NZ751741B2 - Hepcidin analogues and uses therof - Google Patents
Hepcidin analogues and uses therof Download PDFInfo
- Publication number
- NZ751741B2 NZ751741B2 NZ751741A NZ75174114A NZ751741B2 NZ 751741 B2 NZ751741 B2 NZ 751741B2 NZ 751741 A NZ751741 A NZ 751741A NZ 75174114 A NZ75174114 A NZ 75174114A NZ 751741 B2 NZ751741 B2 NZ 751741B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- peptide
- lys
- absent
- arg
- Prior art date
Links
- 102000018511 hepcidin family Human genes 0.000 title abstract description 76
- 108060003558 hepcidin family Proteins 0.000 title abstract description 76
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 83
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 83
- 201000010099 disease Diseases 0.000 abstract description 47
- 206010065973 Iron overload Diseases 0.000 abstract description 19
- 206010057873 Hereditary haemochromatosis Diseases 0.000 abstract description 7
- 208000006756 X-linked sideroblastic anemia Diseases 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical group NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 249
- 150000001875 compounds Chemical class 0.000 description 179
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 155
- 239000000539 dimer Substances 0.000 description 124
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 description 116
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 112
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 99
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical group SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 93
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 81
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 72
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical group OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 68
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 66
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 65
- MTCFGRXMJLQNBG-REOHCLBHSA-N L-serine Chemical group OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 64
- -1 Ala Chemical compound 0.000 description 62
- 239000000203 mixture Substances 0.000 description 49
- 102100017041 SLC40A1 Human genes 0.000 description 40
- 108091006892 SLC40A1 Proteins 0.000 description 40
- 230000000694 effects Effects 0.000 description 40
- 239000011780 sodium chloride Substances 0.000 description 39
- 235000002639 sodium chloride Nutrition 0.000 description 39
- 125000000631 L-cysteino group Chemical group [H]OC(=O)[C@@]([H])(N([H])*)C([H])([H])S[H] 0.000 description 38
- 150000003839 salts Chemical class 0.000 description 37
- AGPKZVBTJJNPAG-RFZPGFLSSA-N D-isoleucine Chemical compound CC[C@@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-RFZPGFLSSA-N 0.000 description 36
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 36
- 229910052742 iron Inorganic materials 0.000 description 36
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 35
- 239000003814 drug Substances 0.000 description 35
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical group C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 33
- 235000001014 amino acid Nutrition 0.000 description 33
- 229920001223 polyethylene glycol Polymers 0.000 description 32
- 150000001413 amino acids Chemical class 0.000 description 29
- 125000000237 D-prolino group Chemical group [H]OC(=O)[C@]1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 28
- 229940079593 drugs Drugs 0.000 description 27
- KQNPFQTWMSNSAP-UHFFFAOYSA-N Isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 26
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- XUJNEKJLAYXESH-UWTATZPHSA-N D-cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 description 24
- 239000012071 phase Substances 0.000 description 24
- 239000012453 solvate Substances 0.000 description 24
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 21
- 125000000241 L-isoleucino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])[C@@](C([H])([H])[H])(C(C([H])([H])[H])([H])[H])[H] 0.000 description 21
- GWYFCOCPABKNJV-UHFFFAOYSA-N 3-Methylbutanoic acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 20
- 125000000570 L-alpha-aspartyl group Chemical group [H]OC(=O)C([H])([H])[C@]([H])(N([H])[H])C(*)=O 0.000 description 20
- 125000005647 linker group Chemical group 0.000 description 20
- 230000003647 oxidation Effects 0.000 description 20
- 238000007254 oxidation reaction Methods 0.000 description 20
- 125000003275 alpha amino acid group Chemical group 0.000 description 19
- 229910052740 iodine Inorganic materials 0.000 description 19
- 238000000034 method Methods 0.000 description 19
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 description 18
- 125000002068 L-phenylalanino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 18
- 125000000205 L-threonino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])[C@](C([H])([H])[H])([H])O[H] 0.000 description 18
- 238000000338 in vitro Methods 0.000 description 17
- 239000008194 pharmaceutical composition Substances 0.000 description 17
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 16
- 206010018872 Haemochromatosis Diseases 0.000 description 15
- 125000000539 amino acid group Chemical group 0.000 description 15
- 125000000052 D-arginine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])N([H])C(N([H])[H])=N[H] 0.000 description 14
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 14
- 230000027455 binding Effects 0.000 description 14
- 230000015556 catabolic process Effects 0.000 description 14
- 210000004027 cells Anatomy 0.000 description 14
- 230000004059 degradation Effects 0.000 description 14
- 238000006731 degradation reaction Methods 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 13
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 12
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical group OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 description 12
- AYFVYJQAPQTCCC-STHAYSLISA-N D-threonine Chemical compound C[C@H](O)[C@@H](N)C(O)=O AYFVYJQAPQTCCC-STHAYSLISA-N 0.000 description 12
- 230000036499 Half live Effects 0.000 description 12
- POULHZVOKOAJMA-UHFFFAOYSA-N Lauric acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 12
- 230000036740 Metabolism Effects 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 230000004060 metabolic process Effects 0.000 description 12
- 230000035786 metabolism Effects 0.000 description 12
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical group CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 11
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 235000018417 cysteine Nutrition 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- IPCSVZSSVZVIGE-UHFFFAOYSA-N Palmitic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 10
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 description 10
- 230000035772 mutation Effects 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 210000004369 Blood Anatomy 0.000 description 9
- 101700039549 PEG3 Proteins 0.000 description 9
- 102100014963 PEG3 Human genes 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 208000007502 Anemia Diseases 0.000 description 8
- 235000021314 Palmitic acid Nutrition 0.000 description 8
- 210000002966 Serum Anatomy 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 238000004166 bioassay Methods 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 7
- 101700079635 RTL1 Proteins 0.000 description 7
- 102100017191 RTL1 Human genes 0.000 description 7
- 230000021615 conjugation Effects 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- BVQVLAIMHVDZEL-UHFFFAOYSA-N 1-phenyl-1,2-propanedione Chemical group CC(=O)C(=O)C1=CC=CC=C1 BVQVLAIMHVDZEL-UHFFFAOYSA-N 0.000 description 6
- SGCGMORCWLEJNZ-UWVGGRQHSA-N His-His Chemical group C([C@H]([NH3+])C(=O)N[C@@H](CC=1NC=NC=1)C([O-])=O)C1=CN=CN1 SGCGMORCWLEJNZ-UWVGGRQHSA-N 0.000 description 6
- 239000005639 Lauric acid Substances 0.000 description 6
- IGRMTQMIDNDFAA-UHFFFAOYSA-N Lysyl-Histidine Chemical group NCCCCC(N)C(=O)NC(C(O)=O)CC1=CN=CN1 IGRMTQMIDNDFAA-UHFFFAOYSA-N 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 125000001589 carboacyl group Chemical group 0.000 description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 6
- 239000005090 green fluorescent protein Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000710 homodimer Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000007523 nucleic acids Chemical class 0.000 description 6
- 230000001603 reducing Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- SNFUTDLOCQQRQD-UHFFFAOYSA-N 2-[(2-amino-4-carboxybutanoyl)amino]-3-methylpentanoic acid Chemical compound CCC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SNFUTDLOCQQRQD-UHFFFAOYSA-N 0.000 description 5
- BUQICHWNXBIBOG-LMVFSUKVSA-N Ala-Thr Chemical group C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)N BUQICHWNXBIBOG-LMVFSUKVSA-N 0.000 description 5
- 206010012601 Diabetes mellitus Diseases 0.000 description 5
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 5
- 102100008155 IGF2-AS Human genes 0.000 description 5
- 101710032210 IGF2-AS Proteins 0.000 description 5
- UWBDLNOCIDGPQE-UHFFFAOYSA-N Isoleucyl-Lysine Chemical compound CCC(C)C(N)C(=O)NC(C(O)=O)CCCCN UWBDLNOCIDGPQE-UHFFFAOYSA-N 0.000 description 5
- FMIIKPHLJKUXGE-GUBZILKMSA-N Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN FMIIKPHLJKUXGE-GUBZILKMSA-N 0.000 description 5
- 229920001850 Nucleic acid sequence Polymers 0.000 description 5
- JWBLQDDHSDGEGR-DRZSPHRISA-N Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 JWBLQDDHSDGEGR-DRZSPHRISA-N 0.000 description 5
- 210000002381 Plasma Anatomy 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- DSGIVWSDDRDJIO-ZXXMMSQZSA-N Thr-Thr Chemical group C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DSGIVWSDDRDJIO-ZXXMMSQZSA-N 0.000 description 5
- 102000004965 antibodies Human genes 0.000 description 5
- 108090001123 antibodies Proteins 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- 150000002019 disulfides Chemical class 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 229920000023 polynucleotide Polymers 0.000 description 5
- 239000002157 polynucleotide Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- UKNAYQWNMMGCNX-UHFFFAOYSA-N sodium;[hydroxy(phenyl)methyl]-oxido-oxophosphanium Chemical compound [Na+].[O-][P+](=O)C(O)C1=CC=CC=C1 UKNAYQWNMMGCNX-UHFFFAOYSA-N 0.000 description 5
- 230000001225 therapeutic Effects 0.000 description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- XITLYYAIPBBHPX-UHFFFAOYSA-N γ-glutamyl-Isoleucine Chemical compound CCC(C)C(C(O)=O)NC(=O)C(N)CCC(N)=O XITLYYAIPBBHPX-UHFFFAOYSA-N 0.000 description 5
- XZWXFWBHYRFLEF-FSPLSTOPSA-N Ala-His Chemical group C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 XZWXFWBHYRFLEF-FSPLSTOPSA-N 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N Diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 206010022489 Insulin resistance Diseases 0.000 description 4
- 125000003338 L-glutaminyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000008425 Protein Deficiency Diseases 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- 229960005070 ascorbic acid Drugs 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 125000004432 carbon atoms Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 235000018977 lysine Nutrition 0.000 description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 229920002676 Complementary DNA Polymers 0.000 description 3
- 208000002705 Glucose Intolerance Diseases 0.000 description 3
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N Glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 229960003180 Glutathione Drugs 0.000 description 3
- 102000000213 Hemojuvelin Human genes 0.000 description 3
- 108050008605 Hemojuvelin Proteins 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 3
- 101700035261 PY Proteins 0.000 description 3
- 108010077895 Sarcosine Proteins 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000001684 chronic Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 230000001808 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 230000002255 enzymatic Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000833 heterodimer Substances 0.000 description 3
- 230000002209 hydrophobic Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000011068 load Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine zwitterion Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 3
- 231100000486 side effect Toxicity 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 229940005605 valeric acid Drugs 0.000 description 3
- 230000003442 weekly Effects 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 description 2
- 102100001249 ALB Human genes 0.000 description 2
- 101710027066 ALB Proteins 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000036912 Bioavailability Effects 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
- 229960001489 Deferasirox Drugs 0.000 description 2
- FMSOAWSKCWYLBB-VBGLAJCLSA-N Deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N(N\C(N\1)=C\2C(C=CC=C/2)=O)C/1=C\1C(=O)C=CC=C/1 FMSOAWSKCWYLBB-VBGLAJCLSA-N 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- MUCZHBLJLSDCSD-UHFFFAOYSA-N Diisopropyl fluorophosphate Chemical compound CC(C)OP(F)(=O)OC(C)C MUCZHBLJLSDCSD-UHFFFAOYSA-N 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 108010053070 Glutathione Disulfide Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 206010019641 Hepatic cirrhosis Diseases 0.000 description 2
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 2
- 206010022971 Iron deficiency Diseases 0.000 description 2
- 206010022970 Iron deficiency Diseases 0.000 description 2
- 206010022983 Iron metabolism disease Diseases 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 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
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Chemical group OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 2
- 208000004201 Neonatal hemochromatosis Diseases 0.000 description 2
- 229960003104 Ornithine Drugs 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 206010038444 Renal failure chronic Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229940043230 Sarcosine Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 102100017285 TFR2 Human genes 0.000 description 2
- 101700061903 TFR2 Proteins 0.000 description 2
- 206010043391 Thalassaemia beta Diseases 0.000 description 2
- 208000002903 Thalassemia Diseases 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- SRUIBJVUBBOHHY-UHFFFAOYSA-N [2H-benzotriazol-4-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CN(C)C(=[N+](C)C)OC1=CC=CC2=C1N=NN2 SRUIBJVUBBOHHY-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 229940050528 albumin Drugs 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 201000006288 alpha thalassemia Diseases 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000975 bioactive Effects 0.000 description 2
- 230000035514 bioavailability Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- WRZXKWFJEFFURH-UHFFFAOYSA-N dodecaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO WRZXKWFJEFFURH-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000004220 glutamic acid Chemical group 0.000 description 2
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 239000001963 growth media Substances 0.000 description 2
- 201000000361 hemochromatosis type 2 Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000004044 liver cirrhosis Diseases 0.000 description 2
- 229920001427 mPEG Polymers 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003204 osmotic Effects 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 230000001590 oxidative Effects 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 125000001312 palmitoyl 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])[H] 0.000 description 2
- 239000000546 pharmaceutic aid Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- 230000002685 pulmonary Effects 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 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
- 230000036962 time dependent Effects 0.000 description 2
- 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 2
- 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 2
- WMQPXXOMYXZNQY-UHFFFAOYSA-N (2,4-dimethoxyphenyl)-(4-methoxyphenyl)methanol Chemical group C1=CC(OC)=CC=C1C(O)C1=CC=C(OC)C=C1OC WMQPXXOMYXZNQY-UHFFFAOYSA-N 0.000 description 1
- KWMLJOLKUYYJFJ-AIECOIEWSA-N (2R,3R,4R,5S,6R)-2,3,4,5,6,7-hexahydroxyheptanoic acid Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-AIECOIEWSA-N 0.000 description 1
- OFVBLKINTLPEGH-VIFPVBQESA-N (3S)-3-amino-4-phenylbutanoic acid Chemical compound OC(=O)C[C@@H](N)CC1=CC=CC=C1 OFVBLKINTLPEGH-VIFPVBQESA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-Ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- ADSALMJPJUKESW-RXMQYKEDSA-N 2-[(2R)-pyrrolidin-1-ium-2-yl]acetate Chemical compound OC(=O)C[C@H]1CCCN1 ADSALMJPJUKESW-RXMQYKEDSA-N 0.000 description 1
- JALGRPFYCOBGHM-UHFFFAOYSA-M 2-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]ethyl-trimethylazanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NCC[N+](C)(C)C JALGRPFYCOBGHM-UHFFFAOYSA-M 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical group C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine zwitterion Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- 201000000359 African iron overload Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010001627 Alcoholic liver disease Diseases 0.000 description 1
- 206010001897 Alzheimer's disease Diseases 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- PRKQVKDSMLBJBJ-UHFFFAOYSA-N Ammonium carbonate Chemical compound N.N.OC(O)=O PRKQVKDSMLBJBJ-UHFFFAOYSA-N 0.000 description 1
- 206010002073 Anaemia of chronic disease Diseases 0.000 description 1
- 208000009050 Anemia, Dyserythropoietic, Congenital Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 102100005030 BCS1L Human genes 0.000 description 1
- 101710017812 BCS1L Proteins 0.000 description 1
- 208000005950 Bantu siderosis Diseases 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N Benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 230000037177 Biodistribution Effects 0.000 description 1
- 230000035639 Blood Levels Effects 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 210000003229 CMP Anatomy 0.000 description 1
- 102100006077 CP Human genes 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
- FSBIGDSBMBYOPN-VKHMYHEASA-N Canavanine Chemical compound OC(=O)[C@@H](N)CCONC(N)=N FSBIGDSBMBYOPN-VKHMYHEASA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 206010007554 Cardiac failure Diseases 0.000 description 1
- 206010061592 Cardiac fibrillation Diseases 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 230000036536 Cave Effects 0.000 description 1
- 108010075016 Ceruloplasmin Proteins 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 229960001231 Choline Drugs 0.000 description 1
- 208000006154 Chronic Hepatitis C Diseases 0.000 description 1
- 208000009863 Chronic Kidney Failure Diseases 0.000 description 1
- 230000037250 Clearance Effects 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000007277 Congenital atransferrinemia Diseases 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N Cypionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 125000001711 D-phenylalanine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 229960000958 Deferoxamine Drugs 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229950010286 Diolamine Drugs 0.000 description 1
- PECGVEGMRUZOML-UHFFFAOYSA-N Diphenylalanine Chemical compound C=1C=CC=CC=1C(C(N)C(O)=O)C1=CC=CC=C1 PECGVEGMRUZOML-UHFFFAOYSA-N 0.000 description 1
- 230000035695 Efflux Effects 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N Ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 229940024583 Exjade Drugs 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 208000002373 Finnish lethal neonatal metabolic syndrome Diseases 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N Fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 206010017374 Friedreich's ataxia Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 102100016195 HAMP Human genes 0.000 description 1
- 101710007394 HAMP Proteins 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- 208000006454 Hepatitis Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 201000001971 Huntington's disease Diseases 0.000 description 1
- 208000006278 Hypochromic Anemia Diseases 0.000 description 1
- 208000009995 Idiopathic pulmonary hemosiderosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N Iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 206010022972 Iron deficiency anaemia Diseases 0.000 description 1
- 208000002014 Iron-Refractory Iron Deficiency Anemia Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N Isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-2-aminohexanoic acid zwitterion Chemical group CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 210000004185 Liver Anatomy 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
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[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 VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229960003194 Meglumine Drugs 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 125000000534 N(2)-L-lysino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C([H])([H])C(C([H])([H])N([H])[H])([H])[H] 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 210000004897 N-terminal region Anatomy 0.000 description 1
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229950004864 Olamine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 102100014962 PEG10 Human genes 0.000 description 1
- 101700049205 PEG10 Proteins 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 208000002593 Pantothenate Kinase-Associated Neurodegeneration Diseases 0.000 description 1
- 206010061536 Parkinson's disease Diseases 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 229960003531 Phenolsulfonphthalein Drugs 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 241001482237 Pica Species 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N Pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000036908 Plasma Stability Effects 0.000 description 1
- 241000209048 Poa Species 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 206010036181 Porphyria Diseases 0.000 description 1
- 241000097929 Porphyria Species 0.000 description 1
- 206010036186 Porphyria non-acute Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229940107700 Pyruvic Acid Drugs 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N Raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000036045 Renal clearance Effects 0.000 description 1
- GHMLBKRAJCXXBS-UHFFFAOYSA-N Resorcinol Natural products OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- GHSJKUNUIHUPDF-BYPYZUCNSA-N S-Aminoethyl-L-cysteine Chemical compound NCCSC[C@H](N)C(O)=O GHSJKUNUIHUPDF-BYPYZUCNSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 206010040661 Sideroblastic anaemia Diseases 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229940108519 Trasylol Drugs 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 229940035504 Tromethamine Drugs 0.000 description 1
- OHGNSVACHBZKSS-KWQFWETISA-N Trp-Ala Chemical compound C1=CC=C2C(C[C@H]([NH3+])C(=O)N[C@@H](C)C([O-])=O)=CNC2=C1 OHGNSVACHBZKSS-KWQFWETISA-N 0.000 description 1
- 201000001203 Wilson disease Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000001594 aberrant Effects 0.000 description 1
- 230000002159 abnormal effect Effects 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
- 159000000021 acetate salts Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229940087168 alpha Tocopherol Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated Effects 0.000 description 1
- 229960003692 aminobutyric acid Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000000511 arginine group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 201000007867 atransferrinemia Diseases 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 208000005980 beta-Thalassemia Diseases 0.000 description 1
- 229960000074 biopharmaceuticals Drugs 0.000 description 1
- 230000037348 biosynthesis Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- CRBHXDCYXIISFC-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CC[O-] CRBHXDCYXIISFC-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 201000000522 chronic kidney disease Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000035512 clearance Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 201000004440 congenital dyserythropoietic anemia Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- MQYQOVYIJOLTNX-UHFFFAOYSA-N dichloromethane;N,N-dimethylformamide Chemical compound ClCCl.CN(C)C=O MQYQOVYIJOLTNX-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000447 dimerizing Effects 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical group CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting Effects 0.000 description 1
- 230000012953 feeding on blood of other organism Effects 0.000 description 1
- 230000002600 fibrillogenic Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960005051 fluostigmine Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000000174 gluconic acid Chemical group 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000009300 hypochromic microcytic Anemia Diseases 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 125000000400 lauroyl 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])[H] 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000003278 mimic Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000001419 myristoyl 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])[H] 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 201000010273 porphyria cutanea tarda Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000644 propagated Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 201000003456 pulmonary hemosiderosis Diseases 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Chemical group 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
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960001663 sulfanilamide Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N α-aminoisobutanoic acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
Abstract
The present invention relates, inter alia, to certain hepcidin peptide analogues, including peptides and dimers thereof, and to the use of the peptides and peptide dimers in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein. on overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein.
Description
(12) Granted patent specificaon (19) NZ (11) 751741 (13) B2
(47) Publicaon date: 2021.12.24
(54) HEPCIDIN ANALOGUES AND USES THEROF
(51) Internaonal Patent Classificaon(s):
A61K 38/10 A61K 38/08 A61K 38/04 C07K 5/00 C07K 7/00 C07K 16/00 C07K 17/00
(22) Filing date: (73) Owner(s):
2014.03.17 PROTAGONIST THERAPEUTICS, INC.
(23) Complete specificaon filing date: (74) Contact:
2014.03.17 DAVIES COLLISON CAVE PTY LTD
(62) Divided out of 712029 (72) Inventor(s):
SMYTHE, Mark Leslie
(30) Internaonal Priority Data: BOURNE, Gregory Thomas
US 61/800,048 2013.03.15 VINK, Simone
US 61/800,284 2013.03.15 FREDERICK, Brian T.
MADALA, Praveen
TOFTENG SHELTON, Anne Pernille
FOG, Jacob Ulrik
(57) Abstract:
The present invenon relates, inter alia, to certain hepcidin pepde analogues, including pepdes
and dimers thereof, and to the use of the pepdes and pepde dimers in the treatment and/or
prevenon of a variety of diseases, condions or disorders, including treatment and/or prevenon
of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias,
and other condions and disorders described herein.
NZ 751741 B2
HEPCIDIN ANALOGUES AND USES THEROF
This application is a divisional of New Zealand Patent Application No. 712029, the
entire content of which is incorporated herein by reference.
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No. 61/800,048,
filed on March 15, 2013, and U.S. Provisional Application No. 61/800,284, filed on March
, 2013, each of which is incorporated by reference herein in its entirety.
STATEMENT REGARDING SEQUENCE LISTING
The Sequence Listing associated with this application is provided in text format in
lieu of a paper copy, and is hereby incorporated by reference into the specification. The
name of the text file containing the Sequence Listing is PRTH_001_01WO_ST25.txt. The
text file is 126 KB, was created on March 17, 2014, and is being submitted electronically
via EFS-Web.
FIELD OF THE INVENTION
The present invention relates, inter alia, to certain hepcidin peptide analogues,
including peptides and dimers thereof, as well as compositions comprising the peptides and
peptide dimers, and to the use of the peptides and peptide dimers in the treatment and/or
prevention of a variety of diseases, conditions or disorders, including treatment and/or
prevention of iron overload diseases including hereditary hemochromatosis, iron-loading
anemias, and other conditions and disorders described herein.
BACKGROUND
Hepcidin (also referred to as LEAP-1), a peptide hormone produced by the liver, is
a regulator of iron homeostasis in humans and other mammals. Hepcidin acts by binding to
its receptor, the iron export channel ferroportin, causing its internalization and degradation.
Human hepcidin is a 25-amino acid peptide (Hep25). See Krause et al. (2000) FEBS Lett
480:147-150, and Park et al. (2001) J Biol Chem 276:7806-7810. The structure of the
bioactive 25-amino acid form of hepcidin is a simple hairpin with 8 cysteines that form 4
disulfide bonds as described by Jordan et al. J Biol Chem 284:24155-67. The N terminal
region is required for iron-regulatory function, and deletion of 5 N-terminal amino acid
residues results in a loss of iron-regulatory function. See Nemeth et al. (2006) Blood
107:328-33.
Abnormal hepcidin activity is associated with iron overload diseases, including
hereditary hemochromatosis (HH) and iron-loading anemias. Hereditary hemochromatosis
is a genetic iron overload disease that is mainly caused by hepcidin deficiency, or in some
cases by hepcidin resistance. This allows excessive absorption of iron from the diet and
development of iron overload. Clinical manifestations of HH may include liver disease
(e.g., hepatic cirrhosis and hepatocellular carcinoma), diabetes, and heart failure. Currently,
the only treatment for HH is regular phlebotomy, which is very burdensome for the
patients. Iron-loading anemias are hereditary anemias with ineffective erythropoiesis such
as β-thalassemia, which are accompanied by severe iron overload. Complications from iron
overload are the main cause of morbidity and mortality for these patients. Hepcidin
deficiency is the main cause of iron overload in non-transfused patients, and contributes to
iron overload in transfused patients. The current treatment for iron overload in these
patients is iron chelation which is very burdensome, sometimes ineffective, and
accompanied by frequent side effects.
Hepcidin has a number of limitations which restrict its use as a drug, including a
difficult synthesis process due in part to aggregation and precipitation of the protein during
folding, which in turn leads to high cost of goods. What are needed in the art are
compounds having hepcidin activity and also possessing other beneficial physical
properties such as improved solubility, stability, and/or potency , so that hepcidin-like
biologics might be produced affordably, and used to treat hepcidin-related diseases and
disorders such as, e.g., those described herein.
The present invention addresses such needs, providing novel peptide analogues, and
dimers thereof, having hepcidin activity and also having other beneficial properties making
the peptides of the present invention suitable alternatives to hepcidin.
BRIEF SUMMARY OF THE INVENTION
The present invention generally relates to peptides exhibiting hepcidin activity and
methods of using the same.
In some embodiments, the invention provides peptides, which may be isolated
and/or purified, comprising, consisting essentially of, or consisting of, the following
structural formula I:
R -X-Y-R (I) (SEQ ID NO:12)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R is hydrogen, an C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl
(e.g. methyl, acetyl, formyl, benzoyl or trifluoroacetyl, isovaleric acid, isobutyric acid,
octanoic acid, lauric acid and hexadecanoic acid), γ-Glu-hexadecanoic acid) or pGlu,
appended to the N-terminus, and including PEGylated versions (e.g. PEG3 to PEG11),
alone or as spacers of any of the foregoing;
R is -NH or -OH;
X is a peptide sequence having the formula (Ia)
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (Ia) (SEQ ID NO:1)
wherein
X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Lys, Ala, or D-His;
X4 is Phe, Ala, Dpa, bhPhe, of D-Phe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or
Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent;
Y is absent or Y is a peptide having the formula (IIa)
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (IIa) (SEQ ID NO:5)
wherein
Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent;
Y2 is Pro, Ala, Cys, Gly or absent;
Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent;
Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent;
Y5 is Lys, Met, Arg, Ala or absent;
Y6 is Gly, Ser, Lys, Ile, Arg, Ala, Pro, Val or absent;
Y7 is Trp, Lys, Gly, Ala Ile, Val or absent;
Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent;
Y9 is Cys, Tyr or absent;
Y10 is Met, Lys, Arg, Tyr or absent;
Y11 is Arg, Met, Cys, Lys or absent;
Y12 is Arg, Lys, Ala or absent;
Y13 is Arg, Cys, Lys, Val or absent;
Y14 is Arg, Lys, Pro, Cys, Thr or absent; and
Y15 is Thr, Arg or absent;
wherein if Y is absent from the peptide of formula (I), X7 is Ile; and
wherein said compound of formula (I) is optionally PEGylated on R , X, or Y.
In some embodiments, the compound of formula (I) comprises two or more
cysteine residues, wherein at least two of said cysteine residues are linked via a disulfide
bond.
In some embodiments, the invention provides peptides, which may be isolated
and/or purified, comprising, consisting essentially of, or consisting of the following
structural formula I’:
R ’- X’-Y’-R ’ (I’) (SEQ ID NO:21)
or a pharmaceutically acceptable salt or solvate thereof,
wherein
R ’ is hydrogen, an C -C alkyl, C -C aryl, C -C aryl C -C alkyl, C -C alkanoyl (e.g.
1 6 6 12 6 12 1 6 1 20
methyl, acetyl, formyl, benzoyl or trifluoroacetyl, isovaleric acid, isobutyric acid, octanoic
acid, lauric acid and hexadecanoic acid), γ-Glu-hexadecanoic acid) or pGlu , appended to
the N-terminus, and including PEGylated versions (e.g. PEG3 to PEG11), alone or as
spacers of any of the foregoing;
R ’ is -NH or -OH;
X’ is a peptide sequence having the formula Ia’
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (Ia’) (SEQ ID NO:13)
wherein
X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Ala, D-His or Lys;
X4 is Phe, Ala, Dpa, bhPhe or D-Phe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg , D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or
Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent;
and provided that if Y’ is absent, X7 is Ile;
Y’ is a peptide having the formula IIa’
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (IIa’) (SEQ ID NO:16)
wherein
Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent;
Y2 is Pro, Ala, Cys, Gly or absent;
Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent;
Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent;
Y5 is Lys, Met, Arg, Ala or absent;
Y6 is Gly, Ser, Lys, Ile, Ala, Pro, Val or absent;
Y7 is Trp, Lys, Gly, Ala, Ile, Val or absent;
Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent;
Y9 is Cys, Tyr or absent;
Y10 is Met, Lys, Arg, Tyr or absent;
Y11 is Arg, Met, Cys, Lys or absent;
Y12 is Arg, Lys, Ala or absent;
Y13 is Arg, Cys, Lys, Val or absent;
Y14 is Arg, Lys, Pro, Cys, Thr or absent; and
Y15 is Thr, Arg or absent;
wherein said compound of formula I’ is optionally PEGylated on R ’, X’, or Y’; and
wherein when said compound of formula I’ comprises two or more cysteine residues, at
least two of said cysteine residues being linked via a disulfide bond.
In some embodiments, the compound of formula I’ comprises an R ’ moiety that is
hydrogen, isovaleric acid, isobutyric acid, or acetyl.
In some embodiments, the compound of formula I’ comprises an X’ peptide of
formula Ia’ as described herein, wherein
X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp or absent;
X2 is Thr, Ala, or D-Thr;
X3 is His, Lys, D-His or Lys;
X4 is Phe, Ala, Dpa or D-Phe;
X5 is Pro, Gly, Arg, Lys, Ala, D-Pro or bhPro;
X6 is Ile, Cys, Arg, Lys, D-Ile or D-Cys;
X7 is Cys, Ile, Leu, Val, Phe, D-Ile or D-Cys;
X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu or D-Ile;
X9 is Phe or bhPhe; and
X10 is Lys, Phe or absent.
In some embodiments, the compound of formula I’ comprises an X’ peptide of
formula Ib’:
X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (Ib’)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, Ile, Leu or Val;
X8 is Ile Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
In some embodiments, the compound of formula I’ comprises an X’ peptide of
formula Ic’:
X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (Ic’)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X8 is Ile Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
In some embodiments, the compound of formula I’ comprises a Y’ peptide of
formula IIb’.
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Cys-Y10 (IIb’)
wherein
Y1 is Gly, Ala, Lys, Pro or D-Pro;
Y2 is Pro, Ala or Gly;
Y3 is Arg, Ala, Lys or Trp;
Y4 is Ser, Gly or Ala;
Y5 is Lys, Met, Arg or Ala;
Y6 is Gly, Arg or Ala;
Y7 is Trp or Ala;
Y8 is Val, Thr, Ala or Glu; and
Y10 is Met, Lys or absent.
In some embodiments, the compound of formula I’ comprises a Y’ peptide of
formula IIc’.
Y1-Y2-Y3-Ser-Lys-Gly-Trp-Y8-Cys-Y10 (IIc’)
wherein
Y1 is Gly, Pro or D-Pro;
Y2 is Pro or Gly;
Y3 is Arg or Lys;
Y8 is Val or Thr; and
Y10 is Met, Lys or absent.
In some embodiments, the compound of formula I’ comprises a Y’ peptide of
formula IId’:
Cys-Y3-Y4-Arg-Y6-Y7-Y8-Cys-Y10-Y11-Y12-Y13-Y14-Y15 (IId’)
wherein
Y1 is Val or Ala or absent;
Y3 is Gly, Pro or absent;
Y4 is His, Trp or Tyr; Y6 is Ser, Gly or Pro;
Y7 is Ile, Gly or Lys;
Y8 is Gly, Met or absent;
Y10 is Tyr or Cys;
Y11 is Arg, Lys, Met or Ala;
Y12is Arg or Ala;
Y13 is Cys or Val or absent;
Y14 is Cys, Lys, Pro, Arg, Thr or absent; and
Y15 is Arg, Thr or absent.
In some embodiments, the compound of formula I’ comprises a Y’ peptide of
formula IIe’:
Val-Cys-Y3-His-Arg-Y6-Y7-Y8-Cys-Tyr-Arg-Y12-Y13-Y14-Y15 (IIe’)
wherein
Y3 is Gly or absent;
Y6 is Ser or Pro;
Y7 is Ile or Lys;
Y8 is Gly or absent;
Y12 is Arg or Ala;
Y13 is Cys or Val or absent;
Y14 is Cys, Arg, Thr or absent; and
Y15 is Arg or absent.
In some embodiments, the invention provides peptides, which may be isolated
and/or purified, comprising, consisting essentially of, or consisting of the following
structural formula I’’:
R ’’-X’’-Y’’-R ’’ (I’’) (SEQ ID NO:27)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R ’’ is hydrogen, an C -C alkyl, C -C aryl, C -C aryl C -C alkyl, C -C alkanoyl (e.g.
1 6 6 12 6 12 1 6 1 20
methyl, acetyl, formyl, benzoyl or trifluoroacetyl, isovaleric acid, isobutyric acid, octanoic
acid, lauric acid and hexadecanoic acid), γ-Glu-hexadecanoic acid) or pGlu, appended to
the N-terminus, and including PEGylated versions (e.g. PEG3 to PEG11), alone or as
spacers of any of the foregoing;
R ’’ is -NH or -OH;
X’’ is a peptide sequence having the formula Ia’’
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (Ia’’ ) (SEQ ID NO:22)
wherein
X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Ala, D-His or Lys;
X4 is Phe, Ala, Dpa, bhPhe or D-Phe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or
Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent;
and provided that if Y’’ is absent, X7 is Ile.
In some embodiments, the compound of formula I’’ is PEGylated on R ’’, X’’, or
Y’’.
In some embodiments, the compound of formula I’’ comprises two or more
cysteine residues, at least two of said cysteine residues being linked via a disulfide bond.
In some embodiments, the compound of formula I’’ comprises an R ’’ that is
hydrogen, isovaleric acid, iso-butyric acid or acetyl.
In some embodiments, the compound of formula I’’ comprises an X’’ peptide
according to formula Ia’’, disclosed herein,
wherein
X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp or absent;
X2 is Thr, Ala, or D-Thr;
X3 is His, Lys, D-His or Lys;
X4 is Phe, Ala, or Dpa;
X5 is Pro, Gly, Arg, Lys, Ala, D-Pro or bhPro;
X6 is Ile, Cys, Arg, Lys, D-Ile or D-Cys;
X7 is Cys, Ile, Leu, Val, Phe, D-Ile or D-Cys;
X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu or D-Ile;
X9 is Phe or bhPhe; and
X10 is Lys or absent.
In some embodiments, the compound of formula I’’ comprises an X’’ peptide of
formula Ib’’:
X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (Ib’’)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, Ile, Leu or Val;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys, Phe or absent.
In some embodiments, the compound of formula I’’ comprises an X’’ peptide of
formula Ic’’:
X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (Ic’’)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
In some embodiments, the compound of formula I’’ comprises a Y’’ peptide of
formula IIa’’:
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Cys-Y10 (IIa’’) (SEQ ID NO:25)
wherein
Y1 is Gly, Ala, Lys, Pro or D-Pro;
Y2 is Pro, Ala or Gly;
Y3 is Arg, Ala, Lys or Trp;
Y4 is Ser, Gly or Ala;
Y5 is Lys, Met, Arg or Ala;
Y6 is Gly, Arg or Ala;
Y7 is Trp, Ala or absent;
Y8 is Val, Thr, Lys, Ala, Glu or absent; and
Y10 is Met, Lys or absent.
In some embodiments, the compound of formula I’’ comprises a Y’’ peptide of
formula IIb’’:
Y1-Y2-Y3-Ser-Lys-Gly-Trp-Y8-Cys-Y10 (IIb’’)
wherein
Y1 is Gly, Pro or D-Pro;
Y2 is Pro, Gly;
Y3 is Arg, Lys;
Y8 is Val or Thr; and
Y10 is Met, Lys or absent.
In related embodiments, the present invention includes dimers, e.g., homodimers, of
any of the peptides of the present invention.
In some embodiments, the peptides or dimers of the present invention exhibit
hepcidin activity. In some embodiments, the peptides or dimers bind ferroportin, e.g.,
human ferroportin.
In some embodiments, the present invention provides methods of binding a
ferroportin or inducing ferroportin internalization and degradation which comprise
contacting the ferroportin with at least one peptide, dimer or composition as disclosed
herein.
In some embodiments, the present invention provides compositions and
medicaments comprising at least one peptide or dimer as disclosed herein.
In some embodiments, the present invention provides a method of manufacturing
medicaments comprising at least one peptide or dimer as disclosed herein for the treatment
of diseases of iron metabolism, such as iron overload diseases.
Also provided are methods of treating a disease of iron metabolism in a subject,
such as a mammalian subject, e.g., a human subject, comprising administering at least one
peptide, dimer or composition as disclosed herein to the subject. In some embodiments,
the peptide or dimer is administered in a therapeutically effective amount. In some
embodiments, the disease of iron metabolism is an iron overload disease.
In some embodiments, the present invention provides a method of manufacturing a
peptide or peptide dimer of the present invention synthetically. In some embodiments, the
present invention provides a method of manufacturing a peptide or peptide dimer of the
present invention recombinantly.
In some embodiments, the present invention provides a pharmaceutical composition
comprising a peptide analogue (e.g., a peptide or dimer of the present invention), or
pharmaceutically acceptable salt or solvate thereof, as described herein, in combination
with one or more peptide analogue (e.g., a peptide or dimer of the present invention) or
pharmaceutically acceptable salt or solvate thereof, as described herein together with a
pharmaceutically acceptable carrier, excipient or vehicle.
In some embodiments, the invention provides a process for manufacturing a
compound or a pharmaceutical composition as disclosed herein.
In some embodiments, the invention provides a device comprising at least one
peptide analogue (e.g., a peptide or dimer of the present invention), or pharmaceutically
acceptable salt or solvate thereof for delivery of the peptide analogue to a subject.
In some embodiments, the present invention provides kits comprising at least one
peptide, dimer, or composition as disclosed herein packaged together with a reagent, a
device, instructional material, or a combination thereof.
In some embodiments, the present invention provides complexes which comprise at
least one peptide or dimer as disclosed herein bound to a ferroportin, e.g., a human
ferroportin, or an antibody, such as an antibody which specifically binds a peptide as
disclosed herein, Hep25, or a combination thereof.
Both the foregoing general description and the following detailed description are
exemplary and explanatory only and are intended to provide further explanation of the
invention as claimed. The accompanying drawings are included to provide a further
understanding of the invention and are incorporated in and constitute part of this
specification, illustrate several embodiments of the invention, and together with the
description serve to explain the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the results of an in vitro activity assay measuring the induction of
degradation of the human ferroportin protein. Presented are dose response curves for
Compound No. 1 as compared to Hepcidin and the Mini-Hepcidin control.
Figure 2 shows time dependent changes in serum iron following animal exposure
to vehicle, Compound No. 2 and reference compound RI Mini-Hepcidin. The responses are
normalized to the initial (t=0) levels.
Figure 3 shows relative decrease of serum iron relative to vehicle control measured
with Compound No. 2 as well as the reference compound RI-Mini-Hepcidin at timepoints
0, 30, 60, 120, 240 and 360 minutes. 100% represents the measured average level of serum
iron in the vehicle treated animals.
Figure 4 shows the in vivo serum iron reducing abilities of selected peptides of the
present invention and Hepcidin.
Figure 5 shows a dose response of the in vivo serum iron reducing abilities of
selected peptides of the present invention and Hepcidin.
Figure 6 shows the PK/PD effects for the in vivo serum iron reducing abilities of
selected peptides of the present invention and Hepcidin. For Hepcidin and the 300 nmol/kg
treatment with compound #181, only one timepoint was taken at t=120 min. The Hepcidin
response is not clearly visible on this graph, as it overlapped with the Cmpd #181 1000
nmol/kg plot at the t-120 min point. The single data point for compound #181 300 nmol/kg
is located directly above the Hepcidin point.
Figure 7 shows selected examples of linkers that were used to dimerize the
peptides.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise defined herein, scientific and technical terms used in this
application shall have the meanings that are commonly understood by those of ordinary
skill in the art. Generally, nomenclature used in connection with, and techniques of,
chemistry, molecular biology, cell and cancer biology, immunology, microbiology,
pharmacology, and protein and nucleic acid chemistry, described herein, are those well-
known and commonly used in the art.
All publications, patents and published patent applications referred to in this
application are specifically incorporated by reference herein. In case of conflict, the
present specification, including its specific definitions, will control.
Each embodiment of the invention described herein may be taken alone or in
combination with one or more other embodiments of the invention.
DEFINITIONS
Throughout this specification, the word “comprise” or variations such as
“comprises” or “comprising” will be understood to imply the inclusion of a stated integer
(or components) or group of integers (or components), but not the exclusion of any other
integer (or components) or group of integers (or components).
The singular forms “a,” “an,” and “the” include the plurals unless the context
clearly dictates otherwise.
The term “including” is used to mean “including but not limited to.” “Including”
“including but not limited to” are used interchangeably.
The terms “patient,” “subject,” and “individual” may be used interchangeably and
refer to either a human or a non-human animal. These terms include mammals such as
humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g.,
canines, felines) and rodents (e.g., mice and rats).
The term formula (I), is used herein interchangeably with the term formula I (i.e.,
without the parentheses). The term formula (I’), is used herein interchangeably with the
term formula I’ (i.e., without the parentheses). The term formula (I’’), is used herein
interchangeably with the term formula I’’ (i.e., without the parentheses).
The recitations “sequence identity”, “percent identity”, “percent homology”, or, for
example, comprising a “sequence 50% identical to,” as used herein, refer to the extent that
sequences are identical on a nucleotide-by-nucleotide basis or an amino acid-by-amino acid
basis over a window of comparison. Thus, a “percentage of sequence identity” may be
calculated by comparing two optimally aligned sequences over the window of comparison,
determining the number of positions at which the identical nucleic acid base (e.g., A, T, C,
G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe,
Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) occurs in both sequences to
yield the number of matched positions, dividing the number of matched positions by the
total number of positions in the window of comparison (i.e., the window size), and
multiplying the result by 100 to yield the percentage of sequence identity.
Calculations of sequence similarity or sequence identity between sequences (the
terms are used interchangeably herein) can be performed as follows. To determine the
percent identity of two amino acid sequences, or of two nucleic acid sequences, the
sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in
one or both of a first and a second amino acid or nucleic acid sequence for optimal
alignment and non-homologous sequences can be disregarded for comparison purposes). In
certain embodiments, the length of a reference sequence aligned for comparison purposes
is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more
preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The
amino acid residues or nucleotides at corresponding amino acid positions or nucleotide
positions are then compared. When a position in the first sequence is occupied by the same
amino acid residue or nucleotide as the corresponding position in the second sequence, then
the molecules are identical at that position.
The percent identity between the two sequences is a function of the number of
identical positions shared by the sequences, taking into account the number of gaps, and the
length of each gap, which need to be introduced for optimal alignment of the two
sequences.
The comparison of sequences and determination of percent identity between two
sequences can be accomplished using a mathematical algorithm. In some embodiments, the
percent identity between two amino acid sequences is determined using the Needleman and
Wunsch, (1970, J. Mol. Biol. 48: 444-453) algorithm which has been incorporated into the
GAP program in the GCG software package, using either a Blossum 62 matrix or a
PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2,
3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two
nucleotide sequences is determined using the GAP program in the GCG software package,
using an NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length
weight of 1, 2, 3, 4, 5, or 6. Another exemplary set of parameters includes a Blossum 62
scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap
penalty of 5. The percent identity between two amino acid or nucleotide sequences can also
be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4: 11-17)
which has been incorporated into the ALIGN program (version 2.0), using a PAM120
weight residue table, a gap length penalty of 12 and a gap penalty of 4.
The peptide sequences described herein can be used as a “query sequence” to
perform a search against public databases to, for example, identify other family members
or related sequences. Such searches can be performed using the NBLAST and XBLAST
programs (version 2.0) of Altschul, et al., (1990, J. Mol. Biol, 215: 403-10). BLAST
nucleotide searches can be performed with the NBLAST program, score = 100, wordlength
= 12 to obtain nucleotide sequences homologous to nucleic acid molecules of the
invention. BLAST protein searches can be performed with the XBLAST program, score =
50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the
invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be
utilized as described in Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997). When
utilizing BLAST and Gapped BLAST programs, the default parameters of the respective
programs (e.g., XBLAST and NBLAST) can be used.
As used herein, the term “pharmaceutically acceptable salt” is intended to indicate a
salt which is not harmful to a patient or subject to which the salt in question is
administered. It may suitably be a salt chosen, e.g., among acid addition salts and basic
salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts.
Examples of basic salts include salts where the cation is selected among alkali metal
cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or
magnesium ions, as well as substituted ammonium ions, such as ions of the type
N(R1)(R2)(R3)(R4)+, where R1, R2, R3 and R4 independently will typically designate
hydrogen, optionally substituted C1alkyl or optionally substituted C2alkenyl.
Examples of relevant C1alkyl groups include methyl, ethyl, 1-propyl and 2-propyl
groups. Examples of C2alkenyl groups of possible relevance include ethenyl, 1-propenyl
and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in
“Remington’s Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark
Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the
“Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.),
Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977). Also,
for a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties,
Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Other suitable base salts are
formed from bases which form non-toxic salts. Representative examples include the
aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine,
magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.
Hemisalts of acids and bases may also be formed, e.g., hemisulphate and hemicalcium
salts. Compositions to be used in the invention suitable for parenteral administration may
comprise sterile aqueous solutions and/or suspensions of the pharmaceutically active
ingredients preferably made isotonic with the blood of the recipient, generally using
sodium chloride, glycerin, glucose, mannitol, sorbitol, and the like. Organic acids suitable
for forming pharmaceutically acceptable acid addition salts include, by way of example
and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic
acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic
acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-
chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
camphorsulfonic acid, etc.), 4-methylbicyclo(2.2.2)-octenecarboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,
lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid,
stearic acid, muconic acid, and the like.
The term “solvate” in the context of the present invention refers to a complex of
defined stoichiometry formed between a solute (in casu, a peptide analogue or
pharmaceutically acceptable salt thereof according to the invention) and a solvent. The
solvent in this connection may, for example, be water, ethanol or another pharmaceutically
acceptable, typically small-molecular organic species, such as, but not limited to, acetic
acid or lactic acid. When the solvent in question is water, such a solvate is normally
referred to as a hydrate.
The term “agonist” as employed in the context of the invention refers to a substance
(ligand) that causes internalization of the ferroportin protein.
As used herein, a "disease of iron metabolism" includes diseases where aberrant
iron metabolism directly causes the disease, or where iron blood levels are dysregulated
causing disease, or where iron dysregulation is a consequence of another disease, or where
diseases can be treated by modulating iron levels, and the like. More specifically, a disease
of iron metabolism according to this disclosure includes iron overload diseases, iron
deficiency disorders, disorders of iron biodistribution, other disorders of iron metabolism
and other disorders potentially related to iron metabolism, etc. Diseases of iron metabolism
include hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation
hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation
hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis,
neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, thalassemia,
thalassemia intermedia, alpha thalassemia, sideroblastic anemia, porphyria, porphyria
cutanea tarda, African iron overload, hyperferritinemia, ceruloplasmin deficiency,
atransferrinemia, congenital dyserythropoietic anemia, anemia of chronic disease, anemia
of inflammation, anemia of infection, hypochromic microcytic anemia, iron- deficiency
anemia, iron-refractory iron deficiency anemia, anemia of chronic kidney disease,
erythropoietin resistance, iron deficiency of obesity, other anemias, benign or malignant
tumors that overproduce hepcidin or induce its overproduction, conditions with hepcidin
excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease,
pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver,
pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative
disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's
disease.
In some embodiments, the disease and disorders are related to iron overload
diseases such as iron hemochromatosis, HFE mutation hemochromatosis, ferroportin
mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin
mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile
hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron
overload, thalassemia, thalassemia intermedia, alpha thalassemia.
In some embodiments, the peptides of the invention are used to treat diseases and
disorders that are not typically identified as being iron related. For example, hepcidin is
highly expressed in the murine pancreas suggesting that diabetes (Type I or Type II),
insulin resistance, glucose intolerance and other disorders may be ameliorated by treating
underlying iron metabolism disorders. See Ilyin, G. et al. (2003) FEBS Lett. 542 22-26,
which is herein incorporated by reference. As such, peptides of the invention may be used
to treat these diseases and conditions. Those skilled in the art are readily able to determine
whether a given disease can be treated with a peptide according to the present invention
using methods known in the art, including the assays of WO 2004092405, which is herein
incorporated by reference, and assays which monitor hepcidin, hemojuvelin, or iron levels
and expression, which are known in the art such as those described in U.S. Patent No.
7,534,764, which is herein incorporated by reference.
In certain embodiments of the present invention, the diseases of iron metabolism
are iron overload diseases, which include hereditary hemochromatosis, iron-loading
anemias, alcoholic liver diseases and chronic hepatitis C.
As used herein, the terms "protein", "polypeptide" and "peptide" are used
interchangeably to refer to two or more amino acids linked together. Except where
indicated otherwise, e.g., for the abbreviations for the uncommon or unnatural amino acids
set forth herein, the three-letter and one-letter abbreviations, as used in the art, are used
herein to represent amino acid residues. Except when preceded with "D-", the amino acid is
an L-amino acid. Groups or strings of amino acid abbreviations are used to represent
peptides. Except when specifically indicated, peptides are indicated with the N- terminus
on the left and the sequence is written from the N-terminus to the C- terminus.
The term “peptide analogue” in the context of the present invention refers to a
molecule in which a first peptide moiety is attached (i.e. coupled or linked), either directly
or via a linking (i.e. bridging or spacing) chemical moiety, to a second peptide moiety, by
means of covalent chemical bonding. In certain embodiments, a peptide analogue is a
peptide described herein comprising an X peptide sequence and a Y peptide sequence. In
certain embodiments, a peptide analogue is a peptide described herein comprising an X’
peptide sequence and a Y’ peptide sequence. In certain embodiments, a peptide analogue
is a peptide described herein comprising an X’’ peptide sequence and a Y’’ peptide
sequence. In certain embodiments, a peptide analogue is a peptide described herein
comprising an X peptide sequence and/or a Y peptide sequence conjugated to an additional
chemical moiety. In certain embodiments, a peptide analogue is a peptide described herein
comprising an X’ peptide sequence and/or a Y’ peptide sequence conjugated to an
additional chemical moiety. In certain embodiments, a peptide analogue is a peptide
described herein comprising an X’’ peptide sequence and/or a Y’’ peptide sequence
conjugated to an additional chemical moiety. The peptides of the present invention
described herein are peptide analogues. Peptide analogues also include any of the peptide
dimers described herein.
Peptides and peptide dimers of the present invention may also be referred to herein
as compounds or peptide analogues.
The term "conservative substitution" as used herein denotes that one or more amino
acids are replaced by another, biologically similar residue. Examples include substitution
of amino acid residues with similar characteristics, e.g., small amino acids, acidic amino
acids, polar amino acids, basic amino acids, hydrophobic amino acids and aromatic amino
acids. See, for example, the table below. In some embodiments of the invention, one or
more Met residues are substituted with norleucine (Nle) which is a bioisostere for Met, but
which, as opposed to Met, is not readily oxidized. Another example of a conservative
substitution with a residue normally not found in endogenous, mammalian peptides and
proteins is the conservative substitution of Arg or Lys with, for example, ornithine,
canavanine, aminoethylcysteine or another basic amino acid. In some embodiments, one or
more cysteines of a peptide analogue of the invention may be substituted with another
residue, such as a serine. For further information concerning phenotypically silent
substitutions in peptides and proteins, see, for example, Bowie et.al. Science 247, 1306-
1310, 1990. In the scheme below, conservative substitutions of amino acids are grouped
by physicochemical properties. I: neutral, hydrophilic, II: acids and amides, III: basic, IV:
hydrophobic, V: aromatic, bulky amino acids.
I II III IV V
A N H M F
S D R L Y
T E K I W
P Q V
G C
In the scheme below, conservative substitutions of amino acids are grouped by
physicochemical properties. VI: neutral or hydrophobic, VII: acidic, VIII: basic, IX: polar,
X: aromatic.
VI VII VIII IX X
A E H M F
L D R S Y
I K T W
P C
G N
V Q
In certain embodiments, the present invention provides peptides which are useful in
the study and treatment of diseases of iron metabolism.
Throughout the present specification, unless naturally occurring amino acids are
referred to by their full name (e.g. alanine, arginine, etc.), they are designated by their
conventional three-letter or single-letter abbreviations (e.g. Ala or A for alanine, Arg or R
for arginine, etc.). In the case of less common or non-naturally occurring amino acids,
unless they are referred to by their full name (e.g. sarcosine, ornithine, etc.), frequently
employed three- or four-character codes are employed for residues thereof, including, Sar
or Sarc (sarcosine, i.e. N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-
diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba
(γ-aminobutanoic acid), β-Pro (pyrrolidinecarboxylic acid), and 8Ado (8-amino-3,6-
dioxaoctanoic acid), Abu (4-amino butyric acid), bhPro (β-homoproline), bhPhe (β-
homophenylalanine) and Dpa (β,β diphenylalanine), and Ida (Iminodiacetic acid).
As is clear to the skilled artisan, the peptide sequences disclosed herein are shown
proceeding from left to right, with the left end of the sequence being the N-terminus of the
peptide and the right end of the sequence being the C-terminus of the peptide. Among
sequences disclosed herein are sequences incorporating a “Hy-” moiety at the amino
terminus (N-terminus) of the sequence, and either an “-OH” moiety or an “–NH ” moiety
at the carboxy terminus (C-terminus) of the sequence. In such cases, and unless otherwise
indicated, a “Hy-” moiety at the N-terminus of the sequence in question indicates a
1 1 1
hydrogen atom [e.g., R , R ’, or R ’’ = hydrogen (Hy-) in formula I, I’, or I’’, respectively,
corresponding to the presence of a free primary or secondary amino group at the N-
terminus], while an “-OH” or an “–NH ” moiety at the C-terminus of the sequence
2 2 2
indicates a hydroxy group [e.g., R , R ’, or R ’’ = OH in formula I, I’, or I’’, respectively,
corresponding to the presence of a carboxy (COOH) group at the C-terminus] or an amino
2 2 2
group [e.g., R , R ’, or R ’’ = NH in formula I, I’, or I’’, respectively, corresponding to the
presence of an amido (CONH ) group at the C-terminus], respectively. In each sequence of
the invention, a C-terminal “–OH” moiety may be substituted for a C-terminal “–NH ”
1 1 1
moiety, and vice-versa. Furthermore, R , R ’, or R ’’ can in all sequences be substituted
with isovaleric acids or equivalent. In some embodiments, wherein a peptide of the present
invention is conjugated to an acidic compound such as, e.g., isovaleric acid, isobutyric
acid, valeric acid, and the like, the presence of such a conjugation is referenced in the acid
form. So, for example, but not to be limited in any way, instead of indicating a conjugation
of isovaleric acid to a peptide DTHFPCIKFCK (SEQ ID NO:215) by referencing
isovaleroyl (e.g., isovaleroyl-DTHFPCIKFCK [SEQ ID NO:215]), in some embodiments,
the present application references such a conjugation as isovaleric acid- DTHFPCIKFCK
(SEQ ID NO:215). Unless otherwise indicated, reference is made to the L-isomeric forms
of the amino acids in question. Where appropriate, the D-isomeric form of an amino acid
is indicated in the conventional manner by the prefix “D” before the conventional three-
letter code (e.g., DAsp or D-Asp; DPhe or D-Phe).
In some embodiments, the invention provides peptides, which may be isolated
and/or purified, comprising, consisting essentially of, or consisting of, the following
structural formula:
R -X-Y-R (I) (SEQ ID NO:12)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R is hydrogen, an C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl
(e.g., methyl, acetyl, formyl, benzoyl or trifluoroacetyl, isovaleric acid, isobutyric acid,
octanoic acid, lauric acid and hexadecanoic acid), γ-Glu-hexadecanoic acid) or pGlu,
appended to the N-terminus, and including PEGylated versions (e.g., PEG3 to PEG11),
alone or as spacers of any of the foregoing;
R is -NH or -OH;
X is a peptide sequence having the formula (Ia)
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (Ia) (SEQ ID NO:1)
wherein
X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Lys, Ala, or D-His;
X4 is Phe, Ala, Dpa, bhPhe, or D-Phe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or
Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent;
Y is absent or Y is a peptide having the formula (IIa)
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (IIa) (SEQ ID NO:5)
wherein
Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent;
Y2 is Pro, Ala, Cys, Gly or absent;
Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent;
Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent;
Y5 is Lys, Met, Arg, Ala or absent;
Y6 is Gly, Ser, Lys, Ile, Arg, Ala, Pro, Val or absent;
Y7 is Trp, Lys, Gly, Ala Ile, Val or absent;
Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent;
Y9 is Cys, Tyr or absent;
Y10 is Met, Lys, Arg, Tyr or absent;
Y11 is Arg, Met, Cys, Lys or absent;
Y12 is Arg, Lys, Ala or absent;
Y13 is Arg, Cys, Lys, Val or absent;
Y14 is Arg, Lys, Pro, Cys, Thr or absent; and
Y15 is Thr, Arg or absent;
wherein if Y is absent from the peptide of formula (I), X7 is Ile; and
wherein said compound of formula (I) is optionally PEGylated on R , X, or Y.
In some embodiments, the compound or peptide of formula (I) comprises two or
more cysteine residues, wherein at least two of said cysteine residues are linked via a
disulfide bond.
In some embodiments, X is a peptide sequence according to formula (Ia), described
herein,
wherein
X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Lys, Ala, or D-His;
X4 is Phe, Ala, Dpa, or bhPhe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or
Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent.
In some embodiments, X is a peptide sequence according to formula (Ia), described
herein, wherein
X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp or absent;
X2 is Thr, Ala, or D-Thr;
X3 is His, Lys, or D-His;
X4 is Phe, Ala, or Dpa;
X5 is Pro, Gly, Arg, Lys, Ala, D-Pro or bhPro;
X6 is Ile, Cys, Arg, Lys, D-Ile or D-Cys;
X7 is Cys, Ile, Leu, Val, Phe, D-Ile or D-Cys;
X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu or D-Ile;
X9 is Phe or bhPhe; and
X10 is Lys, Phe or absent.
In some embodiments, X is a peptide sequence having the formula (Ib)
X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (Ib) (SEQ ID NO:2)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, Ile, Leu or Val;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys, Phe or absent;
In some embodiments, X is a peptide sequence according to formula (Ib), as
described herein, wherein
X1 is Asp, Glu, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, Ile, Leu or Val;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
In some embodiments, X is a peptide sequence having the formula (Ic)
X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (Ic) (SEQ ID NO:3)
wherein
X1 is Asp, Glu, Ida, pGlu, bhAsp or absent;
X4 is: Phe or Dpa;
X5 is Pro or bhPro;
X8 is Ile Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
In some embodiments, X is a peptide sequence having the formula (Id)
X1-Thr-His-Phe-X5-Cys-Ile-X8-Phe-X10 (Id) (SEQ ID NO:4)
wherein
X1 is Asp, Glu, or Ida;
X4 is: Phe;
X5 is Pro or bhPro;
X8 is Ile, Lys or Phe; and
X10 is absent.
In some embodiments, Y is a peptide sequence having the formula IIb
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Cys-Y10 (IIb) (SEQ ID NO:6)
wherein
Y1 is Gly, Ala, Lys, Pro or D-Pro;
Y2 is Pro, Ala or Gly;
Y3 is Arg, Ala, Lys or Trp;
Y4 is Ser, Gly or Ala;
Y5 is Lys, Met, Arg or Ala;
Y6 is Gly, Arg or Ala;
Y7 is Trp, Ala or absent;
Y8 is Val, Thr, Lys, Ala, Glu or absent; and
Y10 is Met, Lys or absent.
In some embodiments, Y is a peptide sequence according to formula (IIb), as
described herein,
wherein
Y1 is Gly, Ala, Lys, Pro or D-Pro;
Y2 is Pro, Ala or Gly;
Y3 is Arg, Ala, Lys or Trp;
Y4 is Ser, Gly or Ala;
Y5 is Lys, Met, Arg or Ala;
Y6 is Gly, Arg or Ala;
Y7 is Trp or Ala;
Y8 is Val, Thr, Ala, or Glu; and
Y10 is Met, Lys or absent.
In some embodiments, Y is a peptide sequence having the formula (IIc)
Y1-Y2-Y3-Ser-Lys-Gly-Trp-Y8-Cys-Y10 (IIc) (SEQ ID NO:7)
wherein
Y1 is Gly, Pro or D-Pro;
Y2 is Pro or Gly;
Y3 is Arg or Lys;
Y8 is Val or Thr; and
Y10 is Met, Lys or absent.
In some embodiments, Y is a peptide sequence having the formula (IId)
Y1-Cys-Y3-Y4-Arg-Y6-Y7-Y8-Cys-Y10-Y11-Y12-Y13-Y14-Y15 (IId) (SEQ ID NO:8)
wherein
Y1 is Val, Ala or absent;
Y3 is Gly, Pro or absent;
Y4 is His, Trp or Tyr;
Y6 is Ser, Gly or Pro;
Y7 is Ile, Gly or Lys;
Y8 is Gly, Met or absent;
Y10 is Tyr or Cys;
Y11 is Arg, Lys, Met or Ala;
Y12is Arg or Ala;
Y13 is Cys or Val or absent;
Y14 is Cys, Lys, Pro, Arg, Thr or absent; and
Y15 is Arg, Thr or absent.
In some embodiments, Y is a peptide sequence having the formula (IIe)
Val-Cys-Y3-His-Arg-Y6-Y7-Y8-Cys-Tyr-Arg-Y12-Y13-Y14-Y15 (IIe) (SEQ ID NO:9)
wherein
Y3 is Gly or absent;
Y6 is Ser or Pro;
Y7 is Ile or Lys;
Y8 is Gly or absent;
Y12 is Arg or Ala;
Y13 is Cys, Val or absent;
Y14 is Cys, Arg, Thr or absent; and
Y15 is Arg or absent.
In some embodiments, Y is a peptide sequence having the formula (IIf)
Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y10 (IIf) (SEQ ID NO:10)
wherein
Y1 is Gly, Glu, Val, or Lys;
Y3 is Arg or Lys;
Y5 is Arg or Lys;
Y6 is Gly, Ser, Lys, Ile or Arg;
Y7 is Trp or absent;
Y8 is Val, Thr, Asp, Glu or absent; and
Y10 is Lys or absent.
In some embodiments, Y is a peptide sequence having the formula (IIg)
Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y10 (IIg) (SEQ ID NO:11)
wherein
Y1 is Glu or Lys;
Y3 is Arg or Lys;
Y5 is Arg or Lys;
Y6 is Gly, Ser, Lys, Ile or Arg;
Y7 is Trp or absent;
Y8 is Val or absent; and
Y10 is Lys or absent.
In some embodiments, the peptide of formula (I) comprises at least three, at least
four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least
eleven, at least twelve, at least thirteen, at least fourteen or at least fifteen Y residues in Y.
In some embodiments, Y1 to Y3 are present and Y4 to Y15 are absent.
In some embodiments, Y1 to Y11 are present and Y12 to Y15 are absent.
In some embodiments, Y1 to Y10 are present and Y11 to Y15 are absent.
In some embodiments, Y8 and Y15 are absent.
In some embodiments, Y3 and Y15 are absent
In some embodiments, Y3, Y14 and Y15 are absent.
In some embodiment Y5 is absent.
In some embodiments Y1, Y5, Y7, Y12, Y13, Y14 and Y15 are absent.
In some embodiments Y1, Y5, and Y7 are absent. In some embodiments, Y8 is
absent. In some embodiments, Y3 is absent.In some embodiments Y1, Y5, Y7, and Y11-
Y15 are absent. In some embodiments, Y8 and Y11-Y15 are absent. In some
embodiments, Y3 and Y11-Y15 are absent.
In some embodiments, the present invention provides a compound of formula (I),
wherein the compound comprises any one of the X / Y peptide sequence formula
combinations presented in Table 1 below.
Table 1: Illustrative combinations of X and Y peptides of a compound of Formula (I)
Formula I combinations
X Peptide Y Peptide
Combination
Sequence Sequence
Number
Formula Formula
1 Ia IIa
2 Ia IIb
3 Ia IIc
4 Ia IId
Ia IIe
6 Ia IIf
7 Ia IIg
8 Ib IIa
9 Ib IIb
Ib IIc
11 Ib IId
12 Ib IIe
13 Ib IIf
14 Ib IIg
Ic IIa
16 Ic IIb
17 Ic IIc
18 Ic IId
19 Ic IIe
Ic IIf
21 Ic IIg
22 Id IIa
23 Id IIb
24 Id IIc
Id IId
26 Id IIe
27 Id IIf
28 Id IIg
In some embodiments, the invention provides peptides, which may be isolated
and/or purified, comprising, consisting essentially of, or consisting of, the following
structural formula:
R ’-X’-Y’-R ’ (I’) (SEQ ID NO:21)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R ’ is hydrogen, an C -C alkyl, C -C aryl, C -C aryl C -C alkyl, C -C alkanoyl (e.g.,
1 6 6 12 6 12 1 6 1 20
methyl, acetyl, formyl, benzoyl or trifluoroacetyl, isovaleric acid, isobutyric acid, octanoic
acid, lauric acid and hexadecanoic acid), γ-Glu-hexadecanoic acid) or pGlu, appended to
the N-terminus, and including PEGylated versions (e.g., PEG3 to PEG11), alone or as
spacers of any of the foregoing;
R ’ is -NH or -OH;
X’ is a peptide sequence having the formula (Ia’)
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (Ia’) (SEQ ID NO:13)
wherein
X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Lys, Ala, or D-His;
X4 is Phe, Ala, Dpa, bhPhe or D-Phe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg , D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg or
Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent;
and provided that if Y’ is absent, X7 is Ile; and
Y’ is a peptide having the formula (IIa’)
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (IIa’) (SEQ ID NO:16)
wherein
Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent;
Y2 is Pro, Ala, Cys, Gly or absent;
Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent;
Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent;
Y5 is Lys, Met, Arg, Ala or absent;
Y6 is Gly, Ser, Lys, Ile, Arg, Ala, Pro, Val or absent;
Y7 is Trp, Lys, Gly, Ala Ile, Val or absent;
Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent;
Y9 is Cys, Tyr or absent;
Y10 is Met, Lys, Arg, Tyr or absent;
Y11 is Arg, Met, Cys, Lys or absent;
Y12 is Arg, Lys, Ala or absent;
Y13 is Arg, Cys, Lys, Val or absent;
Y14 is Arg, Lys, Pro, Cys, Thr or absent; and
Y15 is Thr, Arg or absent;
wherein said compound of formula (I’) is optionally PEGylated on R ’, X’, or Y’; and
wherein when said compound of formula (I’) comprises two or more cysteine residues, at
least two of said cysteine residues being linked via a disulfide bond.
In some embodiments, R ’ is hydrogen, isovaleric acid, isobutyric acid or acetyl.
In some embodiments of the peptide compound of formula (I’), X’ is a peptide
sequence according to formula (Ia’), wherein
X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp or absent;
X2 is Thr, Ala, or D-Thr;
X3 is His, Lys, D-His or Lys;
X4 is Phe, Ala, Dpa or D-Phe;
X5 is Pro, Gly, Arg, Lys, Ala, D-Pro or bhPro;
X6 is Ile, Cys, Arg, Lys, D-Ile or D-Cys;
X7 is Cys, Ile, Leu, Val, Phe, D-Ile or D-Cys;
X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu or D-Ile;
X9 is Phe or bhPhe; and
X10 is Lys, Phe or absent.
In some embodiments of the peptide compound of formula I’, X’ is a peptide
sequence having the formula (Ib’)
X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (Ib’) (SEQ ID NO:14)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, Ile, Leu or Val;
X8 is Ile Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
In some embodiments of the peptide compound of formula I’, X’ is a peptide
sequence having the formula (Ic’)
X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (Ic’) (SEQ ID NO:15)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is: Phe or Dpa;
X5 is Pro or bhPro;
X8 is Ile Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent;
In some embodiments of the peptide compound of formula I’, X’ is a peptide
sequence having the formula (Id’)
X1-Thr-His-Phe-X5-Cys-Ile-X8-Phe-X10 (Id’) (SEQ ID NO:4)
wherein
X1 is Asp, Glu, or Ida;
X4 is: Phe;
X5 is Pro or bhPro;
X8 is Ile, Lys, or Phe; and
X10 is absent;
In some embodiments of the peptide compound of formula I’, Y’ is a peptide
sequence having the formula (IIb’)
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Cys-Y10 (IIb’) (SEQ ID NO:17)
wherein
Y1 is Gly, Ala, Lys, Pro or D-Pro;
Y2 is Pro, Ala or Gly;
Y3 is Arg, Ala, Lys or Trp;
Y4 is Ser, Gly or Ala;
Y5 is Lys, Met, Arg or Ala;
Y6 is Gly, Arg or Ala;
Y7 is Trp or Ala;
Y8 is Val, Thr, Ala or Glu; and
Y10 is Met, Lys or absent.
In some embodiments of the peptide compound of formula I’, Y’ is a peptide
sequence having the formula (IIc’)
Y1-Y2-Y3-Ser-Lys-Gly-Trp-Y8-Cys-Y10 (IIc’) (SEQ ID NO:18)
wherein
Y1 is Gly, Pro or D-Pro;
Y2 is Pro or Gly;
Y3 is Arg or Lys;
Y8 is Val or Thr; and
Y10 is Met, Lys or absent.
In some embodiments of the peptide compound of formula I’, Y’ is a peptide
sequence having the formula (IId’)
Y1-Cys-Y3-Y4-Arg-Y6-Y7-Y8-Cys-Y10-Y11-Y12-Y13-Y14-Y15 (IId’) (SEQ ID NO:19)
wherein
Y1 is Val or Ala or absent;
Y3 is Gly, Pro or absent;
Y4 is His, Trp or Tyr;
Y6 is Ser, Gly or Pro;
Y7 is Ile, Gly or Lys;
Y8 is Gly, Met or absent;
Y10 is Tyr or Cys;
Y11 is Arg, Lys, Met or Ala;
Y12is Arg or Ala;
Y13 is Cys or Val or absent;
Y14 is Cys, Lys, Pro, Arg, Thr or absent; and
Y15 is Arg, Thr or absent.
In some embodiments of the peptide compound of formula I’, Y’ is a peptide
sequence having the formula (IIe’)
Val-Cys-Y3-His-Arg-Y6-Y7-Y8-Cys-Tyr-Arg-Y12-Y13-Y14-Y15 (IIe’) (SEQ ID NO:20)
wherein
Y3 is Gly or absent;
Y6 is Ser or Pro;
Y7 is Ile or Lys;
Y8 is Gly or absent;
Y12 is Arg or Ala;
Y13 is Cys, Val or absent;
Y14 is Cys, Arg, Thr or absent; and
Y15 is Arg or absent.
In some embodiments of the peptide compound of formula I’, Y’ is a peptide
sequence having the formula (IIf’)
Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y10 (IIf’) (SEQ ID NO:10)
wherein
Y1 is Gly, Glu, Val, or Lys;
Y3 is Arg or Lys;
Y5 is Arg or Lys;
Y6 is Gly, Ser, Lys, Ile or Arg;
Y7 is Trp or absent;
Y8 is Val, Thr, Asp, Glu or absent; and
Y10 is Lys or absent.
In some embodiments of the peptide compound of formula I’, Y’ is a peptide
sequence having the formula (IIg’)
Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y10 (IIg’) (SEQ ID NO:11)
wherein
Y1 is Glu or Lys;
Y3 is Arg or Lys;
Y5 is Arg or Lys;
Y6 is Gly, Ser, Lys, Ile or Arg;
Y7 is Trp or absent;
Y8 is Val or absent; and
Y10 is Lys or absent.
In some embodiments, the peptide of formula I’ comprises at least three, at least
four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least
eleven, at least twelve, at least thirteen, at least fourteen or at least fifteen Y residues in Y’.
In some embodiments, Y1 to Y3 are present and Y4 to Y15 are absent.
In some embodiments, Y1 to Y11 are present and Y12 to Y15 are absent.
In some embodiments, Y1 to Y10 are present and Y11 to Y15 are absent.
In some embodiments, Y8 and Y15 are absent.
In some embodiments, Y3 and Y15 are absent
In some embodiments, Y3, Y14 and Y15 are absent.
In some embodiment Y5 is absent.
In some embodiments Y1, Y5, Y7, Y12, Y13, Y14 and Y15 are absent.
In some embodiments, the present invention provides a compound of formula (I’),
wherein the compound comprises any one of the X’ / Y’ peptide sequence formula
combinations presented in Table 2 below.
Table 2: Illustrative combinations of X’ and Y’ peptides of a compound of Formula
(I’)
Formula I’ combinations
X’ Peptide Y’ Peptide
Combination
Sequence Sequence
Number
Formula Formula
1 Ia’ IIa’
2 Ia’ IIb’
3 Ia’ IIc’
4 Ia’ IId’
Ia’ IIe’
6 Ia’ IIf’
7 Ia’ IIg’
8 Ib’ IIa’
9 Ib’ IIb’
Ib’ IIc’
11 Ib’ IId’
12 Ib’ IIe’
13 Ib’ IIf’
14 Ib’ IIg’
Ic’ IIa’
16 Ic’ IIb’
17 Ic’ IIc’
18 Ic’ IId’
19 Ic’ IIe’
Ic’ IIf’
21 Ic’ IIg’
22 Id’ IIa’
23 Id’ IIb’
24 Id’ IIc’
Id’ IId’
26 Id’ IIe’
27 Id’ IIf’
28 Id’ IIg’
In some embodiments, the invention provides peptides, which may be isolated
and/or purified, comprising, consisting essentially of, or consisting of, the following
structural formula:
R ’’-X’’-Y’’-R ’’ (I’’) (SEQ ID NO:27)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R ’’ is hydrogen, an C -C alkyl, C -C aryl, C -C aryl C -C alkyl, C -C alkanoyl
1 6 6 12 6 12 1 6 1 20
(e.g., methyl, acetyl, formyl, benzoyl or trifluoroacetyl, isovaleric acid, isobutyric acid,
octanoic acid, lauric acid and hexadecanoic acid), γ-Glu-hexadecanoic acid) or pGlu,
appended to the N-terminus, and including PEGylated versions (e.g., PEG3 to PEG11),
alone or as spacers of any of the foregoing;
R ’’ is -NH or -OH;
X’’ is a peptide sequence having the formula (Ia’’)
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (Ia’’) (SEQ ID NO:22)
wherein
X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Lys, Ala, D-His or Lys;
X4 is Phe, Ala, Dpa, bhPhe or D-Phe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or
Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent;
and provided that if Y’’ is absent, X7 is Ile;
wherein said compound of formula I’’ is optionally PEGylated on R ’’, X’’, or Y’’; and
wherein when said compound of formula I’’ comprises two or more cysteine residues, at
least two of said cysteine residues being linked via a disulfide bond.
In some embodiments, Y’’ is absent.
In some embodiments, R ’’ is hydrogen, isovaleric acid, isobutyric acid or acetyl.
In some embodiments of the compound of formula (I’’), X’’ is a peptide sequence
according to formula (Ia’’), wherein
X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp or absent;
X2 is Thr, Ala, or D-Thr;
X3 is His, Lys, or D-His;
X4 is Phe, Ala, or Dpa;
X5 is Pro, Gly, Arg, Lys, Ala, D-Pro or bhPro;
X6 is Ile, Cys, Arg, Lys, D-Ile or D-Cys;
X7 is Cys, Ile, Leu, Val, Phe, D-Ile or D-Cys;
X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu or D-Ile;
X9 is Phe or bhPhe; and
X10 is Lys or absent.
In some embodiments of the compound of formula (I’’), X’’ is a peptide sequence
having the formula (Ib’’)
X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (Ib’’) (SEQ ID NO:23)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, Ile, Leu or Val;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys, Phe or absent.
In some embodiments of the compound of formula (I’’), X’’ is a peptide sequence
having the formula (Ic’’)
X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (Ic’’) (SEQ ID NO:24)
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
In some embodiments of the compound of formula (I’’), X’’ is a peptide sequence
having the formula (Id’’)
X1-Thr-His-Phe-X5-Cys-Ile-X8-Phe-X10 (Id’’) (SEQ ID NO:4)
wherein
X1 is Asp, Glu or Ida;
X4 is Phe;
X5 is Pro or bhPro;
X8 is Ile, Lys, or Phe; and
X10 is absent.
In some embodiments of the compound of formula (I’’), Y’’ is a peptide having the
formula (IIa’’)
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Cys-Y10 (IIa’’) (SEQ ID NO:25)
wherein
Y1 is Gly, Ala, Lys, Pro or D-Pro;
Y2 is Pro, Ala or Gly;
Y3 is Arg, Ala, Lys or Trp;
Y4 is Ser, Gly or Ala;
Y5 is Lys, Met, Arg or Ala;
Y6 is Gly, Arg or Ala;
Y7 is Trp Ala or absent;
Y8 is Val, Thr, Lys, Ala, Glu or absent; and
Y10 is Met, Lys or absent.
In some embodiments of the compound of formula (I’’), Y’’ is a peptide sequence
according to formula (IIa’’) (SEQ ID NO:25)
wherein
Y1 is Gly, Glu, Val, or Lys
Y2 is Pro
Y3 is Arg or Lys;
Y4 is Ser
Y5 is Arg or Lys;
Y6 is Gly, Ser, Lys, Ile or Arg
Y7 is Trp or absent
Y8 is Val, Thr, Asp, Glu or absent;
Y10 is Lys or absent
In some embodiments of the compound of formula (I’’), Y’’ is a peptide sequence
according to formula (IIa’’) (SEQ ID NO:25)
wherein
Y1 is Glu or Lys
Y2 is Pro
Y3 is Arg or Lys;
Y4 is Ser
Y5 is Arg or Lys;
Y6 is Gly, Ser, Lys, Ile or Arg;
Y7 is Trp or absent;
Y8 is Val or absent;
Y10 is Lys or absent
In some embodiments of the compound of formula (I’’), Y’’ is a peptide sequence
according to formula (IIa’’) (SEQ ID NO:25)
wherein
Y1 is Gly, Pro or D-Pro;
Y2 is Pro or Gly;
Y3 is Arg or Lys;
Y4 is Ser;
Y5 is Lys;
Y6 is Gly;
Y7 is Trp;
Y8 is Val or Thr; and
Y10 is Met, Lys or absent.
In some embodiments of the compound of formula (I’’), Y’’ is a peptide sequence
having the formula (IIb’’)
Y1-Y2-Y3-Ser-Lys-Gly-Trp-Y8-Cys-Y10 (IIb’’) (SEQ ID NO:26)
wherein
Y1 is Gly, Pro or D-Pro;
Y2 is Pro or Gly;
Y3 is Arg or Lys;
Y8 is Val or Thr; and
Y10 is Met, Lys or absent.
In some embodiments, the present invention provides a compound of formula (I’’),
wherein the compound comprises any one of the X’’ / Y’’ peptide sequence formula
combinations presented in Table 3 below.
Table 3: Illustrative combinations of X’’ and Y’’ peptides of a compound of Formula
(I’’)
Formula I” combinations
X” Peptide Y” Peptide
Combination
Sequence Sequence
Number
Formula Formula
1 Ia” IIa”
2 Ia” IIb”
3 Ib” IIa”
4 Ib” IIb”
Ic” IIa”
6 Ic” IIb”
7 Id” IIa”
8 Id” IIb”
In some embodiments the peptide of formula (I’’) comprises at least three, at least
four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten Y
residues in Y’’. In some embodiments, Y1 to Y3 are present and Y4 to Y10 are absent. In
some embodiments Y5 is absent. In some embodiments Y1, Y5, and Y7 are absent. In
some embodiments, Y8 is absent. In some embodiments, Y3 is absent.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Leu. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Val. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Cys. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Ile. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Ile. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X8 is Ile. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X8 is Lys. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys and X7 is Ile. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys and X8 is Ile. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Ile, and X8 is Ile.
In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Ile and X7 is Cys. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Cys and X8 is Ile. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Ile, X7 is Cys, and X8 is Ile.
In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys and X8 is Lys. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Ile, and X8 is Lys.
In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys and C7 is Leu. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys and C7 is Val. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Ile and X8 is Lys. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Leu and X8 is Lys. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X7 is Val and X8 is Lys. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Leu and X8 is Lys.
In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Val, and X8 is Lys.
In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Ile, Leu, or Val. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Ile, Leu, or Val,
and X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and,
optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is ASP or IDA, X6 is Cys, X7 is
Ile, Leu, or Val, and X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib,
Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In
particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b)
IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments,
formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as
described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp or IDA, X6 is Cys, X7 is
Ile, Leu, or Val, and X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib,
Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In
particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b)
IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments,
formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as
described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X2 is Thr, X6 is Cys, X7 is Ile, Leu,
or Val, and X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id
and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X3 is His, X6 is Cys, X7 is Ile, Leu,
or Val, and X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id
and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X4 is Phe, X6 is Cys, X7 is Ile, Leu,
or Val, and X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id
and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X5 is Pro, X6 is Cys, X7 is Ile, Leu,
or Val, and X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id
and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Ile, Leu, or Val, X8
is Lys, and X9 is Phe. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id
and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X2 is Thr, X6 is Cys, X7 is Ile and
X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and,
optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X3 is His, X6 is Cys, X7 is Ile, and
X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and,
optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X4 is Phe, X6 is Cys, X7 Ile, and
X8 is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and,
optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X5 is Pro, X6 is Cys, X7 Ile, and X8
is Lys. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and,
optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X6 is Cys, X7 is Ile, X8 is Lys, and
X9 is Phe. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and,
optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X5 is Pro, X6 is Cys, X7 is Ile, X8
is Lys, and X9 is Phe. In particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id
and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular
embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’,
IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments, formula (I’’)
comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X4 is Phe, X5 is Pro, X6 is Cys, X7
is Ile, X8 is Lys, and X9 is Phe. In particular embodiments, formula (I) comprises (a) Ia,
Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In
particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b)
IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular embodiments,
formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or IIb’, as
described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X3 is His, X4 is Phe, X5 is Pro, X6
is Cys, X7 is Ile, X8 is Lys, and X9 is Phe. In particular embodiments, formula (I)
comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as
described herein. In particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’
and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular
embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or
IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X2 is Thr, X3 is His, X4 is Phe, X5
is Pro, X6 is Cys, X7 is Ile, X8 is Lys, and X9 is Phe. In particular embodiments, formula
(I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as
described herein. In particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’
and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular
embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or
IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp or IDA, X2 is Thr, X3 is
His, X4 is Phe, X5 is Pro, X6 is Cys, X7 is Ile, X8 is Lys, and X9 is Phe. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp or IDA, X2 is Thr, X3 is
His, X4 is Phe, X5 is Pro, X6 is Cys, X7 is Ile, Leu, or Val, X8 is Lys, and X9 is Phe. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp, X2 is Thr, X3 is His, X4
is Phe, X5 is Pro X6 is Cys, X7 is Ile, X8 is Lys, and X9 is Phe. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is IDA, X2 is Thr, X3 is His, X4
is Phe, X5 is Pro, X6 is Cys, X7 is Ile, X8 is Lys, and X9 is Phe. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, wherein the compound comprises an R that is isovaleric
acid.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp or IDA, X2 is Thr, X3 is
His, X4 is Phe, X5 is Pro, X6 is Cys, X7 is Ile, Leu, or Val, X8 is Lys, and X9 is Phe;
wherein said peptide further comprises an R that is isovaleric acid. In particular
embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId,
IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’) comprises (a)
Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described
herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and,
optionally, (ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp, X2 is Thr, X3 is His, X4
is Phe, X5 is Pro, X6 is Cys, X7 is Ile, Leu, or Val, and X8 is Lys; wherein said peptide
further comprises an R that is isovaleric acid. In particular embodiments, formula (I)
comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as
described herein. In particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’
and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular
embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or
IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp, X2 is Thr, X3 is His, X4
is Phe, X5 is Pro, X6 is Cys, X7 is Ile, Leu, or Val, X8 is Lys, and X9 is Phe; wherein said
peptide further comprises an R group that is isovaleric acid. In particular embodiments,
formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg,
as described herein. In particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or
Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In
particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally,
(ii) IIa’’ or IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, each respectively comprising an X, X’, or X’’ peptide
sequence, according to the present disclosure, wherein X1 is Asp, X2 is Thr, X3 is His, X4
is Phe, X5 is Pro, X6 is Cys, X7 is Ile, X8 is Lys, and X9 is Phe; wherein said peptide
further comprises an R group that is isovaleric acid. In particular embodiments, formula (I)
comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa, IIb, IIc, IId, IIe, IIf, or IIg, as
described herein. In particular embodiments, formula (I’) comprises (a) Ia’, Ib’, Ic’, or Id’
and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as described herein. In particular
embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or Id’’ and, optionally, (ii) IIa’’ or
IIb’, as described herein.
In some embodiments, the present invention provides a compound of formula (I),
(I’), or (I’’), as described herein, wherein the compound comprises a peptide sequence that
is 85% or higher (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
99.5%) homologous to an amino acid sequence set forth in any one of Tables 5-15. In
particular embodiments, formula (I) comprises (a) Ia, Ib, Ic, or Id and, optionally, (b) IIa,
IIb, IIc, IId, IIe, IIf, or IIg, as described herein. In particular embodiments, formula (I’)
comprises (a) Ia’, Ib’, Ic’, or Id’ and, optionally, (b) IIa’, IIb’, IIc’, IId’, IIe’, IIf’, or IIg’, as
described herein. In particular embodiments, formula (I’’) comprises (i) Ia’’, Ib’’, Ic’’, or
Id’’ and, optionally, (ii) IIa’’ or IIb’, as described herein.
In certain embodiments, a peptide or a peptide dimer of the present invention
comprises any one of the compounds shown in any one of Tables 5-15.
In certain embodiments, a peptide or a peptide dimer of the present invention
comprises any one of the amino acid sequences provided as SEQ ID NOS: 1-334 and 338-
375, or as shown in any one of Tables 5-15
In certain embodiments, a peptide or a peptide dimer of the present invention
comprises an amino acid sequence set forth in any one of Tables 5-15.
In certain embodiments, a peptide or a peptide dimer of the present invention has a
structure shown in any one of Tables 5-15, e.g., Tables 7 or 12-15. In one certain
embodiment, a peptide or a peptide dimer of the present invention comprises an amino acid
sequence set forth in any one of Tables 5-15, e.g., Tables 7 or 12-15. In some
embodiments, a peptide of the present invention comprises an amino acid sequence having
at least about 85% identical or at least about 90%, 95%, 97%, 98%, 99% identical to any
amino acid sequence set forth in any one of Tables 5-15, e.g., Tables 7 or 12-15, or any one
of SEQ ID NOS: 1-334 and 338-375. In one certain embodiment, a peptide or a peptide
dimer of the present invention comprises an amino acid sequence having at least about 85%
identical or at least about 90%, 95%, 97%, 98%, 99% identical to any amino acid sequence
set forth in Table 7 or any one of Tables 5-15.
It is understood that in the context of the invention, a peptide or peptide dimer
comprising a peptide sequence shown in one of the accompanying Tables or sequence
listing may have certain minor alterations to one or more amino acid residues of the peptide
sequence, as compared to the native amino acid, yet still be considered to comprises the
peptide sequence shown in the Tables or sequence listing. For example, one or more side
chains of one or more amino acid residues present in the peptide or peptide dimer may be
slightly altered due to the attachment of a linker or dimerization via cysteine residues, or an
N-terminal or C-terminal amino acid may be amidated.
In some embodiments, a peptide or a peptide dimer of the present invention exhibits
hepcidin activity. In some embodiments, a peptide or a peptide dimer of the present
invention exhibits at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%,
greater than 99%, greater than 100%, greater than 110%, greater than 120%, greater than
150%, greater than 200% greater than 500%, or greater than 1000% of the activity of a
reference hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table
4). In some embodiments, the activity is an in vitro or an in vivo activity as described
herein.
In some embodiments, a peptide or a peptide dimer of the present invention exhibits
at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or greater than 99% of
the in vitro activity for inducing the degradation of human ferroportin protein as that of a
reference hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table
4), wherein the activity is measured according to the methods described herein (e.g.,
according to Example 2).
In some embodiments, a peptide or a peptide dimer of the present invention exhibits
at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or greater than 99% of
the in vivo activity for inducing the reduction of free plasma iron in an individual as does a
reference hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table
4), wherein the activity is measured according to the methods described herein (e.g.,
according to Example 8).
In some embodiments, a peptide or a peptide dimer of the present invention exhibits
increased hepcidin activity as compared to a hepcidin reference peptide, (e.g., any one of
the hepcidin reference compounds provided in Table 4). In certain embodiments, a peptide
or a peptide dimer of the present invention exhibits 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200-fold
greater or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%,
300%, 400%, 500% , 700%, or 1000% greater activity than a reference hepcidin, (e.g., any
one of the hepcidin reference compounds provided in Table 4). In some embodiments, a
peptide or a peptide dimer of the present invention exhibits at least about 50%, 60%, 70%,
80%, 90%, 95%, 97%, 98%, 99%, or greater than 99% of the activity exhibited by a
hepcidin reference compound. In some embodiments, the activity is an in vitro or an in
vivo activity, e.g., an in vivo or an in vitro activity described herein. In certain
embodiments, a peptide or a peptide dimer of the present invention exhibits 1.5, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120,
140, 160, 180, or 200-fold greater or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 100%, 200%, 300%, 400%, 500% , 700%, or 1000% greater activity than a
reference hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table
4), wherein the activity is an in vitro activity for inducing the degradation of ferropontin,
e.g., as measured according to Example 2; or wherein the activity is an in vivo activity for
reducing free plasma iron, e.g., as measured according to Example 8.
In some embodiments, a peptide or a peptide dimer of the present invention binds
ferroportin, e.g., human ferroportin. In some embodiments, a peptide or a peptide dimer of
the present invention exhibits at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%,
99%, or greater than 99% of the ferroportin binding ability that is exhibited by a reference
hepcidin (e.g., any one of the hepcidin reference compounds provided in Table 4). In some
embodiments, a peptide or a peptide dimer of the present invention has a lower IC (i.e.,
higher binding affinity) for binding to ferroportin, (e.g., human ferroportin) compared to a
reference hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table
4). In some embodiments, the peptide of the present invention has an IC in a ferroportin
competitive binding assay which is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 100%, 200%, 300%, 400%, 500% , 700%, or 1000% lower than a reference
hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table 4).
In some embodiments, the present invention provides a compound of formula I, I’,
or I’’, as described herein, wherein the peptide exhibits increased stability (e.g., as
measured by half-life, rate of protein degradation) as compared to a reference hepcidin,
(e.g., any one of the hepcidin reference compounds provided in Table 4). In some
embodiments, the present invention provides a dimer of such a compound, and in certain
embodiments the dimer is a homodimer. In certain embodiments, the stability of a peptide
or a peptide dimer of the present inveniton is increased at least about 1.5, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160,
180, or 200-fold greater or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,
90%, 100%, 200%, 300%, 400%, or 500% greater than a reference hepcidin, (e.g., any one
of the hepcidin reference compounds provided in Table 4). In some embodiments, the
stability is a stability that is described herein. In some embodiments, the stability is a
plasma stability, e.g., as optionally measured according to the method described in
Example 7.
In particular embodiments, the present invention provides a compound of formula I,
I’, or I’’, as described herein, wherein the peptide exhibits a longer half-life than a
reference hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table
4). In some embodiments, the present invention provides a dimer of such a compound, and
in certain embodiments the dimer is a homodimer. In particular embodiments, a peptide or
a peptide dimer of the present invention has a half-life under a given set of conditions (e.g.,
temperature, pH) of at least about 5 minutes, at least about 10 minutes, at least about 20
minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least
about 2 hour, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least
about 6 hours, at least about 12 hours, at least about 18 hours, at least about 1 day, at least
about 2 days, at least about 4 days, at least about 7 days, at least about 10 days, at least
about two weeks, at least about three weeks, at least about 1 month, at least about 2
months, at least about 3 months, or more, or any intervening half-life or range in between,
about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes,
about 1 hour, about 2 hour, about 3 hours, about 4 hours, about 5 hours, about 6 hours,
about 12 hours, about 18 hours, about 1 day, about 2 days, about 4 days, about 7 days,
about 10 days, about two weeks, about three weeks, about 1 month, about 2 months, about
3 months, or more, or any intervening half-life or range in between. In some embodiments,
the half life of a peptide or a peptide dimer of the present invention is extended due to its
conjugation to one or more lipophilic substituent, e.g., any of the lipophilic substituents
disclosed herein. In some embodiments, the half life of a peptide or a peptide dimer of the
present invention is extended due to its conjugation to one or more polymeric moieties,
e.g., any of the polymeric moieties disclosed herein. In certain embodiments, the
temperature is about 25 °C, about 4 ºC, or about 37 ºC, and the pH is a physiological pH, or
a pH about 7.4.
In some embodiments, the half-life is measured in vitro using any suitable method
known in the art, e.g., in some embodiments, the stability of a peptide or a peptide dimer of
the present invention is determined by incubating the peptide or the peptide dimer with pre-
warmed human serum (Sigma) at 37 º C. Samples are taken at various time points,
typically up to 24 hours, and the stability of the sample is analyzed by separating the
peptide or peptide dimer from the serum proteins and then analyzing for the presence of the
peptide or peptide dimer of interest using LC-MS.
In some embodiments, the stability of the peptide is measured in vivo using any
suitable method known in the art, e.g., in some embodiments, the stability of a peptide or a
peptide dimer is determined in vivo by administering the peptide or peptide dimer to a
subject such as a human or any mammal (e.g., mouse) and then samples are taken from the
subject via blood draw at various time points, typically up to 24 hours. Samples are then
analyzed as described above in regard to the in vitro method of measuring half-life. In
some embodiments, in vivo stability of a peptide or a peptide dimer of the present
invention is determined via the method disclosed in Example 7.
In some embodiments, the present invention provides a compound of formula I, I’,
or I’’, as described herein, or a dimer thereof, wherein the peptide or the dimer exhibits
improved solubility or improved aggregation characteristics as compared to a reference
hepcidin, (e.g., any one of the hepcidin reference compounds provided in Table 4).
Solubility may be determined via any suitable method known in the art. In some
embodiments, suitable methods known in the art for determining solubility include
incubating peptides in various buffers (Acetate pH4.0, Acetate pH5.0, Phos/Citrate pH5.0,
Phos Citrate pH6.0, Phos pH 6.0, Phos pH 7.0, Phos pH7.5, Strong PBS pH 7.5, Tris
pH7.5, Tris pH 8.0, Glycine pH 9.0, Water, Acetic acid (pH 5.0 and other known in the art)
and testing for aggregation or solubility using standard techniques. These include, but are
not limited to, visual precipitation, dynamic light scattering, Circular Dichroism and
fluorescent dyes to measure surface hydrophobicity, and detect aggregation or fibrillation,
for example. In some embodiments, improved solubility means the peptide is more soluble
in a given liquid than is a reference hepcidin (e.g., any one of the hepcidin reference
compounds provided in Table 4).
In some embodiments, the present invention provides a compound of formula I, I’,
or I’’, as described herein, or a dimer thereof, wherein the peptide or the dimer exhibits less
degradation (i.e., more degradation stability), e.g., greater than or about 10% less, greater
than or about 20% less, greater than or about 30% less, greater than or about 40 less, or
greater than or about 50% less than a reference hepcidin (e.g., any one of the hepcidin
reference compounds provided in Table 4). In some embodiments, degradation stability is
determined via any suitable method known in the art. In some embodiments, suitable
methods known in the art for determining degradation stability include the method
described in Hawe et al J Pharm Sci, VOL. 101, NO. 3, 2012, p 895-913, incorporated
herein in its entirety. Such methods are in some embodiments used to select potent
sequences with enhanced shelf lifes.
In some embodiments, the present invention provides compositions and
medicaments comprising at least one peptide or peptide dimer as disclosed herein. In some
embodiments, the present invention provides a method of manufacturing medicaments
comprising at least one peptide or peptide dimer as disclosed herein for the treatment of
diseases of iron metabolism, such as iron overload diseases. In some embodiments, the
present invention provides a method of manufacturing medicaments comprising at least
one peptide or pepitde dimer as disclosed herein for the treatment of diabetes (Type I or
Type II), insulin resistance, or glucose intolerance. Also provided are methods of treating a
disease of iron metabolism in a subject, such as a mammalian subject, and preferably a
human subject, comprising administering at least one peptide, peptide dimer, or
composition as disclosed herein to the subject. In some embodiments, the peptide, peptide
dimer, or the composition is administered in a therapeutically effective amount. Also
provided are methods of treating diabetes (Type I or Type II), insulin resistance, or glucose
intolerance in a subject, such as a mammalian subject, and preferably a human subject,
comprising administering at least one peptide, peptide dimer, or composition as disclosed
herein to the subject. In some embodiments, the peptide, peptide dimer, or composition is
administered in a therapeutically effective amount.
In some embodiments, thepeptide, or peptide dimer of this invention is synthetically
manufactured. In other embodiments, the peptide or peptide dimer of this invention is
recombinantly manufactured.
In some embodiments, the invention provides a process for manufacturing a
compound, peptide, peptide analogue, peptide dimer, or pharmaceutical composition as
disclosed herein.
In some embodiments, the invention provides a device comprising at least one
peptide, peptide analogue, or peptide dimer of the present invention, or pharmaceutically
acceptable salt or solvate thereof for delivery of the peptide analogue or the peptide dimer
to a subject.
In some embodiments, the present invention provides methods of binding a
ferroportin or inducing ferroportin internalization and degradation which comprises
contacting the ferroportin with at least one peptide or peptide analogue, peptide dimer, or
composition as disclosed herein.
In some embodiments, the present invention provides kits comprising at least one
peptide, peptide analogue, peptide dimer, or composition as disclosed herein packaged
together with a reagent, a device, instructional material, or a combination thereof.
In some embodiments, the present invention provides complexes which comprise at
least one peptide or peptide dimer as disclosed herein bound to a ferroportin, preferably a
human ferroportin, or an antibody, such as an antibody which specifically binds a peptide
or a peptide dimer as disclosed herein, Hep25, or a combination thereof.
In some embodiments, the compound has a measurement (e.g., an EC50) of less
than 500 nM within the Fpn internalization assay. As a skilled person will realize, the
function of the peptide is dependent on the tertiary structure of the peptide and the binding
surface presented. It is then possible to make minor changes of the sequence that do not
affect the fold or are not on the binding surface and maintain function. In other
embodiments, the compound of the invention is a peptide or peptidomimetic compound, or
a dimer thereof having 85% or higher (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, 99%, or 99.5%) identity or homology to an amino acid sequence of any
compound of formula I, I’, or I’’ that exhibits an activity, or lessens a symptom of a disease
or indication for which hepcidin is involved.
In some embodiments, the peptide, peptide analogue, or dimer thereof of the
invention may comprise functional fragments or variants thereof that have at most 10, 9, 8,
7, 6, 5, 4, 3, 2, or 1 amino acid substitutions compared to one or more of the specific
sequences recited below.
In addition to the methods disclosed herein in Example 1, the peptides and the
peptide dimers of the present invention may be produced using methods known in the art
including chemical synthesis, biosynthesis or in vitro synthesis using recombinant DNA
methods, and solid phase synthesis. See e.g. Kelly & Winkler (1990) Genetic Engineering
Principles and Methods, vol. 12, J. K. Setlow ed., Plenum Press, NY, pp. 1-19; Merrifield
(1964) J Amer Chem Soc 85:2149; Houghten (1985) PNAS USA 82:5131-5135; and
Stewart & Young (1984) Solid Phase Peptide Synthesis, 2ed. Pierce, Rockford, IL, which
are herein incorporated by reference. The peptides of the present invention may be purified
using protein purification techniques known in the art such as reverse phase high-
performance liquid chromatography (HPLC), ion-exchange or immunoaffinity
chromatography, filtration or size exclusion, or electrophoresis. See Olsnes, S. and A. Pihl
(1973) Biochem. 12(16):3121-3126; and Scopes (1982) Protein Purification, Springer-
Verlag, NY, which are herein incorporated by reference. Alternatively, the peptides of the
present invention may be made by recombinant DNA techniques known in the art. Thus,
polynucleotides that encode the polypeptides of the present invention are contemplated
herein. In preferred embodiments, the polynucleotides are isolated. As used herein
"isolated polynucleotides" refers to polynucleotides that are in an environment different
from that in which the polynucleotide naturally occurs.
In certain embodiments, peptides of the present invention bind ferroportin,
preferably human ferroportin. Preferred peptides of the present invention specifically bind
human ferroportin. As used herein, "specifically binds" refers to a specific binding agent's
preferential interaction with a given ligand over other agents in a sample. For example, a
specific binding agent that specifically binds a given ligand, binds the given ligand, under
suitable conditions, in an amount or a degree that is observable over that of any nonspecific
interaction with other components in the sample. Suitable conditions are those that allow
interaction between a given specific binding agent and a given ligand. These conditions
include pH, temperature, concentration, solvent, time of incubation, and the like, and may
differ among given specific binding agent and ligand pairs, but may be readily determined
by those skilled in the art.
The peptides of the present invention that mimic the hepcidin activity of
Hep25, the bioactive human 25-amino acid form, are herein referred to as "mini-
hepcidins". As used herein, in certain embodiments, a compound having "hepcidin activity"
means that the compound has the ability to lower plasma iron concentrations in subjects
(e.g. mice or humans), when administered thereto (e.g. parenterally injected or orally
administered), in a dose-dependent and time-dependent manner. See e.g. as demonstrated
in Rivera et al. (2005), Blood 106:2196-9. In some embodiments, the peptides of the
present invention lower the plasma iron concentration in a subject by at least about 1.2, 1.5,
2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or at least about 5%, 10%, 20%, 25%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or about 99%.
In some embodiments, the peptides of the present invention have in vitro activity as
assayed by the ability to cause the internalization and degradation of ferroportin in a
ferroportin-expressing cell line as taught in Nemeth et al. (2006) Blood 107:328-33. In
vitro activity may be measured by the dose-dependent loss of fluorescence of cells
engineered to display ferroportin fused to green fluorescent protein as in Nemeth et al.
(2006) Blood 107:328-33. Aliquots of cells are incubated for 24 hours with graded
concentrations of a reference preparation of Hep25 or a mini-hepcidin. As provided herein,
the EC50 values are provided as the concentration of a given compound (e.g. peptide) that
elicits 50% of the maximal loss of fluorescence generated by the reference Hep25
preparation. EC50 of Hep25 preparations in this assay range from 5 to 15 nM and preferred
mini-hepcidins have EC50 values in in vitro activity assays of about 1,000 nM or less. In
certain embodiments, a peptide of the present invention has an EC50 in an in vitro activity
assay (e.g., as described in Nemeth et al. (2006) Blood 107:328-33 or Example 2 herein) of
less than about any one of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200 or
500 nM. In some embodiments, a peptide analogue or biotherapeutic composition has an
EC value of about 1nM or less.
Other methods known in the art for calculating the hepcidin activity and in vitro
activity of peptides according to the present invention may be used. For example, the in
vitro activity of compounds may be measured by their ability to internalize cellular
ferroportin, which is determined by immunohistochemistry or flow cytometry using
antibodies which recognizes extracellular epitopes of ferroportin. Alternatively, the in vitro
activity of compounds may be measured by their dose- dependent ability to inhibit the
efflux of iron from ferroportin-expressing cells that are preloaded with radioisotopes or
stable isotopes of iron, as in Nemeth et al. (2006) Blood 107:328-33.
Conjugation
The skilled person will be well aware of suitable techniques for preparing the
compounds employed in the context of the invention. For examples of suitable chemistry,
see, e.g., WO98/08871, WO00/55184, WO00/55119, Madsen et al (J. Med. Chem. 2007,
50, 6126-32), and Knudsen et al. 2000 (J. Med Chem. 43, 1664-1669).
The side chains of one or more amino acid residues (e.g. Lys residues) in a
compound of the invention may be further conjugated (i.e. covalently attached) to a
lipophilic substituent. The lipophilic substituent may be covalently bonded to an atom in
the amino acid side chain, or alternatively may be conjugated to the amino acid side chain
via one or more spacers. The amino acid(s) in question may be part of the peptide moiety
X, or a part of the peptide moiety Y.
Without wishing to be bound by any particular theory, it is believed that the
lipophilic substituent binds to albumin in the blood stream, thereby shielding the peptide
analogue of the invention from enzymatic degradation, and thus enhancing its half-life.
The spacer, when present, may provide spacing between the peptide analogue and the
lipophilic substituent.
In certain embodiments, the lipophilic substituent may comprise a hydrocarbon
chain having from 4 to 30 C atoms, for example at least 8 or 12 C atoms, and preferably 24
C atoms or fewer, or 20 C atoms or fewer. The hydrocarbon chain may be linear or
branched and may be saturated or unsaturated. In certain embodiments, the hydrocarbon
chain is substituted with a moiety which forms part of the attachment to the amino acid side
chain or the spacer, for example an acyl group, a sulfonyl group, an N atom, an O atom or
an S atom. In some embodiments, the hydrocarbon chain is substituted with an acyl group,
and accordingly the hydrocarbon chain may form part of an alkanoyl group, for example
palmitoyl, caproyl, lauroyl, myristoyl or stearoyl.
A lipophilic substituent may be conjugated to any amino acid side chain in a
compound of the invention. In certain embodiment, the amino acid side chain includes a
carboxy, hydroxyl, thiol, amide or amine group, for forming an ester, a sulphonyl ester, a
thioester, an amide or a sulphonamide with the spacer or lipophilic substituent. For
example, the lipophilic substituent may be conjugated to Asn, Asp, Glu, Gln, His, Lys,
Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Orn. In certain embodiments, the lipophilic
substituent is conjugated to Lys. An amino acid shown as Lys in any of the formulae
provided herein may be replaced by, e.g., Dbu, Dpr or Orn where a lipophilic substituent is
added.
In further embodiments of the present invention, alternatively or additionally, the
side-chains of one or more amino acid residues in the compound of the invention may be
conjugated to a polymeric moiety, for example, in order to increase solubility and/or half-
life in vivo (e.g. in plasma) and/or bioavailability. Such modifications are also known to
reduce clearance (e.g. renal clearance) of therapeutic proteins and peptides.
As used herein, “Polyethylene glycol” or “PEG” is a polyether compound of
general formula H-(O-CH2-CH2)n-OH. PEGs are also known as polyethylene oxides
(PEOs) or polyoxyethylenes (POEs), depending on their molecular weight PEO, PEE, or
POG, as used herein, refers to an oligomer or polymer of ethylene oxide. The three names
are chemically synonymous, but PEG has tended to refer to oligomers and polymers with a
molecular mass below 20,000 g/mol, PEO to polymers with a molecular mass above
,000 g/mol, and POE to a polymer of any molecular mass. PEG and PEO are liquids or
low-melting solids, depending on their molecular weights. Throughout this disclosure, the
3 names are used indistinguishably. PEGs are prepared by polymerization of ethylene
oxide and are commercially available over a wide range of molecular weights from 300
g/mol to 10,000,000 g/mol. While PEG and PEO with different molecular weights find use
in different applications, and have different physical properties (e.g. viscosity) due to chain
length effects, their chemical properties are nearly identical. The polymeric moiety is
preferably water-soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically
inert. Suitable polymeric moieties include polyethylene glycols (PEG), homo- or co-
polymers of PEG, a monomethyl-substituted polymer of PEG (mPEG), or polyoxyethylene
glycerol (POG). See, for example, Int. J. Hematology 68:1 (1998); Bioconjugate Chem.
6:150 (1995); and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also encompassed
are peptides that are prepared for purpose of half life extension, for example, mono-
activated, alkoxy-terminated polyalkylene oxides (POA’s) such as mono-methoxy-
terminated polyethyelene glycols (mPEG’s); bis activated polyethylene oxides (glycols) or
other PEG derivatives are also contemplated. Suitable polymers will vary substantially by
weights ranging from about 70 to about 40,000 or from about 200 to about 40,000 are
usually selected for the purposes of the present invention. Molecular weights from 200 to
2,000 are preferred and 200 to 500 are particularly preferred. There are different forms of
PEG are also available, depending on the initiator used for the polymerization process – the
most common initiator is a monofunctional methyl ether PEG, or methoxypoly(ethylene
glycol), abbreviated mPEG.
As used herein, lower-molecular-weight PEGs are also available as pure oligomers,
referred to as monodisperse, uniform, or discrete. These are used in certain embodiments of
the present invention.
PEGs are also available with different geometries: Branched PEGs have three to ten
PEG chains emanating from a central core group; Star PEGs have 10 to 100 PEG chains
emanating from a central core group; Comb PEGs have multiple PEG chains normally
grafted onto a polymer backbone. PEGs can also be linear. The numbers that are often
included in the names of PEGs indicate their average molecular weights (e.g. a PEG with n
= 9 would have an average molecular weight of approximately 400 daltons, and would be
labeled PEG 400.
As used herein, “PEGylation” is the act of covalently coupling a PEG structure to
the peptide of the invention, which is then referred to as a “PEGylated peptide”. In some
embodiments, the X moiety of formula I, the Y moiety of formula I, the R moiety of
formula I, the R moiety of formula I, or any combination thereof, is PEGylated. In some
embodiments, the X’ moiety of formula I’, the Y’ moiety of formula I’, the R ’ moiety of
formula I’, the R ’ moiety of formula I’, or any combination thereof, is PEGylated. In
some embodiments, the X’’ moiety of formula I’’, the Y’’ moiety of formula I’’, the R ’’
moiety of formula I’’, the R ’’ moiety of formula I’’, or any combination thereof, is
PEGylated. In some embodiments, one or more side chains of an amino acid in the peptide
of formula I, formula I’, or formula I’’ is PEGylated. In certain embodiments, the PEG of
the PEGylated side chain is a PEG with a molecular weight from about 200 to about
40,000. In some embodiments, a spacer of a peptide of formula I, formula I’, or formula I’’
is PEGylated. In certain embodiments, the PEG of a PEGylated spacer is PEG3, PEG4,
PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, the PEG of
a PEGylated spacer is PEG3 or PEG8. In certain embodiments, the PEG of a PEGylated
spacer is PEG3 or PEG8.
Other suitable polymeric moieties include poly-amino acids such as poly-lysine,
poly-aspartic acid and poly-glutamic acid (see for example Gombotz, et al. (1995),
Bioconjugate Chem., vol. 6: 332-351; Hudecz, et al. (1992), Bioconjugate Chem., vol. 3,
49-57 and Tsukada, et al. (1984), J. Natl. Cancer Inst., vol. 73, : 721-729. The polymeric
moiety may be straight-chain or branched. In some embodiments, it has a molecular
weight of 500-40,000 Da, for example 500-10,000 Da, 1000-5000 Da, 10,000-20,000 Da,
or 20,000-40,000 Da.
In some embodiments, a compound of the invention may comprise two or more
such polymeric moieties, in which case the total molecular weight of all such moieties will
generally fall within the ranges provided above.
In some embodiments, the polymeric moiety may be coupled (by covalent linkage)
to an amino, carboxyl or thiol group of an amino acid side chain. Preferred examples are
the thiol group of Cys residues and the epsilon amino group of Lys residues, and the
carboxyl groups of Asp and Glu residues may also be involved.
The skilled worker will be well aware of suitable techniques which can be used to
perform the coupling reaction. For example, a PEG moiety bearing a methoxy group can
be coupled to a Cys thiol group by a maleimido linkage using reagents commercially
available from Nektar Therapeutics AL. See also , and the references
cited above, for details of suitable chemistry. A maleimide-functionalised PEG may also be
conjugated to the side-chain sulfhydryl group of a Cys residue.
As used herein, disulfide bond oxidation can occur within a single step or is a two
step process. As used herein, for a single oxidation step the trityl protecting group is often
employed during assembly, allowing deprotection during cleavage, followed by solution
oxidation. When a second disulfide bond is required one has the option of native or
selective oxidation. For selective oxidation requiring orthogonal protecting groups Acm
and Trityl is used as the protecting groups for cysteine. Cleavage results in the removal of
one protecting pair of cysteine allowing oxidation of this pair. The second oxidative
deprotection step of the cysteine protected Acm group is then performed. For native
oxidation the trityl protecting group is used for all cysteines, allowing for natural folding of
the peptide.
A skilled worker will be well aware of suitable techniques which can be used to
perform the oxidation step.
Peptide Dimers
The term “dimer,” as in a peptide dimer, refers to compounds in which two peptide
chains are linked, either identical (homo-dimer) or non-identical (hetero-dimer) through a
linking moiety. A cysteine dimer is then two peptides chains linked through the amino acid
cysteine disulfide bond.
In some embodiments, the peptides of the present invention may be active in a
dimer conformation or a hetero-dimer conformation, in particular when free cysteine
residues are present in the peptide. In certain embodiments, this occurs either as a
synthesized dimer or, in particular, when a free cysteine monomer peptide is present and
under oxidizing conditions, dimerizes. In some embodiments, the dimer is a homodimer.
In other embodiments, the dimer is a heterodimer.
In certain embodiments, a peptide analogue of the present invention is a peptide
dimer comprising a peptide of the invention. In particular embodiments, the peptide dimers
comprise a peptide of formula I, a peptide of formula I’, or a peptide of formula I’’. In
particular embodiments, the peptide dimers comprise two peptides of formula I, two
peptides of formula I’, or two peptides of formula I’’. In certain embodiments, the peptide
dimers are homodimers. In particular embodiments wherein the peptide dimer comprises a
peptide of formula I, X has the formula Ia, Ib, Ic, or Id. In particular embodiments wherein
the peptide dimer comprises a peptide of formula I, Y has the formula IIa, IIb, IIc, IId, IIe,
IIf, or IIg. In particular embodiments wherein the peptide dimer comprises a peptide of
formula I’, X’ has the formula Ia’, Ib’, Ic’, or Id’. In particular embodiments wherein the
peptide dimer comprises a peptide of formula I’, Y’ has the formula IIa’, IIb’, IIc’, IId’,
IIe’, IIf’, or IIg’. In particular embodiments wherein the peptide dimer comprises a peptide
of formula I’’, X’’ has the formula Ia’’, Ib’’, Ic’’, or Id’’. In particular embodiments
wherein the peptide dimer comprises a peptide of formula I’’, Y’’ has the formula IIa’’ or
IIb’’.
In some embodiments, the dimer is between two X groups of formula I, two X’
groups of formula I’, or two X’’ groups of formula I’’, e.g., the two peptides of the dimer
are linked through two X groups of formula I, two X’ groups of formula I’, or two X’’
groups of formula I’’. In some embodiments, the dimer comprises two X groups of
formula I, two X’ groups of formula I’, or two X’’ groups of formula I’’. In some
embodiments, the two X groups, X’ groups, or X’’ groups in the dimers comprise the same
amino acid residues. In some embodiments, the two X groups, X’ groups, or X’’ groups in
the dimers comprise different amino acid residues (i.e., each amino acid in each of the two
X, X’ or X’’ groups is independently selected). In some embodiments, the dimer is
between two Y groups of formula I, two Y groups of formula I’, or two Y’’ groups of
formula I’’, e.g., the two peptides of the dimer are linked through two Y groups of formula
I, two Y’ groups of formula I’, or two Y’’ groups of formula I’’. In some embodiments,
the dimer comprises two Y groups of formula I, two Y groups of formula I’, or two Y’’
groups of formula I’’. In some embodiments, the two Y groups, Y’ groups, or Y’’ groups
in the dimer comprise the same amino acid residues. In some embodiments, the two Y
groups, Y’ groups or Y’’ groups in the dimer comprise different amino acid residues (i.e.,
each amino acid in each of the Y, Y’ or Y’’ groups is independently selected). In some
embodiments, a dimer is between an X group of formula I and a Y group of formula I (e.g.,
the two peptides of the dimer are linked through an X group of formula I and a Y group of
formula I), an X’ group of formula I’ and a Y’ group of formula I (e.g., the two peptides of
the dimer are linked through an X’ group of formula I’ and a Y’ group of formula I’), or an
X’’ group of formula I’’ and a Y’’ group of formula I’’ (e.g., the two peptides of the dimer
are linked through an X’’ group of formula I’’ and a Y’’ group of formula I’’).
In particular embodiments, a peptide dimer of the present invention comprises a
peptide comprising: a peptide sequence set forth in any one of Tables 5-15 or SEQ ID NOs:
1-334 and 338-375; or a peptide sequence having at least 85%, at least 90%, at least 91%,
at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least
98%, or at least 99% identity to a peptide sequence set forth in any one of Tables 5-15 or
SEQ ID NOs: 1-334 and 338-375. In particular embodiments, a peptide dimer of the
present invention is a homodimer comprising two peptides, each comprising: a peptide
sequence set forth in any one of Tables 5-15 or SEQ ID NOs: 1-334 and 338-375; or a
peptide sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least
93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%
identity to a peptide sequence set forth in any one of Tables 5-15 or SEQ ID NOs: 1-334
and 338-375. In particular embodiments, a peptide dimer of the present invention
comprises a compound set forth in any one of Tables 5-15. In particular embodiments, a
peptide dimer of the present invention is a homodimer comprising two peptides, each
comprising a compound set forth in any one of Tables 5-15.
In certain embodiments, the peptide dimers comprise two peptides dimerized via a
disulfide linkage between a cysteine residue present in one of the peptides and a cysteine
residue present in the second peptide, i.e., an intermolecular disulfide bond between these
cysteine residues.
In certain embodiments, the peptide dimers comprise two peptides dimerized by
covalent attachment of each peptide to a common linking moeity, i.e., a linker. A variety
of linkers suitable for dimerizing two peptides are known in the art and commercially
available, including, e.g., diethylene glycol (DIG), iminodiacetic acid (IDA), -Ala-IDA,
PEG13, and PEG25. In particular embodiments, peptide dimers include any of the linking
moieties shown below or have any of the structures shown below. In particular
embodiments, peptide dimers are dimerized via both a linking moiety and a disulphide
bond between a cysteine residue in one peptide and a cysteine residue in the other peptide
of the dimer.
In certain embodiments, the linking moiety comprises the formula: -NH-R -NH-,
wherein R is a lower (C ) alkyl. In certain embodiments, the linking moiety comprises
1-20
the formula: -CO-(CH2)n-(X-(CH2)m)o-X-(CH2)pCO-, wherein n is 1-3, m is 1-3, p is 1-3,
o is 0-24, and X is O or NH. In one embodiment, n, m and p are each 2, o is 1-25, X is O.
In certain embodiments, the linking moiety comprises the formula: -NH-(CH ) -
[O-(CH ) ] -O -(CH ) -Y-, wherein , and are each integers whose values are
2 2
independently selected from 1 to 6, is 0 or 1, is an integer selected from 0 to 10, and y is
selected from NH or CO, provided that is 2 when is greater than 1.
In various embodiments, the linker is attached to the N-terminal amino acid of one
or both peptides of the dimer, the linker is attached to the C-terminal amino acid of one or
both peptides of the dimer, or the linker is attached to an internal amino acid of one or both
peptides of the dimer. In one embodiment, the linker is attached to lysine residues in each
of the peptides of the dimer. In particular embodiments, the linker is not attached to the N-
terminal amino acid of one or both peptides of the dimer.
In particular embodiments, one or both peptides present in a dimer comprise an
amino acid residue that is conjugated (i.e., covalently attached) to a lipophilic substituent,
including any of those described herein. In certain embodiments, one or both peptides
present in a dimer comprise an amino acid residue that is conjugated to a polymeric moiety,
including any of those described herein. In certain embodiments, one or both of the
peptides present in the peptide dimers is conjugated to an acidic compound, e.g., isovaleric
acid, isobutyric acid, valeric acid, or the like.
In particular embodiments, a linking moiety present in a dimer is conjugated (i.e.,
covalently attached) to a lipophilic substituent, including any of those described herein. In
certain embodiments, a linking moiety present in a dimer is conjugated to a polymeric
moiety, including any of those described herein. In certain embodiments, a linking moiety
present in a peptide dimer is conjugated to an acidic compound, e.g., isovaleric acid,
isobutyric acid, valeric acid, or the like.
Pharmaceutical compositions
It is to be understood that the inclusion of a peptide analogue or a dimer thereof of
the invention (i.e., one or more peptide analogues of the invention or one or more peptide
dimers of the present invention) in a pharmaceutical composition also encompasses
inclusion of a pharmaceutically acceptable salt or solvate of a peptide analogue or a peptide
dimer of the invention.
The invention also provides a pharmaceutical composition comprising a peptide
analogue, or a pharmaceutically acceptable salt or solvate thereof, according to the
invention. In particular embodiments, the invention provides a pharmaceutical
composition comprising a peptide dimer, or a pharmaceutically acceptable salt or solvate
thereof, according to the invention. In particular embodiments, the pharmaceutical
compositions further comprise one or more pharmaceutically acceptable carrier, ecxcipient,
or vehicle.
The invention also provides a pharmaceutical composition comprising a peptide
analogue, or a pharmaceutically acceptable salt or solvate thereof, for treating a variety of
conditions, diseases, or disorders as disclosed herein elsewhere (see, e.g., therapeutic uses,
supra). In particular embodiments, the invention provides a pharmaceutical composition
comprising a peptide dimer, or a pharmaceutically acceptable salt or solvate thereof, for
treating a variety of conditions, diseases, or disorders as disclosed herein elsewhere (see,
e.g., therapeutic uses, supra).
The peptide analogues, including the peptide dimers, of the present invention may
be formulated as pharmaceutical compositions which are suited for administration with or
without storage, and which typically comprise a therapeutically effective amount of at least
one peptide analogue of the invention, together with a pharmaceutically acceptable carrier,
excipient or vehicle.
The term “pharmaceutically acceptable carrier” includes any of the standard
pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well
known in the pharmaceutical art and are described, for example, in “Remington's
Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing
Company, Easton, PA, USA, 1985. For example, sterile saline and phosphate-buffered
saline at slightly acidic or physiological pH may be used. Suitable pH-buffering agents
may, e.g., be phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-
tris(hydroxymethyl)methylaminopropanesulfonic acid (TAPS), ammonium bicarbonate,
diethanolamine, histidine, arginine, lysine or acetate (e.g. as sodium acetate), or mixtures
thereof. The term further encompasses any carrier agents listed in the US Pharmacopeia for
use in animals, including humans.
A pharmaceutical composition of the invention may be in unit dosage form. In such
form, the composition is divided into unit doses containing appropriate quantities of the
active component or components. The unit dosage form may be presented as a packaged
preparation, the package containing discrete quantities of the preparation, for example,
packaged tablets, capsules or powders in vials or ampoules. The unit dosage form may also
be, e.g., a capsule, cachet or tablet in itself, or it may be an appropriate number of any of
these packaged forms. A unit dosage form may also be provided in single-dose injectable
form, for example in the form of a pen device containing a liquid-phase (typically aqueous)
composition. Compositions may be formulated for any suitable route and means of
administration. Pharmaceutically acceptable carriers or diluents include those used in
formulations suitable for e.g. oral, intravitreal, rectal, vaginal, nasal, topical, enteral or
parenteral (including subcutaneous (SC), intramuscular (IM), intravenous (IV), intradermal
and transdermal) administration or administration by inhalation. The formulations may
conveniently be presented in unit dosage form and may be prepared by any of the methods
well known in the art of pharmaceutical formulation.
Subcutaneous or transdermal modes of administration may be particularly suitable
for the peptide analogues of the invention.
Further embodiments of the invention relate to devices, dosage forms and packages
used to deliver the pharmaceutical formulations of the present invention. Thus, at least one
peptide analogue or specified portion or variant in either the stable or preserved
formulations or solutions described herein, can be administered to a patient in accordance
with the present invention via a variety of delivery methods, including SC or IM injection;
transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micro pump, or
other means appreciated by the skilled artisan as well-known in the art.
Still further embodiments of the invention relate to oral formulations and oral
administration. Formulations for oral administration may rely on the co-administration of
adjuvants (e.g. resorcinols and/or nonionic surfactants such as polyoxyethylene oleyl ether
and n-hexadecylpolyethylene ether) to artificially increase the permeability of the intestinal
walls, and/or the co-administration of enzymatic inhibitors (e.g. pancreatic trypsin
inhibitors, diisopropylfluorophosphate (DFF) or trasylol) to inhibit enzymatic degradation.
The active constituent compound of a solid-type dosage form for oral administration can be
mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose,
raffinose, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum
tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic
polymer, or glyceride. These dosage forms can also contain other type(s) of additives, e.g.,
inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent
such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine,
disintegrators, binders, thickeners, buffering agents, pH adjusting agents, sweetening
agents, flavoring agents or perfuming agents.
Dosages
A typical dosage of a peptide analogue, e.g., a peptide or a dimer of the invention,
as employed in the context of the present invention may be in the range from about 0.0001
to about 100 mg/kg body weight per day, such as from about 0.0005 to about 50 mg/kg
body weight per day, such as from about 0.001 to about 10 mg/kg body weight per day, e.g.
from about 0.01 to about 1 mg/kg body weight per day, administered in one or more doses,
such as from one to three doses. As already indicated to some extent above, the exact
dosage employed will depend, inter alia, on: the nature and severity of the disease or
disorder to be treated; the sex, age, body weight and general condition of the subject to be
treated; possible other, concomitant, disease or disorder that is undergoing or is to undergo
treatment; as well as other factors that will be known to a medical practitioner of skill in
the art.
A peptide analogue, e.g., a peptide or a dimer, of the invention may be administered
continuously (e.g. by intravenous administration or another continuous drug administration
method), or may be administered to a subject at intervals, typically at regular time
intervals, depending on the desired dosage and the pharmaceutical composition selected by
the skilled practitioner for the particular subject. Regular administration dosing intervals
include, e.g., once daily, twice daily, once every two, three, four, five or six days, once or
twice weekly, once or twice monthly, and the like.
Such regular peptide analogue, peptide, or dimer administration regimens of the
invention may, in certain circumstances such as, e.g., during chronic long-term
administration, be advantageously interrupted for a period of time so that the medicated
subject reduces the level of or stops taking the medication, often referred to as taking a
“drug holiday.” Drug holidays are useful for, e.g., maintaining or regaining sensitivity to a
drug especially during long-term chronic treatment, or to reduce unwanted side-effects of
long-term chronic treatment of the subject with the drug. The timing of a drug holiday
depends on the timing of the regular dosing regimen and the purpose for taking the drug
holiday (e.g., to regain drug sensitivity and/or to reduce unwanted side effects of
continuous, long- term administration). In some embodiments, the drug holiday may be a
reduction in the dosage of the drug (e.g. to below the therapeutically effective amount for a
certain interval of time). In other embodiments, administration of the drug is stopped for a
certain interval of time before administration is started again using the same or a different
dosing regimen (e.g. at a lower or higher dose and/or frequency of administration). A drug
holiday of the invention may thus be selected from a wide range of time-periods and
dosage regimens. An exemplary drug holiday is two or more days, one or more weeks, or
one or more months, up to about 24 months of drug holiday. So, for example, a regular
daily dosing regimen with a peptide, a peptide analogue, or a dimer of the invention may,
for example, be interrupted by a drug holiday of a week, or two weeks, or four weeks, after
which time the preceding, regular dosage regimen (e.g. a daily or a weekly dosing regimen)
is resumed. A variety of other drug holiday regimens are envisioned to be useful for
administering the peptides, the dimers, and the peptide analogues of the invention.
Thus, the peptide analogue, peptide, or dimer may be delivered via an
administration regime which comprises two or more administration phases separated by
respective drug holiday phases.
During each administration phase, the peptide analogue, peptide, or dimer is
administered to the recipient subject in a therapeutically effective amount according to a
pre-determined administration pattern. The administration pattern may comprise
continuous administration of the drug to the recipient subject over the duration of the
administration phase. Alternatively, the administration pattern may comprise
administration of a plurality of doses of the peptide analogue to the recipient subject,
wherein said doses are spaced by dosing intervals.
A dosing pattern may comprise at least two doses per administration phase, at least
five doses per administration phase, at least 10 doses per administration phase, at least 20
doses per administration phase, at least 30 doses per administration phase, or more.
Said dosing intervals may be regular dosing intervals, which may be as set out
above, including once daily, twice daily, once every two, three, four, five or six days, once
or twice weekly, once or twice monthly, or a regular and even less frequent dosing interval,
depending on the particular dosage formulation, bioavailability, and pharmacokinetic
profile of the peptide analogue the peptide, or the peptide dimer of the present invention.
An administration phase may have a duration of at least two days, at least a week, at
least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at
least 6 months, or more.
Where an administration pattern comprises a plurality of doses, the duration of the
following drug holiday phase is longer than the dosing interval used in that administration
pattern. Where the dosing interval is irregular, the duration of the drug holiday phase may
be greater than the mean interval between doses over the course of the administration
phase. Alternatively the duration of the drug holiday may be longer than the longest
interval between consecutive doses during the administration phase.
The duration of the drug holiday phase may be at least twice that of the relevant
dosing interval (or mean thereof), at least 3 times, at least 4 times, at least 5 times, at least
times, or at least 20 times that of the relevant dosing interval or mean thereof.
Within these constraints, a drug holiday phase may have a duration of at least two
days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months,
at least 3 months, at least 6 months, or more, depending on the administration pattern
during the previous administration phase.
An administration regime comprises at least 2 administration phases. Consecutive
administration phases are separated by respective drug holiday phases. Thus the
administration regime may comprise at least 3, at least 4, at least 5, at least 10, at least 15,
at least 20, at least 25, or at least 30 administration phases, or more, each separated by
respective drug holiday phases.
Consecutive administration phases may utilise the same administration pattern,
although this may not always be desirable or necessary. However, if other drugs or active
agents are administered in combination with a peptide analogue, a peptide or a peptide
dimer of the invention, then typically the same combination of drugs or active agents is
given in consecutive administration phases. In certain embodiments, the recipient subject
is human.
Devices and Kits
In some embodiments, the invention relates to a device comprising one or more
peptides, peptide analogues, peptide dimersor pharmaceutically acceptable salts or solvates
thereof of the invention, for delivery of the compound of the present invention to a subject.
Thus, one or more peptide analogues, peptides, dimers, or pharmaceutically acceptable
salts or solvates thereof can be administered to a patient in accordance with the present
invention via a variety of delivery methods including intravenous, subcutaneous,
intramuscular, or intraperitoneal injection; oral administration, transdermally, by
pulmonary or transmucosal administration, by implant or osmotic pump, by cartridge or
micro pump, or by other means appreciated by the skilled artisan, as well-known in the art.
In some embodiments, the invention relates to a kit comprising one or more peptide
analogues or pharmaceutically acceptable salts or solvates thereof of the invention. In
some embodiments, the invention relates to a kit comprising one or more peptide dimer of
the present invention, or pharmaceutically acceptable salts or solvates thereof. In other
embodiments, the kit comprises one or more pharmaceutical compositions comprising one
or more peptide analogues or pharmaceutically acceptable salts or solvates thereof. In
certain embodiments, the kit further comprises packaging or instructions for use. In other
embodiments, the kit comprises one or more pharmaceutical compositions comprising one
or more peptide dimer of the present invention, or pharmaceutically acceptable salts or
solvates thereof. In certain embodiments, the kit further comprises packaging or
instructions for use.
Combination therapy
As noted above, it will be understood that reference in the following to a peptide
analogue of the invention (e.g., the compounds listed in any one of Tables 5-15, for
example compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 66, 67, 68, 69, 70, 71, 73, 74,
75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,
100, 101, 102, 103, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 117, 118, 119,
120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,
139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156,
157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 176,
177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194,
195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212,
213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230,
231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248,
249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266,
267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,
285, 286, 287, 288, 289, 290, 291, 293, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306,
307, 308, 309, 310, 355, 356, 357, 358, 359, 360, 361 or dimers thereof, e.g., any one of
the peptide dimers disclosed in Tables 12-15, for example compounds 311-353 also
extends to a pharmaceutically acceptable salt or solvate thereof, as well as to a composition
comprising more than one different peptide, peptide analogue, or peptide dimer of the
invention.
In certain embodiments, a peptide analogue or a peptide dimer of the invention may
have some benefit if administered in combination with an iron chelator, such as
Deferoxamine and Deferasirox (Exjade ™)
EXAMPLES
The following examples demonstrate certain specific embodiments of the present
invention. The following examples were carried out using standard techniques that are
well known and routine to those of skill in the art, except where otherwise described in
detail. It is to be understood that these examples are for illustrative purposes only and do
not purport to be wholly definitive as to conditions or scope of the invention. As such,
they should not be construed in any way as limiting the scope of the present invention.
ABBREVIATIONS:
DCM: dichloromethane
DMF: N,N-dimethylformamide
NMP: N-methylpyrolidone
HBTU: O-(Benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HATU: 2-(7-aza-1H-benzotriazoleyl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
DCC: Dicyclohexylcarbodiimide
NHS: N-hydoxysuccinimide
DIPEA: diisopropylethylamine
EtOH: ethanol
Et2O: diethyl ether
Hy: hydrogen
TFA: trifluoroacetic acid
TIS: triisopropylsilane
ACN: acetonitrile
HPLC: high performance liquid chromatography
ESI-MS: electron spray ionization mass spectrometry
PBS: phosphate-buffered saline
Boc: t-butoxycarbonyl
Fmoc: Fluorenylmethyloxycarbonyl
Acm: acetamidomethyl
IVA: Isovaleric acid (or Isovaleryl)
K( ): In the peptide sequences provided herein, wherein a compound or chemical
group is presented in parentheses directly after a Lysine residue, it is to be
understood that the compound or chemical group in the parentheses is a side
chain conjugated to the Lysine residue. So, e.g., but not to be limited in any
way, K(PEG8) indicates that a PEG8 moiety is conjugated to a side chain of this
Lysine. For a few non-limiting examples of such a conjugated Lysines, please
see, e.g., compounds 54 and 90.
Palm: Indicates conjugation of a palmitic acid (palmitoyl).
As used herein “C( )” refers to a cysteine residue involved in a particular disulfide
bridge. For example, in Hepcidin, there are four disulfide bridges: the first between the
two C(1) residues; the second between the two C(2) residues; the third between the two
C(3) residues; and the fourth between the two C(4) residues. Accordingly, in some
embodiments, the sequence for Hepcidin is written as follows:
Hy-DTHFPIC(1)IFC(2)C(3)GC(2)C(4)HRSKC(3)GMC(4)C(1)KT-OH (SEQ ID NO:335);
and the sequence for other peptides may also optionally be written in the same manner.
The following examples are provided to illustrate certain embodiments of the
invention and are not intended to limit the scope of the invention.
EXAMPLE 1
SYNTHESIS OF COMPOUNDS
Unless otherwise specified, reagents and solvents employed in the following were
available commercially in standard laboratory reagent or analytical grade, and were used
without further purification.
Procedure for solid-phase synthesis of peptides
Illustrative compounds of the invention (e.g., Compound No. 2) were chemically
synthesized using optimized 9-fluorenylmethoxy carbonyl (Fmoc) solid phase peptide
synthesis protocols. For C-terminal amides, rink-amide resin was used, although wang and
trityl resins were also used to produce C-terminal acids. The side chain protecting groups
were as follows: Glu, Thr and Tyr: O-tButyl; Trp and Lys: t-Boc (t-butyloxycarbonyl);
Arg: N-gamma-2,2,4,6,7-pentamethyldihydrobenzofuransulfonyl; His, Gln, Asn, Cys:
Trityl. For selective disulfide bridge formation, Acm (acetamidomethyl) was also used as a
Cys protecting group. For coupling, a four to ten-fold excess of a solution containing
Fmoc amino acid, HBTU and DIPEA (1:1:1.1) in DMF was added to swelled resin
[HBTU: O-(Benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;
DIPEA: diisopropylethylamine; DMF: dimethylformamide]. HATU (O-(7-
azabenzotriazolyl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) was used instead
of HBTU to improve coupling efficiency in difficult regions. Fmoc protecting group
removal was achieved by treatment with a DMF, piperidine (2:1) solution.
Procedure for cleavage of peptides off resin
Side chain deprotection and cleavage of the peptides of the invention (e.g.,
Compound No. 2) was achieved by stirring dry resin in a solution containing trifluoroacetic
acid, water, ethanedithiol and tri-isopropylsilane (90:5:2.5:2.5) for 2 to 4 hours. Following
TFA removal, peptide was precipitated using ice-cold diethyl ether. The solution was
centrifuged and the ether was decanted, followed by a second diethyl ether wash. The
peptide was dissolved in an acetonitrile, water solution (1:1) containing 0.1% TFA
(trifluoroacetic acid) and the resulting solution was filtered. The linear peptide quality was
assessed using electrospray ionisation mass spectrometry (ESI-MS).
Procedure for purification of Peptides
Purification of the peptides of the invention (e.g., Compound No. 2) was achieved
using reverse-phase high performance liquid chromatography (RP-HPLC). Analysis was
performed using a C18 column (3µm, 50 x 2mm) with a flow rate of 1 mL/min.
Purification of the linear peptides was achieved using preparative RP-HPLC with a C18
column (5µm, 250 x 21.2 mm) with a flow rate of 20 mL/min. Separation was achieved
using linear gradients of buffer B in A (Buffer A: Aqueous 0.05% TFA; Buffer B: 0.043%
TFA, 90% acetonitrile in water).
Procedure for oxidation of peptides
Method A (Single disulfide oxidation). Oxidation of the unprotected peptides of
the invention (e.g., Compound No. 2) was achieved by adding drop-wise iodine in MeOH
(1 mg per 1 mL) to the peptide in a solution (ACN: H O, 7: 3, 0.5% TFA). After stirring
for 2 min, ascorbic acid portion wise was added until the solution was clear and the sample
was immediately loaded onto the HPLC for purification.
Method B (Selective oxidation of two disulfides). When more than one
disulfide was present (e.g., Compound 30), selective oxidation was often performed.
Oxidation of the free cysteines was achieved at pH 7.6 NH CO solution at 1mg /10 mL
of peptide. After 24 h stirring and prior to purification the solution was acidified to pH 3
with TFA followed by lyophilization. The resulting single oxidized peptides (with ACM
protected cysteines) were then oxidized / selective deprotection using iodine solution.
The peptide (1 mg per 2 mL) was dissolved in MeOH/H 0, 80:20 iodine dissolved in the
reaction solvent was added to the reaction (final concentration: 5 mg/mL) at room
temperature. The solution was stirred for 7 minutes before ascorbic acid was added
portion wise until the solution is clear. The solution was then loaded directly onto the
HPLC.
Method C (Native oxidation). When more than one disulfide was present and
when not performing selective oxidations, native oxidation was performed (e.g., this
method was used for Compound 19). Native oxidation was achieved with 100 mM
NH4CO3 (pH7.4) solution in the presence of oxidized and reduced glutathione
(peptide/GSH/GSSG, 1:100:10 molar ratio) of (peptide: GSSG: GSH, 1:10, 100). After
24 h stirring and prior to RP-HPLC purification the solution was acidified to pH 3 with
TFA followed by lyophilization.
Procedure of Cysteine oxidation to produce dimers. Oxidation of the
unprotected peptides of the invention (e.g., Compound No. 1) was achieved by adding
drop-wise iodine in MeOH (1 mg per 1 mL) to the peptide in a solution (ACN: H2O, 7: 3,
0.5% TFA). After stirring for 2 min, ascorbic acid portion wise was added until the
solution was clear and the sample was immediately loaded onto the HPLC for purification.
Procedure for Dimerization. Glyxoylic acid, IDA, or Fmoc- -Ala-IDA was pre-
activated as the N-hydoxysuccinimide ester by treating the acid (1 equiv) with 2.2 eq of
both N-hydoxysuccinimide (NHS) and dicyclohexyl carbodiimide (DCC) in NMP (N-
methyl pyrolidone) at a 0.1 M final concentration. For the PEG13 and PEG25 linkers, these
chemical entities were purchased pre-formed as the activated succinimide ester. The
activated ester ~ 0.4 eq was added slowly to the peptide in NMP (1mg/mL) portionwise.
The solution was left stirring for 10 min before 2-3 additional aliquots of the linker ~0.05
eq were slowly added. The solution was left stirring for a further 3 h before the solvent
was removed under vaccuo and the residue was purified by reverse phase HPLC. An
additional step of stirring the peptide in 20% piperidine in DMF (2 x 10 min) before an
additional reverse phase HPLC purification was performed.
One of skill in the art will appreciate that standard methods of peptide synthesis
may be used to generate the compounds of the invention.
EXAMPLE 2
ACTIVITY ASSAYS METHODOLOGY
The designed peptides were tested in vitro for induction of degradation of the
human ferroportin protein.
The cDNA encoding the human ferroportin (SLC40A1) was cloned from a cDNA
clone from Origene (NM_014585). The DNA encoding the ferroportin was amplified by
PCR using primers also encoding terminal restriction sites for subcloning, but without the
termination codon. The ferroportin receptor was subcloned into a mammalian GFP
expression vector containing a neomycin (G418) resistance marker in such that the reading
frame of the ferroportin was fused in frame with the GFP protein. The fidelity of the DNA
encoding the protein was confirmed by DNA sequencing. HEK293 cells were used for
transfection of the ferroportin-GFP receptor expression plasmid. The cells were grown
according to standard protocol in growth medium and transfected with the plasmids using
Lipofectamine (manufacturer’s protocol, Invitrogen). The cells stably expressing
ferroportin-GFP were selected using G418 in the growth medium (in that only cells that
have taken up and incorporated the cDNA expression plasmid survive) and sorted several
times on a Cytomation MoFlo ™ cell sorter to obtain the GFP-positive cells (488nm/530
nm). The cells were propagated and frozen in aliquots.
To determine compound activity on the human ferroportin, the cells were incubated
in 96 well plates in standard media, without phenol red. Compound was added to desired
final concentration for at least 18 hours in the incubator. Following incubation, the
remaining GFP-fluorescence was determined either by whole cell GFP fluorescence
(Envision plate reader,
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361800048P | 2013-03-15 | 2013-03-15 | |
US201361800284P | 2013-03-15 | 2013-03-15 | |
US61/800,048 | 2013-03-15 | ||
US61/800,284 | 2013-03-15 | ||
NZ712029A NZ712029A (en) | 2013-03-15 | 2014-03-17 | Hepcidin analogues and uses therof |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ751741A NZ751741A (en) | 2021-08-27 |
NZ751741B2 true NZ751741B2 (en) | 2021-11-30 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11807674B2 (en) | Hepcidin analogues and uses thereof | |
US11472842B2 (en) | Analogues of hepcidin mimetics with improved in vivo half lives | |
US11753443B2 (en) | Conjugated hepcidin mimetics | |
AU2015279571A1 (en) | Hepcidin and mini-hepcidin analogues and uses therof | |
WO2022026633A1 (en) | Conjugated hepcidin mimetics | |
WO2022212698A1 (en) | Conjugated hepcidin mimetics | |
NZ751741B2 (en) | Hepcidin analogues and uses therof |