90/65b is formed by linking the LP-90/65a to the terminal protecting group; in the LP-90/65a and LP-90/65b, the lipophilicity
- the compound is stearic acid or palmitic acid;
- the LP-87/51 is LP-87/51a or LP-87/51b; the LP-87/51a is derived from the P-87/51 and the procarboxy terminus of the P-87/51 a lipid compound is linked; the LP-87/51b is formed by linking the LP-87/51a to the terminal protecting group; in the LP-87/51a and LP-87/51b, the lipophilicity
- the compound is dihydrosphingosine or palmitic acid;
- the LP-88/62 is LP-88/62a or LP-88/62b; the LP-88/62a is derived from the P-88/62 and the procarboxy terminus of the P-88/62 a lipid compound is linked; the LP-88/62b is formed by linking the LP-88/62a to the terminal protecting group; in the LP-88/62a and LP-88/62b, the lipophilicity
- the compound is stearic acid or palmitic acid;
- the LP-50 is LP-50a or LP-50b; the LP-50a is formed by linking the P50 to palmitic acid linked to the carboxy terminus of the P50; the LP-50b is composed of the LP-50a Connected to the end protecting group;
- the LP-83 is LP-83a or LP-83b; the LP-83a is formed by linking the P83 and cholesterol linked to the carboxy terminus of the P83; the LP-83b is composed of the LP-83a and The end protecting groups are connected;
- the LP-91/55 is LP-91/55a or LP-91/55b, and the LP-91/55a is derived from the P-91/55 and the procarboxy terminus of the P-91/55.
- a lipid compound is linked; the LP-91/55b is formed by linking the LP-91/55a to the terminal protecting group; in the LP-91/55a and LP-91/55b, the lipophilicity
- the compound is stearic acid or palmitic acid;
- the LP-86 is LP-86a or LP-86b; the LP-86a is formed by linking the P86 and cholesterol linked to the carboxy terminus of the P86; the LP-86b is composed of the LP-86a and The terminal protecting group is linked; the LP-63 is LP-63a or LP-63b; the LP-63a is formed by linking the P63 and palmitic acid connected to the carboxyl terminus of the P63; LP-63b is formed by linking the LP-63a to the terminal protecting group; the LP-89/64 is LP-89/64a or LP-89/64b; and the LP-89/64a is composed of the P -89/64 and a lipophilic compound linked to the carboxy terminus of the P-89/64; the LP-89/64b is formed by linking the LP-89/64a to the terminal protecting group; In the LP-89/64a and LP-89/64b, the lipophilic compound is
- the LP-60 is LP-60a or LP-60b; the LP-60a is formed by linking the P60 with palmitic acid linked to the carboxy terminus of the P60; the LP-60b is composed of the LP-60a Attached to the terminal protecting group; the LP-61 is LP-61a or LP-61b; the LP-61a is formed by linking the P61 and palmitic acid connected to the carboxyl terminus of the P61; LP-61b is formed by linking the LP-61a to the terminal protecting group.
- the amino terminal of the lipopeptide of the present invention may have an amino terminal protecting group, and the amino terminal protecting group may be an acetyl group, an amino group, a maleyl group, or a succinyl group.
- any one of a tert-butoxycarbonyl group or a benzyloxy group or other hydrophobic group or a macromolecular carrier group; the carboxy terminus of the lipopeptide of the present invention may have a carboxy terminal protecting group, and the carboxy terminal protecting group may be an amino group, Any of an amide group, a carboxyl group, or a tert-butoxycarbonyl group or other hydrophobic group or a macromolecular carrier group.
- polypeptide of any of the above P1 to P4, a pharmaceutically acceptable salt thereof, or a derivative thereof is also within the scope of the present invention.
- the derivative of the polypeptide may specifically be at least one of the following 1) to 5):
- Multimers of PM1 or PM2 are also within the scope of the invention:
- PM1 a multimer formed from the lipopeptide, a pharmaceutically acceptable salt thereof, or a derivative thereof;
- compositions are also within the scope of the present invention: a composition comprising C1) and C2): C1) is C11), C12) or/and C13); said C11) is said lipopeptide, a derivative, or a pharmaceutically acceptable salt thereof; the C12) is the polypeptide, a derivative thereof, or a pharmaceutically acceptable salt thereof; the C13) is the multimer;
- composition has at least one of the following F1)-F5):
- the virus is any one of the following v1-v7:
- V1 HIV-1, HIV-2 and SIV;
- the E1) is an antiviral product such as a drug or a vaccine
- the E2) is a product, such as a drug or a vaccine, for treating and/or preventing and/or adjuvant treatment of a disease caused by a viral infection, such as AIDS;
- the E3) is a product for inhibiting virus cell fusion, such as a drug or a vaccine
- the E4) is a product that inhibits virus invading cells, such as a drug or a vaccine;
- the E5) is a product that inhibits viral replication, such as a drug or a vaccine
- the virus is any one of the following v1-v7:
- V1 HIV-1, HIV-2 and SIV;
- the invention provides pharmaceutical compounds.
- the pharmaceutical compound provided by the present invention is the C11), the C12) or the C13).
- the pharmaceutical compound has at least one of the following U1)-U5):
- U4 is used to inhibit virus invading cells
- U5 is used to inhibit viral replication
- the virus is any one of the following v1-v7:
- V1 HIV-1, HIV-2 and SIV;
- a method of treating or/and preventing a virus-infected animal comprising administering to the recipient animal the C11), the C12), the C13) or/and C14) to inhibit viral infection of the animal;
- the virus is any one of the following v1-v7:
- V1 HIV-1, HIV-2 and SIV;
- the pharmaceutically acceptable salt of the lipopeptide of the present invention and the pharmaceutically acceptable salt of the polypeptide including acetate, lactobionate, benzenesulfonate, laurate, benzoate ), malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, methanesulfonate (mesylate), borate, methylbromide, bromide, methylnitrate, edetic acid Calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride , nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleic acid Oleate, edetate, oxalate, edisylate, pamoate (hydroxynaphthylate embonate), propionate Estee sulfate, palmitate, esylate, pantothenate, fumarate
- the pharmaceutically acceptable salt may be composed of cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and bismuth. Or formed by a base such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine (ornithine), choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, Pru It is formed by procaine, diethylamine, piperazine, tris(hydroxymethylaminomethane) and tetramethylammonium hydroxide.
- These salts can be prepared by standard methods, for example by reaction of the free acid with an organic or inorganic base.
- an acid salt such as a hydrochloride, a hydrobromide, an acetate, a pamoate or the like can be used as a dosage form;
- an acidic group such as -COOH
- an alcohol group pharmaceutically acceptable esters such as acetate, maleate, pivaloyloxymethyl, etc. Esters known in the literature for improving solubility and hydrolyzability can be used as sustained release and prodrug formulations.
- the antiviral activity may also be referred to as inhibiting viral activity, specifically, inhibiting virus from performing cell fusion and/or inhibiting virus invading cells and/or inhibiting viral replication.
- inhibiting viral activity specifically, inhibiting virus from performing cell fusion and/or inhibiting virus invading cells and/or inhibiting viral replication.
- the lipopeptide or polypeptide, derivative thereof, or pharmaceutically acceptable salt thereof provided by the present invention, the polymer, the composition or the pharmaceutical compound can be used for HIV (HIV-1 and/or HIV- 2) and/or treatment of SIV infection, including various stages of HIV and/or SIV infection, such as AIDS, symptomatic and disease-free Stage.
- the lipopeptide or polypeptide, derivative thereof, or pharmaceutically acceptable salt thereof provided by the present invention, the polymer, the composition or the pharmaceutical compound can also be used for HIV (HIV-1 and/or HIV) -2) and / or prevention of SIV infection, including pre-exposure or suspicious exposure, such as blood transfusion, organ transplantation, body fluid exchange, bite, accidental acupuncture or exposure to the patient's blood during surgery.
- the lipopeptide or polypeptide of the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof, the multimer, the composition or the pharmaceutical compound can be directly administered to a patient as a medicament, or
- the appropriate carrier or excipient is mixed and administered to the patient for the purpose of treating and/or preventing HIV infection.
- the carrier materials herein include, but are not limited to, water-soluble carrier materials (such as polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (such as ethyl cellulose, cholesterol stearate, etc.), enteric carriers. Materials (such as cellulose acetate phthalate and carboxymethylcellulose, etc.). Among them, preferred are water-soluble carrier materials.
- the suppository may be a vaginal suppository, a vaginal ring, or an ointment, cream or gel suitable for vaginal application. It may be a general preparation, a sustained release preparation, a controlled release preparation, and various microparticle delivery systems. In order to form a unit dosage form into tablets, various carriers well known in the art can be widely used.
- carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
- diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
- wetting agent and binder such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, gum arabic, gelatin paste, sodium carboxymethyl cellulose , shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone, etc.
- disintegrating agents such as dried starch, alginates, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxyethylene, Sorbitol fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.
- disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.
- absorption promotion Agents such as quaternary ammonium salts, sodium lauryl sulfate, and the like
- lubricants such as talc, silica,
- Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
- various carriers well known in the art can be widely used.
- the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin , ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, and the like.
- a unit dosage form as a suppository various carriers well known in the art can be widely used.
- the carrier are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like.
- an injectable preparation such as a solution, an emulsion, a lyophilized powder, and a suspension
- all diluents conventionally used in the art for example, water, ethanol, polyethylene glycol, 1, may be used.
- an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional solubilizer, a buffer, a pH adjuster or the like may be added.
- coloring agents, preservatives, perfumes, flavoring agents, sweeteners or other materials may also be added to the pharmaceutical preparations as needed.
- the above dosage forms can be administered by injection, including subcutaneous injection, intravenous injection, intramuscular injection and intraperitoneal injection, intracisterial injection or infusion, etc.; intraluminal administration, such as transrectal, vaginal and sublingual; respiratory administration, such as nasal passage Mucosal administration.
- the above administration route is preferably administered by injection, and the preferred route of injection is subcutaneous injection.
- the lipopeptide or polypeptide of the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof, the multidrug, the composition or the pharmaceutical compound to be administered depends on a number of factors, such as prevention or treatment of the disease The nature and severity of the patient, the gender, age, weight and individual response of the patient, the specific active ingredient used, the route of administration and the number of doses administered.
- the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms.
- the specific therapeutically effective dose level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active ingredient employed; the particular composition employed. The age, weight, general health, sex and diet of the patient; the time of administration, the route of administration and the rate of excretion of the particular active ingredient employed; the duration of treatment; in combination with or in combination with the particular active ingredient employed Drugs; and similar factors well known in the medical field. For example, it is the practice in the art that the dosage of the active ingredient be started from a level lower than that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved.
- the lipopeptide of the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof, the multimer, the composition or the pharmaceutical compound may be administered to a mammal, particularly a human, at a dose of 0.001.
- - 1000 mg / kg body weight / day for example between 0.01 - 100 mg / kg body weight / day, and for example between 0.1 - 10 mg / kg body weight / day.
- the frequency of administration may be 1-2 times a day, 1 time / 2 days, 1 time / 3 days, 1 time / 4 days, 1 time / 5 days, 1 time / 6 days or 1 time / 7 days, preferably It is 1 time / 1-2 days or 1-2 times / week.
- the lipopeptide or polypeptide of the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof, the multimer, the composition or the pharmaceutical compound can be directly used for the treatment and prevention of HIV-infected persons, or Used in combination with one or more anti-HIV drugs, they can be used simultaneously or at intervals to achieve an overall therapeutic effect.
- anti-HIV drugs include, but are not limited to, reverse transcriptase inhibitors, protease inhibitors, invasion inhibitors, integration inhibitors, and maturation inhibitors.
- the above reverse transcriptase inhibitor may be a nucleoside reverse transcriptase inhibitor such as zidovudine (AZT), lamivudine (3TC), didanosine (ddI), zalcitabine (ddC).
- stavudine (d4T), tenofovir (TDF), abacavir (ABC), emtricitabine (FTC), may also be non-nucleoside reverse transcriptase inhibitors, such as nevirapine (NVP) One or more of efavirenz (EFV), delavirdine (DLV), etravirine (ETR), etc.; the above protease inhibitor may be saquinavir (SQV-HGC), depression Navita (IDV), ritonavir (RTV), erinanavir (APV), liqueur (LPV/RTV), nelfinavir (NFV), vesanavir calcium (FPV), Reyataz ( One or more of ATV) and Prezista; the above-mentioned integration inhibitor may be one or more of Raltegravir, Dolutegravir and Elvitegravi; the above-mentioned invasion inhibitors may be Maraviroc, T-20,
- the design strategy of the lipopeptide of the present invention is to replace the 8 amino acid TRM sequence of the C-terminus of the T-20 polypeptide with a lipophilic compound such as long-chain fatty acid palmitic acid and stearic acid, cholesterol, dihydrosphingosine or vitamin E.
- a lipophilic compound such as long-chain fatty acid palmitic acid and stearic acid, cholesterol, dihydrosphingosine or vitamin E.
- a set of lipopeptides having a polypeptide sequence of less than 28 amino acids, ie, 24 to 27 amino acids, is generated and determined to correspond to the T-20
- the sequence of amino acids 5 to 25 corresponding to amino acids 131 to 151 of the HXB2 strain gp41 is the core sequence of the potent HIV inhibitor of the present invention (i.e., the P5 sequence).
- the polypeptide of the present invention has outstanding sequence structural features, chemically modified with a lipophilic compound attached to the C-terminus, has significantly enhanced target sequence binding ability and extremely strong HIV (HIV-1 and/or HIV-2) and/or SIV inhibitory activity is highly potent against HIV envelope protein (Env)-mediated cell fusion, viral entry and infection.
- HIV-1 and/or HIV-2 extremely strong HIV
- Env HIV envelope protein
- the anti-HIV activity of the lipopeptide of the present invention is higher than several thousand times or even tens of thousands of times, and is also significantly higher than that of the anti-HIV lipopeptides C34-Chol, LP-11 and LP-19. Lipopeptides; at the same time, they have many advantages such as stable long-acting, easy synthesis, and low cost.
- the lipopeptides of the invention have various subtypes of HIV-1 (such as A, B, C, A/E and B/C subtypes), T-20 resistant strains, HIV-2 strains and simian immunodeficiency virus (SIV) has a strong inhibitory activity.
- HIV-1 such as A, B, C, A/E and B/C subtypes
- T-20 resistant strains such as A, B, C, A/E and B/C subtypes
- HIV-2 strains simian immunodeficiency virus (SIV) has a strong inhibitory activity.
- SIV simian immunodeficiency virus
- Figure 1 shows the structure and function of the HIV fusion protein gp41 and a polypeptide membrane fusion inhibitor.
- FP refers to a gp41 fusion peptide
- NHR refers to an N-terminal repeat
- CHR refers to a C-terminal repeat
- TM refers to a transmembrane region.
- the arrow refers to the "M-T hook” position or the tryptophan rich motif (TRM) position.
- TRM tryptophan rich motif
- the amino terminus of all polypeptides or lipopeptides in the figure is acetylated (Ac-) and carboxy-terminally amidated (-NH2).
- Figure 2 shows the sequence structure of an HIV membrane fusion inhibitor and its antiviral activity.
- the T-20 TRM sequence is shown in italics, and the MT hook and PBD sequences are underlined.
- AHX refers to 6-aminocaproic acid
- AEEA refers to 8-amino-3,6-dioxaoctanoic acid
- PEG4, PEG8 and PEG12 refers to polyethylene glycol of different length polymerization, wherein PEG4 is Fmoc-NH - PEG4-CH 2 CH 2 COOH, PEG 8 is Fmoc-NH-PEG8-CH 2 CH 2 COOH, and PEG 12 is Fmoc-NH-PEG12-CH 2 CH 2 COOH.
- the NL4-3 pseudovirus is a gp41D36G mutant. The experiment was repeated three times and the average value 50 is calculated IC. Some of the potent lipopeptides are marked in bold.
- HXB2 cell fusion represents the result of HIV-1 mediated cell fusion inhibition assay
- NL4-3 entry indicates HIV-1 pseudovirus mediated cell entry inhibition assay results
- JRCSF replication indicates HIV-1 replication inhibition assay results.
- Figure 3 shows the inhibitory effect of HIV membrane fusion inhibitors on various subtypes of HIV-1 strain. The experiment was repeated three times and the average value 50 is calculated IC.
- Figure 4 shows the inhibitory effect of HIV membrane fusion inhibitors on T-20 resistant mutant strains and HIV-2 and SIV strains.
- the T-20 resistant mutant strain and the SIV strain are pseudoviruses, and HIV-2 is an infectious ROD strain.
- the experiment was repeated three times and the average value 50 is calculated IC.
- Figure 5 is the antiviral activity of HIV membrane fusion inhibitor injected into cynomolgus serum.
- M248, M249, M250, M252, M253 and M254 are the monkey numbers.
- A is T-20 injected macaque serum; in Figure 5, B is LP-19 injection of macaque serum; in Figure 5, C is LP-51 injection of macaque serum; in Figure 5, D is LP-52 injection of macaque serum;
- Figure 5 Medium E is the injection of cynomolgus serum into LP-80; in Figure 5, F is a comparison of serum antiviral activity.
- Figure 6 is a circular dichroism analysis of the interaction of HIV membrane fusion inhibitors with NHR.
- the sequence structure of the inhibitor is the same as that of Figure 2 of the present invention, wherein the potent lipopeptides of the present invention are labeled in bold.
- the inhibitor and N39 polypeptide were dissolved in phosphate buffer (PBS) at pH 7.2 to a final concentration of 10 [mu]M.
- PBS phosphate buffer
- Figure 7 is a circular dichroism analysis of the interaction of T-20 with a representative lipopeptide and NHR.
- A is a CD scan result; in Fig. 7, B is a temperature scan result.
- Figure 8 shows the secondary structure analysis of T-20 and representative lipopeptides themselves.
- Figure 8A and Figure 8B show the CD scan and temperature scan results of the inhibitor at 10 ⁇ ; respectively;
- Figure 8C and Figure 8D show the CD scan and temperature scan results of the inhibitor at 20 ⁇ M.
- E in 8 and F in Figure 8 are CD scan and temperature scan results of the inhibitor at 40 ⁇ M, respectively.
- Figure 9 is the pharmacokinetics of LP-80 in rats.
- A is the serum drug concentration detection of LP-80 after administration; in Fig. 9, B is the metabolic kinetic parameter of LP-80.
- Figure 10 shows the therapeutic effect of LP-80 in a monkey infection model.
- X 1 -X 28 represents a polypeptide sequence corresponding to amino acids 127 to 154 of the HIV-1 strain HXB2gp41 sequence (YTSLIHSLIEESQNQQEKNEQELLELDK), wherein X 1 corresponds to 127 Y, X 2 corresponds to 128 bits of T, X 3 corresponds to 129 bits of S, ...
- X 28 corresponds to 154 bits of K.
- the novel sequence obtained by a large number of mutations is a component of potent inhibitors.
- Representative peptides are LP-50, LP-51, LP-52, LP-80, LP-83, LP-84, LP-85, LP. -86 and LP-87, etc.
- X 1 -X 28 has the same meaning as (Formula I), Z is a lipophilic compound, Ac is an acetyl group, and NH 2 is an amino group.
- the lipopeptide or polypeptide shown in Fig. 2 was synthesized, and the amino terminus of each lipopeptide or polypeptide was linked to an acetyl group as an amino terminal protecting group, and the carboxy terminus was linked to an amino group as a carboxy terminal protecting group.
- palmitic acid (palmitic acid modified lipopeptide: LP-40, LP-41, LP-42, LP-43, LP-44, LP-45, LP-50, LP-51, LP-52, LP- 53, LP-54, LP-55, LP-56, LP-57, LP-58, LP-59, LP-60, LP-61, LP-62, LP-63, LP-64, LP-65, LP-66, LP-67, LP-68, LP-69, LP-70, LP-71, LP-72, LP-73, LP-74, LP-75, LP-11, LP-19, C34- C16), stearic acid (stearic acid modified lipopeptide: LP-80, LP-88, LP-89, LP-90, LP-91, LP-92), dihydrosphingosine (dihydrosphingosine)
- the chemical reagents used such as Rink Amide MBHA resin, various Fmoc amino acids, palmitoyl chloride, Stearoyl chloride, Vitamin E succinate, dihydrosphingosine (D- erythro-Dihydrosphingosine), N,N'-Disuccinimidyl carbonate, N,N'-diisopropylcarbodiimide (DIC), 1-hydroxybenzo Triazole (HOBt), trifluoroacetic acid (TFA), ethanedithiol (EDT), ninhydrin, hexahydropyridine (PIPE), phenol, N,N'-dimethylformamide (DMF), chromatographically pure Acetonitrile and the like are purchased from major chemical reagent suppliers and are not further purified prior to use.
- Rink Amide MBHA resin various Fmoc amino acids
- palmitoyl chloride Stearoyl chloride
- Vitamin E succinate dihydrosphingos
- the N-terminal Fmoc protecting group was again removed with 25% hexahydropyridine/DMF (volume ratio) to make the N-terminus a free amino group.
- the individual amino acid residues are sequentially linked in this order.
- the starting materials and amounts used correspond to Fmoc-Glu(OtBu)-OH (3 eq), Fmoc-Leu-OH (3 eq), Fmoc-Lys(Boc)-OH (3 eq), Fmoc-Lys(Boc)-OH (3 eq, respectively).
- N-terminal acetylation end-capping (3 times equivalent of Ac 2 O, 6-fold equivalent of diisopropylethylamine) was carried out to complete the synthesis of the main chain.
- the reaction time of each step was as follows: deprotection for 8 minutes, twice; grafting of ordinary amino acids for 60 minutes.
- the resin is washed with DMF six times or more, and the reaction is controlled by Kaiser Test. If the condensation reaction of an amino acid is incomplete, the condensation is repeated once until the desired target peptide is obtained.
- the resin was treated with 2% hydrazine hydrate/DMF solution (volume ratio) to remove the side chain Dde protecting group of the C-terminal Lys, and then 3 times equivalent of palmitoyl chloride or stearoyl chloride with 6 times equivalent of diisopropyl After a mixture of ethylamine, amidation reaction (60 minutes) with the side chain amino group of the C-terminal Lys, thereby achieving palmitoylation modification (LP-52) or stearoyl modification (LP-80) on the C-terminal Lys residue. .
- the modification of the polypeptide by dihydrosphingosine (LP-84, LP-87) is carried out by first adding N,N'-disuccinimidyl carbonate after removing the side chain Dde protecting group of Lys, and then adding two Hydrosphingosine, the reaction was carried out for 48 hours; the modification of the polypeptide by vitamin E (LP-85) was carried out by amidation of the deprotected Lys side chain amino group directly with vitamin E succinate.
- Purification and characterization of lipopeptides Purification of crude lipopeptides was performed on a reversed-phase high performance liquid chromatograph using a 10 ⁇ m ( ⁇ m) particle size reversed-phase C18 or C4 silica gel with a pore size of 100 angstroms. The column size is 100 x 250 mm. Chromatographic operating conditions: linear gradient elution, the eluent consists of mobile phase A and mobile phase B.
- the mobile phase A was an aqueous solution containing 20 mM ammonium acetate (pH 4.5), 5% acetonitrile), and the mobile phase B was 80% (volume percent concentration) in an aqueous solution of acetonitrile at a flow rate of 250 ml per minute and an ultraviolet detection wavelength of 220 nm. After lyophilization, the pure polypeptide was obtained in a fluffy state. The chemical structure was characterized by MALDI-TOF mass spectrometry, and the purity was determined by analytical high performance liquid chromatography (C18-10 ⁇ 250 mm, flow rate: 1 ml per minute). Out. The results showed that the purity of the synthesized lipopeptides was greater than 95%.
- the method for synthesizing cholesterol-modified lipopeptides is carried out with reference to Reference 18 and Reference 20 in the background art.
- the cholesteryl bromoacetate was synthesized according to the technical route described in the literature, and then grafted to the polypeptide by a highly chemically selective thioether reaction through the thiol group of the C-terminal cysteine (Cys) side chain and the cholesteryl bromoacetate.
- Each of the lipopeptides and polypeptides in Fig. 2 was used as a test substance, and the anti-viral activity was identified by a cell fusion inhibition test, a pseudovirus inhibition test, and a virus replication inhibition test with reference to Background Art Reference 18.
- the specific method is as follows:
- HIV-1 mediated cell fusion inhibition assay effector cell HL2/3 cells and target cell TZM-bl cells are provided by the National Institutes of Health (NIH) AIDS Reagents and References project (catalog numbers 1294 and 8129, respectively) . Both cells were adherent cells cultured in DMEM cell culture medium containing ampic/streptomycin double antibody and 10% fetal bovine serum (FBS). TZM-bl was first added to a 96-well cell culture plate (1 ⁇ 10 4 cells/well), and cultured overnight at 37 ° C under 5% CO 2 .
- NASH National Institutes of Health
- FBS fetal bovine serum
- test substance was diluted 3 times with DMEM cell culture medium and mixed with HL2/3 effector cells (3 ⁇ 10 4 cells/well), then added to TZM-bl target cells, and cultured for 6 hours to make it sufficient. Fusion. Luciferase activity (relative fluorescence units, RLU) was then determined using Promega's luciferase reporter gene kit according to the instructions. The inhibition rate of each concentration sample was calculated, and the half effective inhibitor amount (IC 50 value) was calculated using GraphPad Prism Software 2.01 software.
- HIV-1 pseudovirus-mediated cell entry inhibition assay basic steps include (1) preparation of HIV-1 pseudovirus: plasmid expressing HIV-1 strain NL4-3 envelope protein (Env) using a cell transfection reagent (Recombinant expression plasmid obtained by inserting the envelope protein (ENV) encoding gene of the D36G mutant of the HIV-1 strain NL4-3 of the HIV-1 strain NL4-3 of Table 2 into the vector pcDNA3.1(-)) and HIV-1
- the backbone plasmid pSG3 ⁇ env (provided by the NIH AIDS Reagents and References Project, catalog number 11051) was co-transfected into 293T cells, incubated at 37 ° C in a 5% CO 2 cell incubator for 6 hours, then changed for 48 hours.
- TZM-bl cells were trypsinized and counted, and the cells were diluted to 1 ⁇ 10 5 /ml with DMEM complete medium, and 100 ⁇ l of cells (containing 15 ⁇ g/ml DEAE-dextran) were added per well at 37 ° C. Incubate for 48 hours with 5% CO 2 . The 96-well plate was then removed from the cell culture incubator, the supernatant was aspirated from the well, and 30 ⁇ l of the cell lysate was added, and after 10 minutes, 100 ⁇ l of luciferase assay reagent was added.
- HIV-1 replication inhibition assay The molecular cloning plasmid pYK-JRCSF encoding the HIV-1 strain JRCSF was provided by the NIH AIDS Reagents and References project (catalog number 2708). pYK-JRCSF was transfected into 293T cells by transfection reagent, and incubated at 37 ° C in a 5% CO 2 cell incubator for 6 hours, and then changed for 48 hours. The cell culture supernatant containing JRCSF virus particles was gently collected by a pipette, and the supernatant was filtered through a 0.45-micron filter.
- test substance was dissolved in DMSO and diluted 3 times with cell culture medium, and then placed in a 96-well cell culture plate in a final volume of 50 ⁇ l, in which 50 ⁇ l of DMEM medium was used instead.
- the analyte was used as a negative control.
- T-20-based lipopeptide (LP-40) has strong antiviral activity
- the present invention has a unique approach to designing a polypeptide drug T-20 that does not contain the NHR pocket binding region (PBD).
- PBD NHR pocket binding region
- the inhibitory activity of the inhibitor on HIV-1 mediated cell fusion, pseudovirus entry and viral replication was evaluated using three antiviral assays ( Figure 2).
- Figure 2 First, by directly deleting the 8 amino acids at the C-terminus of T-20, a T20-TRM containing no TRM motif was synthesized and found to have no significant antiviral activity at a high concentration of 2000 nM, reflecting TRM to T. The importance of the -20 function.
- lipopeptide LP-40 was synthesized by substituting palmitic acid (C16) for T-20.
- the antiviral activity of LP-40 was significantly higher than that of T-20, and its inhibitory activity against HXB2-mediated cell fusion, NL4-3 pseudovirus entry and JRCSF replication was about 59 for T-20, respectively. Times, 21 times and 18 times. It is indicated that the replacement of TRM with a lipophilic compound can significantly improve the antiviral activity of the polypeptide and can be an important strategy for the design of HIV membrane fusion inhibitors.
- the present inventors have previously designed a set of highly active anti-HIV lipopeptides based on modification of short peptides (HP23 and 2P23) targeting the NHR pocket, and found that the lipid compounds C16, cholesterol and dihydrosphingosine are directly linked to the polypeptide.
- the C-terminus will result in a significant decrease in the anti-HIV activity of the polypeptide, while the introduction of a tether between the polypeptide sequence and the modification significantly increases the activity of the polypeptide, and its antiviral activity increases as the length of the tether increases (see Background) Documents 18 and 30).
- the present invention further attempts to promote the helical structure and antiviral activity of LP-40 by introducing ion pairs.
- the present technology introduces EE**KK amino acid residues that contribute to the formation of a "salt bridge structure" by mutating amino acids at the non-NHR binding face of the polypeptide sequence (ie, positions b, c and f, g).
- the 11 amino acids in the LP-40 polypeptide sequence were replaced by E or K, thereby introducing three pairs of EE**KK motifs at the i and i+4 positions, and the synthesized lipopeptide was named LP-50.
- the inhibitory activity of LP-50 was tested by three antiviral experiments, and the results were enormous!
- LP-50 2 cell fusion inhibition, IC 50 values and false viral replication of a virus respectively, 21pM, 7pM and something like 1:23 PM, respectively, which is 1151 times the activity of T-20, 1345-fold and 226-fold, respectively, 20-40, 63 and 12 times the activity of LP-40. Therefore, the introduction of ion pairs may increase the stability of the helical structure of the lipopeptide by forming a "salt bridge structure", thereby greatly increasing the antiviral activity of the lipopeptide. This was confirmed by subsequent circular dichroism detection (see the experimental results of Example 7 below).
- the present invention further attempts to synthesize a lipopeptide by introducing a corresponding amino acid residue derived from HIV-2 and/or SIV at the NHR binding surface of the polypeptide, i.e., at the a and d positions or adjacent positions.
- LP-51 and LP-52 The mutated amino acids are shown in Figure 1.
- the polypeptide sequences of LP-51 and LP-52 retain only 10 gp41 original sequences and are less than 28% identical to the T-20 sequences.
- the polypeptide sequence of the above potent HIV inhibitor is 28 amino acids in length.
- the present invention first synthesized a C-terminally truncated lipopeptide LP-53 based on LP-40, and synthesized a C-terminally truncated lipid based on LP-50.
- the peptide LP-54 was found to have a marked decrease in its antiviral ability (Fig. 2).
- LP-55 and LP-56 were synthesized using LP-52 as a template, wherein LP-56 replaced the three amino acid residues (LEK) at the C-terminus with an AEEA linker.
- a set of N-terminally truncated lipopeptides (LP-60 to LP-68) was further synthesized.
- Antiviral experiments revealed that the activity of two lipopeptides based on LP-50 truncation, LP-60 and LP-61, also decreased significantly; but surprisingly, lipopeptide LP based on LP-52 truncation -62, the activity of LP-63 and LP-65 did not change much, especially the LP-65 with only 24 amino acids, the activity of which was equivalent to that of LP-52, and the activity of LP-64 containing 25 amino acids decreased significantly. In particular, inhibition of cell fusion.
- LP-66 N-terminal truncation results in a significant decrease in lipopeptide activity (LP-66, LP-67) or even loss of antiviral capacity (LP-68).
- LP-69 was synthesized by truncating C-terminal LEK on the basis of LP-65, and although its antiviral activity was significantly decreased, it still had potent viral inhibitory activity relative to a lipopeptide having only 21 amino acids.
- the antiviral activity of LP-57 was decreased by about 15 to 150 times than that of LP-55, indicating the importance of three amino acids of LKK at the end of LP-55, which is not suitable for further truncation; the antiviral activity ratio of LP-66 LP-65 decreased by about 54 to 158 times, indicating that the first amino acid (Ile) of LP-65 is critical and should not be further truncated.
- LP-65 differs from LP-61 by two amino acid peptides (in its eighth position) S and A), respectively, but their activity differs by 5 to 9 times, indicating that the substitution from S to A is very important for the potent lipopeptides of the present invention.
- the present invention further designed to synthesize a set of N-terminally extended lipopeptides (LP-70 to LP-75 in Fig. 2), wherein LP-74 Containing a pocket binding region sequence (PBD), LP-75 contains both PBD and MT hook forming sequences.
- LP-70 to LP-75 contains both PBD and MT hook forming sequences.
- PBD pocket binding region sequence
- LP-75 contains both PBD and MT hook forming sequences.
- the present invention continues to design and synthesize lipopeptides modified with different lipophilic compounds, including fatty acids of different chain lengths, cholesterol, dihydrosphingosine, and vitamin E.
- lipophilic compounds including fatty acids of different chain lengths, cholesterol, dihydrosphingosine, and vitamin E.
- the results of antiviral experiments are shown in Figure 2.
- the inhibitory activity of stearic acid (C18) modified LP-80 on NL4-3 entry and JRCSF replication is even greater than that of C16 modified LP-52, but twelve (alkane) Acid (C12) modified LP-81 and octanoic acid (C8) modified LP-82 activity decreased significantly.
- lipopeptides have the same polypeptide sequence, but the fatty acid chain length determines the inhibitory activity of the lipopeptide. Therefore, modification of the polypeptide sequence by long chain fatty acids having a chain length of C18 and C16 is more suitable.
- Antiviral experiments also showed that cholesterol (LP-83, LP-86), dihydrosphingosine (LP-84, LP-87), and vitamin E (LP-85) modified lipopeptides also have potent antiviral activity. effect.
- the C18-modified N-terminal truncated lipopeptides LP-88, LP-89 and LP-90 also have potent antiviral activity.
- LP-89 with 25 amino acids is less active than LP-90 with 24 amino acids.
- This phenomenon is similar to that of C16-modified LP-64 and LP-65, so the N-terminal lysine (K) pair A potent short lipopeptide based on the core sequence is not necessary.
- K N-terminal lysine
- control lipopeptides including LP-11, LP-19, C34-Chol and C34-C16 (see Figure 2). It can be seen that the control lipopeptide can effectively inhibit HIV-1 mediated cell fusion, entry and replication, and its activity is significantly higher than T-20, but significantly lower than some of the potent lipopeptides of the present invention, such as C16 modified LP- 52, LP-55 and LP-65 and C18 modified LP-80, LP-90 and LP-91 and the like.
- AIDS is mainly caused by HIV-1, and a variety of subtypes, including AD, FH, J, and K subtypes, are produced due to viral variations.
- subtypes A, B and C are the main viruses causing the world AIDS epidemic, while in China, B/C and A/E recombinant viruses are the main ones.
- the present invention produced a group of 35 HIV-1 pseudoviruses, including internationally representative strains and currently prevalent HIV-1 strains in China, including 3 strains of subtype A.
- this example measures T-20, LP-40, LP-50, LP-51, LP-52, LP-55, LP-65, LP-80, LP-85, LP-90, and A total of 12 inhibitors of the lipopeptides LP-19 and C34-Chol had inhibitory activities against the above 35 pseudoviruses.
- the results are shown in Figure 3.
- T-20, LP-40, LP-50, LP-51, LP-52, LP-55, LP-65, LP-80, LP-85 and LP-90 inhibit HIV -1 pseudovirus average IC 50 values were 41410pM, 6369pM, 41pM, 33pM, 16pM, 34pM, 52pM, 6pM, 44pM and 14pM. It can be seen that the inhibitory activity of the newly synthesized lipopeptide of the present invention on different subtypes of HIV-1 is significantly higher than that of T-20, which is 7 times, 1010 times, 1255 times, 2588 times, 1218 times, 796 times, and 6902 of T-20. Times, 941 times and 2958 times.
- LP-80 showed the strongest virus inhibitory activity, and the average IC 50 value for 35 pseudoviruses was 6 pM, and the IC 50 value of many strains was even lower than 1 pM.
- Control LP-19 and C34-Chol inhibited the average IC 50 values of various HIV-1 pseudoviruses at 439 pM and 66 pM, respectively, which were lower than LP-50, LP-51, LP-55, LP-65 and LP-85. More significantly lower than LP-52, LP-80 and LP-90.
- IC 50 values of C18 modified lipopeptides disclosed the antiviral activity of C16 is superior to modified lipopeptides.
- T-20 is currently the only HIV membrane fusion inhibitor approved for clinical use, but its activity is not only lower than that of a new generation of peptides, but also easily induces drug-resistant mutations, often leading to failure of clinical treatment.
- the NL4-3 pseudovirus carrying a common T-20 resistance mutation site of NHR was prepared in this example (see Figure 4, the name of the strain in Figure 4). The subscript is the name of the strain in Table 2 of Background Art Reference 14.
- the plasmids, pseudovirus preparation and antiviral experimental methods used are described in the literature published by the present inventors (Backgrounds References 11, 12, 14 and 18) and the methods in the above Examples 2 and 3.
- the inhibitory activity of the lipopeptide LP-50 designed to form an ion-to-salt bridge structure on the T-resistant strain is further increased by hundreds or even thousands of times on the basis of LP-40;
- the ability of the HIV-2/SIV sequence-modified lipopeptides LP-51, LP-52, LP-80 and LP-85 to overcome resistant strains was greatly improved, which was thousands to tens of thousands of times better than LP-40.
- lipopeptides of potent inhibitors of the invention include LP-50, LP-51, LP-52, LP-55, LP-65, LP-80, LP-85 and LP-90
- the inhibitory capacity of most T-20 resistant strains also decreased significantly, but they still have strong antiviral activity, especially the activities of LP-52 and LP-80 are still rare in the field.
- This example also reveals from one aspect that the NHR sequence of gp41 is still the main target of the potent lipopeptides of the present invention.
- the preparation of the infectious ROD was the same as that of the infectious JRCSF in the above 2.1, and the preparation of the SIV pbj and SIV 239 pseudoviruses was the same as in the above Examples 2 and 3.
- the inhibitory activity of T-20 against HIV-2 and SIV strains was extremely weak, while the activity of LP-40 was only slightly improved.
- the potent lipopeptides tested include LP-50, LP-51, LP-52, LP-65, LP-80, LP-85 and LP-90, which are extremely active for both HIV-2 and SIV. Strong inhibitory activity.
- the potent lipopeptides of the present invention are highly effective not only for various subtypes of HIV-1, but also highly effective against T-20 resistant strains, HIV-2 and SIV strains, and have extremely potent and broad-spectrum resistance.
- Virus effect By comparing LP-52, LP-55 and LP-65, it was found that the truncation of the N-terminal amino acid WEQK had little effect on the inhibition of HIV-2 and SIV activities, while the truncation of the C-terminal amino acid LEK significantly affected its activity.
- the present embodiment focuses on analyzing the antiviral activity of lipopeptides LP-51, LP-52 and LP-80 in vivo, and the method is based on the literature published by the inventor (background) Technical references 18 and 30), by injecting inhibitors into monkeys by subcutaneous route, and then taking blood samples at different time points and measuring their antiviral activity in vitro, not only can the activity of the inhibitor in vivo be reflected, but also indirectly Its stability in the body.
- this example included two controls, T-20 and LP-19, for comparative analysis.
- the specific method is as follows: 6 experimental macaques (rhesus monkeys) were selected, half male and half female, aged 3-4 years old, weighing 3.4-4.7 kg. 3 mg/kg body weight of T-20, LP-19, LP-51, LP-52 or LP-80 (all dissolved in sterile distilled water), before injection (0 hours), 1, 2 after injection 0.4 ml venous blood samples were taken at 4, 6, 8, 12, 18, 24, 36, 48, 60, and 72 hours.
- LP-80 increased the blood collection points at 96, 120, 144 and 168 hours after injection.
- the serum was separated according to a conventional method. The injection interval of each inhibitor was more than 2 weeks to ensure that there was no residue of the last analyte.
- the activity of the serum anti-HIV-1 strain NL4-3 (NL4-3 D36G ) was measured according to the pseudovirus-based experimental method in the above examples. The serum was diluted 3 times. The experimental results are shown in Fig. 5.
- the subcutaneous injection of T-20 showed a peak of inhibition at 2 and 4 hours, and the maximum dilutions of serum inhibiting 50% of NL4-3 infectivity were 45-fold and 46-fold, respectively (A in Fig.
- the peak of serum inhibition of potent lipopeptides can be 11678 to 15235 times the peak of T-20 serum inhibition, which can be 100 to 130 times the peak of LP-19 serum inhibition (calculated as the highest value).
- the more exciting result is the long-acting effect of three lipopeptides, LP-51, LP-52 and LP-80, which have higher serum inhibition peaks even at 72 hours (3 days) after injection, respectively. It is 1122 times, 182 times and 16157 times.
- the lipopeptide of the present invention is not only potent but also long-lasting.
- NHR target sequences including the secondary structure ( ⁇ -helix) and helix stability of the complexes formed. Sex (Tm value).
- the circular dichroic instrument was Nissan Jasco-815, and the experimental method was referred to the paper published by the inventors (Background Technical References 18 and 30).
- the target sequence polypeptide derived from NHR is N39 (see Figure 1), and its sequence is Ac-STMGAASMTLTVQARQLLSGIVQQQQNNLLRAIEAQQHLL-NH 2 , corresponding to the binding target site of T-20 on NHR.
- N39 and the inhibitor were separately dissolved in phosphate buffered saline (PBS) to prepare a PBS solution (pH 7.2) at a concentration of 20 ⁇ M.
- PBS phosphate buffered saline
- N39 and inhibitor were mixed in a 1:1 volume ratio (final concentration was 10 ⁇ M, respectively), and the mixed sample was fully reacted at 37 ° C for 30 minutes, and then the spiral content of the complex was measured on a circular dichroic chromatograph.
- Tm values The instrument scans a wavelength range of 195-260 nm with a wavelength interval of 1 nm and scans three times for averaging. The interaction between the polypeptides and the helix content were determined based on the CD signal.
- the sample for CD signal measurement is transferred to the temperature scanning sample cell, the CD instrument program is set to temperature scanning, the detection wavelength is 220 nm, the scanning range is 20-98 ° C, and the program scan is performed to obtain a CD signal with temperature curve, according to which Calculate the Tm value.
- the stability of the helical structure formed by the inhibitor and N39 was judged based on the Tm value.
- T-20 can interact with N39.
- the formed complex has a helix content of 48.6% and a Tm value of 43.9 °C.
- Tm value could not be determined, again demonstrating the importance of TRM for T-20.
- the interaction between lipopeptide LP-40 and N39 was significantly enhanced, and the complex had a helix content of 57.7% and a Tm value of 51.3 °C.
- the addition of the tether resulted in a decrease in the helix content, but most had little effect on the Tm value, and the only Tm value was significantly reduced to the LP-45 containing the longest tether (PEG12).
- the introduction of the EE**KK ion pair greatly enhanced the binding stability of the lipopeptide, as shown by the increase in the Tm value of the LP-50/N39 complex to 63.3 °C; and the HIV-2/SIV amino acid
- the addition can further enhance the binding ability of lipopeptides, and the Tm values of the LP-51/N39 and LP-52/N39 complexes are 72 ° C and 79.1 ° C, respectively, which are significantly higher than the Tm values of the T-20 and LP-40 complexes.
- LP-52/N39 also has the highest helix content (63.8%).
- the C-terminal or N-terminal truncation of lipopeptides can affect their binding ability to varying degrees, and some of them show a decrease in Tm value, and some exhibit a decrease in both the helix and the Tm value.
- the Tm value of the C-terminally truncated lipopeptide decreased significantly, indicating the importance of the three amino acids (LEK) at the C-terminus in the binding of lipopeptides to NHR.
- Tm values of LP-55 and LP-56 with potent antiviral activity also decreased significantly (from 79.1 to 63.1 °C), but compared to LP-53, LP-54, LP-57, LP-58. It is much higher than LP-59.
- LP-58 and LP-59 have been unable to determine the Tm value due to the lower helix content.
- the Tm value of the N-terminal truncated lipopeptide (from LP-60 to LP-68) also decreased significantly.
- N-terminal truncation based on LP-52 does affect fat The binding stability of the peptide (LP-62 to LP-65), but the Tm value of the complex is still greater than 70 ° C, indicating that it still has a strong binding ability, which may be the reason for their strong antiviral ability. . It is worth noting that the lipopeptide LP-65, which contains only 24 amino acid sequences, also has a higher helix (63%) and Tm value (72.1 °C), while further truncation severely affects its binding capacity, such as LP- 66, LP-67 and LP-68, which are consistent with their antiviral activity.
- Tm value the effect of removing the 3 amino acids (LEK) at the C-terminus on the binding stability (Tm value) was more significant than the removal of the N-terminal 1-4 amino acids (WEQK), indicating that the C-terminus of the lipopeptide is at the target.
- Point binding plays a more important role; while the C-terminal and N-terminal removal, the core sequence lipopeptide LP-69 binding stability is significantly reduced, the Tm value is 51 ° C, 28.1 ° C lower than LP-52.
- N-terminally extended lipopeptide has an increased Tm value, such as the performance of LP-70 to LP-75, which is inconsistent with its decreased antiviral activity.
- LP-74 and LP-75 contain the NHR pocket binding region (PBD) and the M-T hook motif, which makes it impossible to match N39 perfectly.
- LP-80-based N-terminal truncated lipopeptides (LP-88, LP-89, LP-90) was also strong, with Tm values of 76.5 ° C, 70 ° C and 71.1 ° C, respectively;
- This example reveals the correlation between the sequence structure, binding stability and antiviral activity of the inhibitor by a large number of experimental results, and provides important information for understanding the mechanism of action of the potent lipopeptide of the present invention. Although the binding ability of the inhibitor is sometimes insufficiently consistent with its antiviral activity, in general, the potent lipopeptides of the present invention have extremely high Tm values. This example also discloses that the antiviral activity of a lipopeptide is dependent on the polypeptide sequence and also on the nature of the lipophilic compound.
- Example 8 Analysis of the secondary structure of a potent HIV membrane fusion inhibitor
- the present invention analyzed the secondary structure characteristics of T-20 and representative lipopeptides in solution by circular dichroism technique in the same manner as in Example 7 above.
- the ⁇ -helix content and the Tm value (PBS solution) of the inhibitor at concentrations of 10 ⁇ M, 20 ⁇ M, and 40 ⁇ M, respectively, were determined.
- T-20 showed an irregular disorder structure under three concentrations.
- LP-40 exhibited a micro-helical structure at 20 ⁇ M and 40 ⁇ M, and four potent lipopeptides (LP-50) , LP-51, LP, 52, LP-80) showed a distinct spiral structure, in which the spiral content and Tm value of LP-80 were the highest. Therefore, the potent lipopeptide of the present invention itself forms a typical helical structure, which is significantly different from T-20.
- LP-80 is a lipopeptide having high antiviral activity and very stable in vivo and in vitro in the potent lipopeptide of the present invention.
- LP-80 was used as a representative to analyze its pharmacokinetic characteristics in SD rats.
- the test shared 12 SD rats, aged 5-8 weeks, weighing 182-219 grams. Divided into intravenous group and subcutaneous injection group, each group of 6 animals, male and female.
- the dose of LP-80 was 6 mg/kg body weight (mg/kg), and LP-80 was dissolved in sterile distilled water.
- Each group of animals was administered 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 168 hours after the end of administration.
- Serum samples were taken at 216 hours.
- the concentration of LP-80 in rat serum was quantitatively determined by liquid chromatography-mass spectrometry (LC-MS/MS).
- the lower limit of quantification was 1 ng/ml (ng/ml).
- Metabolic parameters were calculated using a non-compartmental model (NCA).
- NCA non-compartmental model
- the test results are shown in Figure 9.
- the average terminal elimination half-life (T 1/2 ) of the LP-80 intravenous group and the subcutaneous injection group was 6.04 hours and 6.28 hours, respectively.
- the concentration of LP-80 in serum after intravenous and subcutaneous injection for 3 days (72 hours) is 7.75 ng/ml and 6.86 ng/ml, respectively, and the molar concentration is 2021.12 pM. and 1789.02pM, the concentration was 50 value of inhibition of LP-80 HIV-1 strains NL4-3 and JRCSF activity IC (2pM) of 894.51 and 1010.56 times times.
- This result confirms the potent and long-lasting antiviral ability of LP-80 in the above Example 6 in the monkey from the viewpoint of pharmacokinetics.
- This example further examines the therapeutic effect of LP-80 on the monkey HIV infection model, and the technical route refers to the method used by the inventors to evaluate LP-19 (i.e., background art reference 30).
- Six adult Chinese rhesus monkeys (numbered A to F) were used in the experiment, and both male and female were screened to determine that SIV, herpesvirus B, and simian T-lymphotropic virus were negative;
- the SHIV strain SF162P3 was provided by the NIH AIDS Reagents and References Program in the United States, and was amplified in monkey peripheral blood lymphocytes (PBMC) and assayed for TCID 50 dose.
- PBMC monkey peripheral blood lymphocytes
- RNA copy number/ml monkey plasma viral load
- LP-80 dissolved in sterile distilled water
- LP-80 was administered at 2 mg (kg/kg) per kilogram of body weight. The drug was administered once a day for 2 weeks and then changed to 4 days for 4 weeks.
- Plasma samples were isolated from monkey blood at defined time points and plasma viral load (RNA copy number/ml) was determined by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR).
- upstream primer was GCAGAGGAGGAAATTACCCAGTAC
- downstream primer was CAATTTTACCCAGGCATTTAATGTT
- detection probe was FAM-ACCTGCCATTAAGCCCGA-MGB.
- the PCR instrument used was PE ABI7500.
- the sensitivity of the assay is 100 RNA copies per milliliter of plasma sample.
- the lipopeptide of the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof, the multimer, the composition or the pharmaceutical compound can be directly administered to a patient as a medicament, or with a suitable The carrier or excipient is mixed and administered to the patient for the purpose of treating and/or preventing HIV infection.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- AIDS & HIV (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Toxicology (AREA)
- Botany (AREA)
- Zoology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims (15)
- 脂肽、其药用盐、或其衍生物,其特征在于:所述脂肽为下述a)或b):a)所述脂肽由具有抗病毒活性的多肽和与所述多肽的羧基末端相连的亲脂性化合物连接而成;b)所述脂肽由具有抗病毒活性的多肽、末端保护基和与所述多肽的羧基末端相连的亲脂性化合物连接而成;所述末端保护基为氨基端保护基和/或羧基端保护基;a)和b)中,所述多肽为P1至P5中的任一种:所述P1的序列为下述(式Ⅰ)所示,(式Ⅰ)X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28(式Ⅰ)中,X1至X28均分别为一个氨基酸残基,所述X1为W、L或Y,所述X2为E或T,所述X3为Q、A或S,所述X4为K、N或L,X5为I或L,X6为E、D、K、R或A,X7为E、D、K、R或A,X8为L或I,X9为L或I,X10为K、R、E、D或A,X11为K、R、E、D或A,X12为A或S,X13为E、D、K、R或A,X14为E、D、K、R或A,X15为Q,X16为Q,X17为K、R、E、D或A,X18为K、R、E、D或A,X19为N,X20为E或D,X21为E、D、K、R或A,X22为E、D、K、R或A,X23为L或I,X24为K、R、E、D或A,X25为K、R、E、D或A,X26为L或I,X27为E或D,X28为K或R;所述P2为缺失所述P1的氨基末端的1至4个氨基酸残基得到的多肽;所述P3为缺失所述P1的羧基末端的1至3个氨基酸残基得到的多肽;所述P4为在所述P1的羧基末端添加半胱氨酸残基得到的多肽;所述P5的序列为下述(式Ⅱ)所示,(式Ⅱ)X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25(式Ⅱ)中,X5至X25的定义同(式Ⅰ);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。
- 根据权利要求1所述的脂肽、其药用盐、或其衍生物,其特征在于:所述脂肽的抗病毒活性高于LP-19和/或T-20和/或C34-Chol;所述脂肽的衍生物为将所述脂肽的所述多肽中的一个或多个氨基酸残基用构象为L-型或D-型的氨基酸残基、人工修饰的氨基酸残基和/或自然界存在的稀有氨基酸残基进行替换,得到的生物利用度、稳定性和/或抗病毒活性高于所述脂肽的脂肽衍生物。
- 根据权利要求1或2所述的脂肽、其药用盐、或其衍生物,其特征在于:所述P1的序列为X1X2X3X4IEELX9KKX12EEQQKKNEEELKKLEK;所述P2为P2-1、P2-2、P2-3或P2-4,所述P2-1的序列为X2X3X4IEELX9KKX12EEQQKKNEEELKKLEK;所述P2-2的序列为X3X4IEELX9KKX12EEQQKKNEEELKKLEK;所述P2-3的序列为X4IEELX9KKX12EEQQKKNEEELKKLEK;所述P2-4的序列为IEELX9KKX12EEQQKKNEEELKKLEK;所述P3的序列为X1X2X3X4IEELX9KKX12EEQQKKNEEELKK;所述P4的序列为X1X2X3X4IEELX9KKX12EEQQKKNEEELKKLEKC;P1、P2-1、P2-2、P2-3、P2-4、P3和P4中,X1、X2、X3、X4、X9和X12的定义同(式Ⅰ)。
- 根据权利要求3所述的脂肽、其药用盐、或其衍生物,其特征在于:所述P1为P-80/84/85/52、P-87/51或P50,所述P-80/84/85/52为序列表中序列1所示的多肽,所述P-87/51为序列表中序列2所示的多肽,所述P50为序列表中序列3所示的多肽;所述P2-1为P-88/62,所述P-88/62为序列表中序列4所示的多肽;所述P2-2为P63或P60,所述P63为序列表中序列5所示的多肽,所述P60为序列表中序列6所示的多肽;所述P2-3为P-89/64,所述P-89/64为序列表中序列7所示的多肽;所述P2-4为P-90/65或P61,所述P-90/65为序列表中序列8所示的多肽,所述P61为序列表中序列9所示的多肽;所述P3为P-91/55,所述P-91/55为序列表中序列10所示的多肽;所述P4为P83或P86,所述P83为序列表中序列11所示的多肽,所述P86为序列表中序列12所示的多肽。
- 根据权利要求1所述的脂肽、其药用盐、或其衍生物,其特征在于:所述亲脂性化合物为含8到20个碳原子的脂肪酸、胆固醇、二氢鞘氨醇或维生素E。
- 根据权利要求5所述的脂肽、其药用盐、或其衍生物,其特征在于:所述含8到20个碳原子的脂肪酸为硬脂酸或棕榈酸。
- 根据权利要求6所述的脂肽、其药用盐、或其衍生物,其特征在于:所述脂肽为LP-80/84/85/52、LP-90/65、LP-87/51、LP-88/62、LP-50、LP-83、LP-91/55、LP-86、LP-63、LP-89/64、LP-60和LP-61这12种脂肽中的任一种;所述LP-80/84/85/52为LP-80/84/85/52a或LP-80/84/85/52b;所述LP-80/84/85/52a由名称为P-80/84/85/52的多肽和与所述P-80/84/85/52的羧基末端相连的亲脂性化合物连接而成;所述LP-80/84/85/52b由所述LP-80/84/85/52a与所述末端保护基连接而成;所述LP-80/84/85/52a和LP-80/84/85/52b中,所述P-80/84/85/52为序列表中序列1所示的多肽,所述亲脂性化合物为二氢鞘氨醇、硬脂酸或维生素E;所述LP-90/65为LP-90/65a或LP-90/65b,所述LP-90/65a由名称为 P-90/65的多肽和与所述P-90/65的羧基末端相连的亲脂性化合物连接而成;所述LP-90/65b由所述LP-90/65a与所述末端保护基连接而成;所述LP-90/65a和LP-90/65b中,所述P-90/65为序列表中序列8所示的多肽,所述亲脂性化合物为硬脂酸或棕榈酸;所述LP-87/51为LP-87/51a或LP-87/51b;所述LP-87/51a由名称为P-87/51的多肽和与所述P-87/51的羧基末端相连的亲脂性化合物连接而成;所述LP-87/51b由所述LP-87/51a与所述末端保护基连接而成;所述LP-87/51a和LP-87/51b中,所述P-87/51为序列表中序列2所示的多肽,所述亲脂性化合物为二氢鞘氨醇或棕榈酸;所述LP-88/62为LP-88/62a或LP-88/62b;所述LP-88/62a由名称为P-88/62的多肽和与所述P-88/62的羧基末端相连的亲脂性化合物连接而成;所述LP-88/62b由所述LP-88/62a与所述末端保护基连接而成;所述LP-88/62a和LP-88/62b中,所述P-88/62为序列表中序列4所示的多肽,所述亲脂性化合物为硬脂酸或棕榈酸;所述LP-50为LP-50a或LP-50b;所述LP-50a由名称为P50的多肽和与所述P50的羧基末端相连的棕榈酸连接而成;所述LP-50b由所述LP-50a与所述末端保护基连接而成;所述LP-50a和LP-50b中,所述P50为序列表中序列3所示的多肽;所述LP-83为LP-83a或LP-83b;所述LP-83a由名称为P83的多肽和与所述P83的羧基末端相连的胆固醇连接而成;所述LP-83b由所述LP-83a与所述末端保护基连接而成;所述LP-83a和LP-83b中,所述P83为序列表中序列11所示的多肽;所述LP-91/55为LP-91/55a或LP-91/55b,所述LP-91/55a由名称为P-91/55的多肽和与所述P-91/55的羧基末端相连的亲脂性化合物连接而成;所述LP-91/55b由所述LP-91/55a与所述末端保护基连接而成;所述LP-91/55a和LP-91/55b中,所述P-91/55为序列表中序列10所示的多肽,所述亲脂性化合物为硬脂酸或棕榈酸;所述LP-86为LP-86a或LP-86b;所述LP-86a由名称为P86的多肽和与所述P86的羧基末端相连的胆固醇连接而成;所述LP-86b由所述LP-86a与所述末端保护基连接而成;所述LP-86a和LP-86b中,所述P86为序列表中序列12所示的多肽;所述LP-63为LP-63a或LP-63b;所述LP-63a由名称为P63的多肽和与所述P63的羧基末端相连的棕榈酸连接而成;所述LP-63b由所述LP-63a与所述末端保护基连接而成;所述LP-63a和LP-63b中,所述P63为序列表中序列5所示的多肽;所述LP-89/64为LP-89/64a或LP-89/64b;所述LP-89/64a由名称为P-89/64的多肽和与所述P-89/64的羧基末端相连的亲脂性化合物连接而成;所 述LP-89/64b由所述LP-89/64a与所述末端保护基连接而成;所述LP-89/64a和LP-89/64b中,所述P-89/64为序列表中序列7所示的多肽,所述亲脂性化合物为硬脂酸或棕榈酸;所述LP-60为LP-60a或LP-60b;所述LP-60a由名称为P60的多肽和与所述P60的羧基末端相连的棕榈酸连接而成;所述LP-60b由所述LP-60a与所述末端保护基连接而成;所述LP-60a和LP-60b中,所述P60为序列表中序列6所示的多肽;所述LP-61为LP-61a或LP-61b;所述LP-61a由名称为P61的多肽和与所述P61的羧基末端相连的棕榈酸连接而成;所述LP-61b由所述LP-61a与所述末端保护基连接而成;所述LP-61a和LP-61b中,所述P61为序列表中序列9所示的多肽。
- 多肽、其药用盐、或其衍生物,其特征在于:所述多肽为权利要求1中所述的多肽。
- 根据权利要求8所述的多肽、其药用盐、或其衍生物,其特征在于:所述的多肽衍生物为下述1)-5)中的至少一种:1)所述多肽的氨基端连接氨基端保护基和/或所述多肽的羧基端连接羧基端保护基得到的连接物;2)所述多肽的羧基端连接寡肽或亲脂性化合物得到的连接物;3)所述多肽的氨基端连接寡肽或亲脂性化合物得到的连接物;4)所述多肽的氨基端和羧基端均连接寡肽或亲脂性化合物得到的连接物;5)所述多肽被蛋白质、聚乙二醇或马来酰亚胺修饰得到的修饰物。
- PM1或PM2的多聚体:PM1、由权利要求1所述的脂肽、其药用盐、或其衍生物形成的多聚体;PM2、由权利要求8所述的多肽、其药用盐、或其衍生物形成的多聚体。
- 一种组合物,其包含C1)和C2):C1)为C11)、C12)或/和C13);所述C11)为权利要求1所述的脂肽、其衍生物、或其可药用盐;所述C12)为权利要求8所述的多肽、其衍生物、或其可药用盐;所述C13)为权利要求10所述的多聚体;C2)药学上可接受的载体或辅料;所述组合物具有下述F1)-F5)中的至少一种功能:F1)抗病毒;F2)治疗和/或预防和/或辅助治疗病毒感染所致疾病;F3)抑制病毒进行细胞融合;F4)抑制病毒侵入细胞;F5)抑制病毒复制;F1)-F5)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。
- C11)、C12)、C13)或/和C14)在制备E1)-E5)中至少一种产品中的应用:所述C11)为权利要求1所述的脂肽、其衍生物、或其可药用盐;所述C12)为权利要求8所述的多肽、其衍生物、或其可药用盐;所述C13)为权利要求10所述的多聚体;所述C14)为权利要求11所述的组合物;所述E1)为抗病毒的产品;所述E2)为治疗和/或预防和/或辅助治疗病毒感染所致疾病的产品;所述E3)为抑制病毒进行细胞融合的产品;所述E4)为抑制病毒侵入细胞的产品;所述E5)为抑制病毒复制的产品;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。
- 药用化合物,其特征在于:所述药用化合物为C11)、C12)或C13);所述C11)为权利要求1所述的脂肽、其衍生物、或其可药用盐;所述C12)为权利要求8所述的多肽、其衍生物、或其可药用盐;所述C13)为权利要求10所述的多聚体。
- 根据权利要求13所述的药用化合物,其特征在于:所述药用化合物具有下述U1)-U5)中的至少一种用途:U1)用于抗病毒;U2)用于治疗和/或预防和/或辅助治疗病毒感染所致疾病;U3)用于抑制病毒进行细胞融合;U4)用于抑制病毒侵入细胞;U5)用于抑制病毒复制;U1)-U5)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。
- 治疗或/和预防病毒感染动物的方法,包括给受体动物施用C11)、C12)、C13)或/和C14)以抑制病毒感染动物;所述C11)为权利要求1所述的脂肽、其衍生物、或其可药用盐;所述C12)为权利要求8所述的多肽、其衍生物、或其可药用盐;所述C13)为权利要求10所述的多聚体;所述C14)为权利要求11所述的组合物;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 (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2017/080860 WO2018191858A1 (zh) | 2017-04-18 | 2017-04-18 | 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 |
RU2019136527A RU2741123C1 (ru) | 2017-04-18 | 2017-04-18 | Липопептид для эффективного ингибирования вич, его производное, фармацевтическая композиция и их применение |
CA3058930A CA3058930A1 (en) | 2017-04-18 | 2017-04-18 | Lipopeptide for potently inhibiting hiv, derivative thereof, pharmaceutical composition thereof and use thereof |
JP2020507724A JP7057822B2 (ja) | 2017-04-18 | 2017-04-18 | Hivを強力に阻害するためのリポペプチド、その誘導体、その医薬組成物及びその使用 |
AU2017410525A AU2017410525B2 (en) | 2017-04-18 | 2017-04-18 | Potent HIV inhibiting lipopeptide, derivative thereof, pharmaceutical composition thereof and use thereof |
KR1020197033826A KR102389792B1 (ko) | 2017-04-18 | 2017-04-18 | Hiv를 강력하게 저해하는 리포펩티드, 그의 유도체, 그의 약학적 조성물 및 그의 용도 |
EP17906191.6A EP3613762A4 (en) | 2017-04-18 | 2017-04-18 | POWERFUL HIV INHIBITOR LIPOPEPTIDE, DERIVATIVE OF HIV, RELATED PHARMACEUTICAL COMPOSITION AND USE |
BR112019021787A BR112019021787A2 (pt) | 2017-04-18 | 2017-04-18 | lipopeptídeo para inibição potente do hiv, seu derivado, composição farmacêutica e uso do mesmo |
US16/606,525 US11680086B2 (en) | 2017-04-18 | 2017-04-18 | Lipopeptide for potently inhibiting HIV, derivative thereof, pharmaceutical composition thereof and use thereof |
ZA2019/07588A ZA201907588B (en) | 2017-04-18 | 2019-11-15 | Potent hiv inhibiting lipopeptide, derivative thereof, pharmaceutical composition thereof and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2017/080860 WO2018191858A1 (zh) | 2017-04-18 | 2017-04-18 | 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018191858A1 true WO2018191858A1 (zh) | 2018-10-25 |
Family
ID=63856164
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2017/080860 WO2018191858A1 (zh) | 2017-04-18 | 2017-04-18 | 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 |
Country Status (10)
Country | Link |
---|---|
US (1) | US11680086B2 (zh) |
EP (1) | EP3613762A4 (zh) |
JP (1) | JP7057822B2 (zh) |
KR (1) | KR102389792B1 (zh) |
AU (1) | AU2017410525B2 (zh) |
BR (1) | BR112019021787A2 (zh) |
CA (1) | CA3058930A1 (zh) |
RU (1) | RU2741123C1 (zh) |
WO (1) | WO2018191858A1 (zh) |
ZA (1) | ZA201907588B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108659105A (zh) * | 2018-05-23 | 2018-10-16 | 中国人民解放军军事科学院军事医学研究院 | 抗病毒多肽及其药物组合物和用途 |
CN108822190A (zh) * | 2018-05-23 | 2018-11-16 | 中国人民解放军军事科学院军事医学研究院 | 多肽及其药物组合物和用途 |
KR20200002923A (ko) * | 2017-04-18 | 2020-01-08 | 인스티튜트 오브 패쏘젠 바이올로지, 차이니즈 아카데미 오브 메디컬 사이언시스 | Hiv를 강력하게 저해하는 리포펩티드, 그의 유도체, 그의 약학적 조성물 및 그의 용도 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102311987B1 (ko) | 2021-04-12 | 2021-10-12 | 이훈 | 탈모 방지 및 모발 생장 촉진용 화장료 조성물 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090298774A1 (en) * | 2008-05-28 | 2009-12-03 | Shibo Jiang | Bifunctional Molecules for Inhibiting HIV Entry |
WO2010019717A2 (en) * | 2008-08-13 | 2010-02-18 | New York Blood Center | Combination therapy of hiv fusion/entry inhibitors targeting gp41 |
CN102247590A (zh) * | 2010-05-18 | 2011-11-23 | 天津市扶素生物技术有限公司 | 用于预防或治疗hiv感染的药物组合及其应用 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003029284A1 (fr) | 2001-09-27 | 2003-04-10 | Nobutaka Fujii | Agent anti-vih |
WO2008050830A1 (fr) | 2006-10-25 | 2008-05-02 | Kyoto University | Agent anti-vih |
CN102770457A (zh) | 2009-03-10 | 2012-11-07 | 贝勒研究院 | 靶向抗原呈递细胞的疫苗 |
CN102427829A (zh) | 2009-04-01 | 2012-04-25 | 耶达研究与发展有限公司 | Hiv-1的脂肽抑制剂 |
EP2691105B1 (en) | 2011-03-28 | 2018-07-11 | University of Utah Research Foundation | Methods and compositions related to inhibition of viral entry |
EP2511295A1 (en) * | 2011-04-15 | 2012-10-17 | Institut National De La Sante Et De La Recherche Medicale | Compositions for preventing and/or treating an infection by an HIV-1 virus |
WO2013127300A1 (zh) | 2012-02-28 | 2013-09-06 | 中国人民解放军军事医学科学院毒物药物研究所 | 用于抑制hiv的多肽、其药物组合物及其用途 |
WO2013150532A1 (en) | 2012-04-04 | 2013-10-10 | Yeda Research And Development Co. Ltd. | Lipopeptide conjugates comprising sphingolipid and hiv gp41 derived peptides |
CN108727475B (zh) | 2017-04-18 | 2020-08-25 | 中国医学科学院病原生物学研究所 | 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 |
CA3058930A1 (en) | 2017-04-18 | 2018-10-25 | Institute Of Pathogen Biology, Chinese Academy Of Medical Sciences | Lipopeptide for potently inhibiting hiv, derivative thereof, pharmaceutical composition thereof and use thereof |
-
2017
- 2017-04-18 CA CA3058930A patent/CA3058930A1/en active Pending
- 2017-04-18 RU RU2019136527A patent/RU2741123C1/ru active
- 2017-04-18 EP EP17906191.6A patent/EP3613762A4/en active Pending
- 2017-04-18 JP JP2020507724A patent/JP7057822B2/ja active Active
- 2017-04-18 BR BR112019021787A patent/BR112019021787A2/pt unknown
- 2017-04-18 US US16/606,525 patent/US11680086B2/en active Active
- 2017-04-18 KR KR1020197033826A patent/KR102389792B1/ko active IP Right Grant
- 2017-04-18 AU AU2017410525A patent/AU2017410525B2/en active Active
- 2017-04-18 WO PCT/CN2017/080860 patent/WO2018191858A1/zh unknown
-
2019
- 2019-11-15 ZA ZA2019/07588A patent/ZA201907588B/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090298774A1 (en) * | 2008-05-28 | 2009-12-03 | Shibo Jiang | Bifunctional Molecules for Inhibiting HIV Entry |
EP2291392B1 (en) * | 2008-05-28 | 2014-03-05 | New York Blood Center | Bifunctional molecules for inhibiting hiv entry |
WO2010019717A2 (en) * | 2008-08-13 | 2010-02-18 | New York Blood Center | Combination therapy of hiv fusion/entry inhibitors targeting gp41 |
CN102247590A (zh) * | 2010-05-18 | 2011-11-23 | 天津市扶素生物技术有限公司 | 用于预防或治疗hiv感染的药物组合及其应用 |
Non-Patent Citations (37)
Title |
---|
ASHKENAZI AVIARD MUNGER LBLUMENTHAL RSHAI Y: "Sphingopeptides: dihydrosphingosine-based fusion inhibitors against wild-type and enfuvirtide-resistant HIV-1", FASEB J, vol. 26, 2012, pages 4628 - 4636 |
BRUGGER BGLASS BHABERKANT PLEIBRECHT IWIELAND FTKRAUSSLICH HG: "The HIV lipidome: a raft with an unusual composition", PROC NATL ACAD SCI U S A, vol. 103, 2006, pages 2641 - 2646 |
CHAN DCCHUTKOWSKI CTKIM PS: "Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target", PROC NATL ACAD SCI U S A, vol. 95, 1998, pages 15613 - 15617, XP002126805, DOI: 10.1073/pnas.95.26.15613 |
CHAN DCFASS DBERGER JMKIM PS: "Core structure of gp41 from the HIV envelope glycoprotein", CELL, vol. 89, 1997, pages 263 - 273, XP001002841, DOI: 10.1016/S0092-8674(00)80205-6 |
CHONG HQIU ZSU YHE Y: "The N-Terminal T-T Motif of a Third-Generation HIV-1 Fusion Inhibitor Is Not Required for Binding Affinity and Antiviral Activity", J MED CHEM, vol. 58, 2015, pages 6378 - 6388 |
CHONG HQIU ZSU YYANG LHE Y: "Design of a highly potent HIV-1 fusion inhibitor targeting the gp41 pocket", AIDS, vol. 29, 2015, pages 13 - 21 |
CHONG HQIU ZSUN JQIAO YLI XHE Y: "Two M-T hook residues greatly improve the antiviral activity and resistance profile of the HIV-1 fusion inhibitor SC29EK", RETROVIROLOGY, vol. 11, 2014, pages 40, XP021188225, DOI: 10.1186/1742-4690-11-40 |
CHONG HWU XSU YHE Y: "Development of potent and long-acting HIV-1 fusion inhibitors", AIDS, vol. 30, 2016, pages 1187 - 1196, XP055544810, DOI: 10.1097/QAD.0000000000001073 |
CHONG HXUE JXIONG SCONG ZDING XZHU YLIU ZCHEN TFENG YHE L: "A lipopeptide HIV-1/2fusion inhibitor with highly potent in vitro, ex vivo and in vivo antiviral activity", J VIROL, vol. 91, 2017, pages e00288 - 17 |
CHONG HYAO XQIU ZQIN BHAN RWALTERSPERGER S ET AL.: "Discovery of critical residues for viral entry and inhibition through structural Insight of HIV-1 fusion inhibitor CP621-652", J BIOL CHEM, vol. 287, 2012, pages 20281 - 20289 |
CHONG HYAO XQIU ZSUN JQIAO YZHANG M ET AL.: "The M-T hook structure increases the potency of HIV-1 fusion inhibitor sifuvirtide and overcomes drug resistance", J ANTIMICROB CHEMOTHER, vol. 69, 2014, pages 6759 |
CHONG HYAO XQIU ZSUN JZHANG MWALTERSPERGER S ET AL.: "Short-peptide fusion inhibitors with high potency against wild-type and enfuvirtide-resistant HIV-1", FASEB J, vol. 27, 2013, pages 1203 - 1213 |
CHONG HYAO XSUN JQIU ZZHANG MWALTERSPERGER S ET AL.: "The M-T hook structure is critical for design of HIV-1 fusion inhibitors", J BIOL CHEM, vol. 287, 2012, pages 34558 - 34568 |
CHONG HYAO XZHANG CCAI LCUI SWANG YHE Y: "Biophysical property and broad anti-HIV activity of Albuvirtide, a 3-maleimimidoproprotionic acid-modified peptide fusion inhibitor", PLOS ONE, vol. 7, no. 3, 2012, pages e 32599 |
CHONG, H. ET AL.: "A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent in Vitro, Ex Vivo, and in Vivo Antiviral Activity", JOURNAL OF VIROLOGY, vol. 91, no. 11, 29 March 2017 (2017-03-29), pages e00288 - 17, XP055544814 * |
CHONG, H. ET AL.: "Development of Potent and Long-acting HIV-1 Fusion Inhibitors", AIDS, vol. 30, no. 8, 31 December 2016 (2016-12-31), pages 1187 - 1196, XP055544810 * |
DATABASE protein [O] 10 January 2013 (2013-01-10), NISHIKAWA, H. ET AL., XP055544808, Database accession no. PDB: 2Z2T_D * |
ECKERT DMKIM PS: "Mechanisms of viral membrane fusion and its inhibition", ANNU REV BIOCHEM, vol. 70, 2001, pages 777 - 810, XP001152929, DOI: 10.1146/annurev.biochem.70.1.777 |
EGELHOFER MBRANDENBURG GMARTINIUS HSCHULT-DIETRICH PMELIKYAN GKUNERT R ET AL.: "Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides", J VIROL, vol. 78, 2004, pages 568 - 575, XP009029114, DOI: 10.1128/JVI.78.2.568-575.2004 |
EGGINK DBERKHOUT BSANDERS RW: "Inhibition of HIV-1 by fusion inhibitors", CURR PHARM DES, vol. 16, 2010, pages 3716 - 3728 |
ESTE JATELENTI A: "HIV entry inhibitors", LANCET, vol. 370, 2007, pages 81 - 88, XP022143956, DOI: 10.1016/S0140-6736(07)61052-6 |
FLEXNER C.: "HIV drug development: the next 25 years", NAT REV DRUG DISCOV, vol. 6, 2007, pages 959 - 966 |
FRANQUELIM HGLOURA LMSANTOS NCCASTANHO MA: "Sifuvirtide screens rigid membrane surfaces. establishment of a correlation between efficacy and membrane domain selectivity among HIV fusion inhibitor peptides", JAM CHEM SOC, vol. 130, 2008, pages 6215 - 6223 |
HE Y.: "Synthesized peptide inhibitors of HIV-1 gp41-dependent membrane fusion", CURR PHARM DES, vol. 19, 2013, pages 1800 - 1809 |
HILDINGER MDITTMAR MTSCHULT-DIETRICH PFEHSE BSCHNIERLE BSTHALER S ET AL.: "Membrane-anchored peptide inhibits human immunodeficiency virus entry", J VIROL, vol. 75, 2001, pages 3038 - 3042, XP001007609, DOI: 10.1128/JVI.75.6.3038-3042.2001 |
INGALLINELLA PBIANCHI ELADWA NAWANG YJHRIN RVENEZIANO M ET AL.: "Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency", PROC NATL ACAD SCI U S A, vol. 106, 2009, pages 5801 - 5806 |
INGALLINELLA, P. ET AL.: "Addition of a Cholesterol Group to an HIV-1 Peptide Fusion Inhibitor Dramatically Increases its Antiviral Potency", PNAS, vol. 106, no. 14, 7 April 2009 (2009-04-07), pages 5801 - 5806, XP055544820 * |
LIU, SHUWEN ET AL.: "Peptidic HIV Fusion Inhibitors Targeting Envelope Glycoprotein Transmembrane Subunit gp41", CHINESE PHARMACOLOGICAL BULLETIN, vol. 19, no. 11, 30 November 2003 (2003-11-30), pages 1201 - 1208, XP009517335, ISSN: 1001-1978 * |
MATOS PMCASTANHO MASANTOS NC: "HIV-1 fusion inhibitor peptides enfuvirtide and T-1249 interact with erythrocyte and lymphocyte membranes", PLOS ONE, vol. 5, 2010, pages e9830 |
ONO AFREED EO: "Plasma membrane rafts play a critical role in HIV-1 assembly and release", PROC NATL ACAD SCI U S A, vol. 98, 2001, pages 13925 - 13930, XP002380457, DOI: 10.1073/pnas.241320298 |
PEISAJOVICH SGGALLO SABLUMENTHAL RSHAI Y: "C-terminal octylation rescues an inactive T20 mutant: implications for the mechanism of HIV/SIMIAN immunodeficiency virus-induced membrane fusion", J BIOL CHEM, vol. 278, 2003, pages 21012 - 21017 |
See also references of EP3613762A4 |
VEIGA ASSANTOS NCLOURA LMFEDOROV ACASTANHO MA: "HIV fusion inhibitor peptide T-1249 is able to insert or adsorb to lipidic bilayers. Putative correlation with improved efficiency", JAM CHEM SOC, vol. 126, 2004, pages 14758 - 14763 |
WEXLER-COHEN YASHKENAZI AVIARD MBLUMENTHAL RSHAI Y: "Virus-cell and cell-cell fusion mediated by the HIV-1 envelope glycoprotein is inhibited by short gp41 N-terminal membrane-anchored peptides lacking the critical pocket domain", FASEB J, vol. 24, 2010, pages 4196 - 4202 |
WEXLER-COHEN YSHAI Y: "Demonstrating the C-terminal boundary of the HIV 1 fusion conformation in a dynamic ongoing fusion process and implication for fusion inhibition", FASEB J, vol. 21, 2007, pages 3677 - 3684 |
WEXLER-COHEN YSHAI Y: "Membrane-anchored HIV-1 N-heptad repeat peptides are highly potent cell fusion inhibitors via an altered mode of action", PLOS PATHOG, vol. 5, 2009, pages el000509 |
XIONG SBORREGO PDING XZHU YMARTINS ACHONG H ET AL.: "A helical short-peptide fusion inhibitor with highly potent activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus", J VIROL, vol. 91, 2017, pages e01839 - 16 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20200002923A (ko) * | 2017-04-18 | 2020-01-08 | 인스티튜트 오브 패쏘젠 바이올로지, 차이니즈 아카데미 오브 메디컬 사이언시스 | Hiv를 강력하게 저해하는 리포펩티드, 그의 유도체, 그의 약학적 조성물 및 그의 용도 |
KR102389792B1 (ko) | 2017-04-18 | 2022-04-22 | 인스티튜트 오브 패쏘젠 바이올로지, 차이니즈 아카데미 오브 메디컬 사이언시스 | Hiv를 강력하게 저해하는 리포펩티드, 그의 유도체, 그의 약학적 조성물 및 그의 용도 |
CN108659105A (zh) * | 2018-05-23 | 2018-10-16 | 中国人民解放军军事科学院军事医学研究院 | 抗病毒多肽及其药物组合物和用途 |
CN108822190A (zh) * | 2018-05-23 | 2018-11-16 | 中国人民解放军军事科学院军事医学研究院 | 多肽及其药物组合物和用途 |
WO2019223642A1 (zh) * | 2018-05-23 | 2019-11-28 | 中国人民解放军军事科学院军事医学研究院 | 抗病毒多肽及其药物组合物和用途 |
CN108822190B (zh) * | 2018-05-23 | 2021-11-09 | 中国人民解放军军事科学院军事医学研究院 | 多肽及其药物组合物和用途 |
CN108659105B (zh) * | 2018-05-23 | 2021-11-09 | 中国人民解放军军事科学院军事医学研究院 | 抗病毒多肽及其药物组合物和用途 |
Also Published As
Publication number | Publication date |
---|---|
US20210277068A1 (en) | 2021-09-09 |
KR102389792B1 (ko) | 2022-04-22 |
KR20200002923A (ko) | 2020-01-08 |
CA3058930A1 (en) | 2018-10-25 |
JP7057822B2 (ja) | 2022-04-20 |
EP3613762A1 (en) | 2020-02-26 |
EP3613762A4 (en) | 2020-10-21 |
US11680086B2 (en) | 2023-06-20 |
ZA201907588B (en) | 2021-08-25 |
JP2020517741A (ja) | 2020-06-18 |
AU2017410525A1 (en) | 2019-10-31 |
AU2017410525B2 (en) | 2022-04-21 |
BR112019021787A2 (pt) | 2020-05-05 |
RU2741123C1 (ru) | 2021-01-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108727475B (zh) | 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 | |
US7456251B2 (en) | HIV fusion inhibitor peptides with improved biological properties | |
WO2018191858A1 (zh) | 强效抑制hiv的脂肽、其衍生物、其药物组合物及其用途 | |
CN111643656B (zh) | 广谱冠状病毒膜融合抑制剂及其抗艾滋病病毒的应用 | |
WO2023155318A1 (zh) | 一种优化病毒膜融合抑制剂的方法及广谱抗冠状病毒脂肽和应用 | |
Schneider et al. | Development of HIV fusion inhibitors | |
CN106749558B (zh) | 广谱抑制hiv的脂肽、其衍生物、其药物组合物及其用途 | |
WO2005067960A1 (en) | HIV gp41 HR2-DERIVED SYNTHETIC PEPTIDES, AND THEIR USE IN THERAPY TO INHIBIT TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS | |
CN115724919B (zh) | 强效抑制艾滋病病毒及其耐药毒株的新型膜融合抑制剂及其药物用途 | |
WO2018141089A1 (zh) | 广谱抑制hiv的脂肽、其衍生物、其药物组合物及其用途 | |
WO2007068163A1 (fr) | Peptides inhibiteurs de la fusion du vih et leur utilisation | |
WO2005034842A2 (en) | Peptides useful as hiv fusion inhibitors | |
WO2001090159A2 (en) | Compositions and methods for delivery of a molecule into a cell | |
OA19487A (en) | Potent HIV inhibiting lipopeptide, derivative thereof, pharmaceutical composition thereof and use thereof. | |
WO2014022947A1 (zh) | 抑制hiv的短小多肽及药物用途 | |
EP1621203A1 (en) | RNAIII-inhibiting peptides for treating HIV infection | |
MXPA06007675A (en) | HIV gp41 HR2-DERIVED SYNTHETIC PEPTIDES, AND THEIR USE IN THERAPY TO INHIBIT TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17906191 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3058930 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2020507724 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112019021787 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2017410525 Country of ref document: AU Date of ref document: 20170418 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20197033826 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017906191 Country of ref document: EP Effective date: 20191118 |
|
ENP | Entry into the national phase |
Ref document number: 112019021787 Country of ref document: BR Kind code of ref document: A2 Effective date: 20191017 |