[发明专利]用于糖尿病治疗的蛋白、蛋白缀合物及其应用

权利要求书

1.一种融合蛋白，所述融合蛋白由白介素-1受体拮抗蛋白与另一种多肽连接而成，另一种多肽是GLP-1受体结合多肽；

所述融合蛋白的结构为：GLP-1受体结合多肽-Lj-白介素-1受体拮抗蛋白；

所述融合蛋白的序列为：

HX_G2EGTFTSDX_G10SX_G12YLEX_G16QAAX_G20EFIAWLVX_G28GRX_G31-L_j-X_IL0RPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVX_IL84ITDLSENRKQDKRFAFIRSDSGPTTSFESAAX_IL116PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE，其中，X_G2为G，X_G10为V或C，X_G12为S，X_G16为E，X_G20为K或C，X_G28为K或C，X_G31为G或C或PSSGAPPPS，L_j为(GGGGS)_n，n为0、1、2或3，X_IL0为缺失，X_IL84为N或C，X_IL116为C或S。

2.根据权利要求1所述的融合蛋白，选自化合物G-18～G-29、G-40～G-43、G-45和G-47～G-50，其中，各化合物的结构如下：

G-18：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE；

G-19：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE；

G-20：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE；

G-21：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE；

G-22：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRPSSGAPPPSGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE；

G-23：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC(S-CH₂-CONH-PEG20K)PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-24：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC(S-CH₂-CONH-PEG20K)PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-25：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVC[S-马来酰亚胺-(CH₂)₄-NH-(N^α-(HOOC(CH₂)₁₄CO)-γ-Glu)]ITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAME ADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-26：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC(S-CH₂-CONH-PEG20K)PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-27：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVC[S-马来酰亚胺-(CH₂)₄-NH-(N^α-(HOOC(CH₂)₁₄CO)-γ-Glu)]ITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-28：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC(S-CH₂-CONH-PEG20K)PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-29：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRPSSGAPPPSGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC[S-马来酰亚胺-(CH₂)₄-NH-(N^α-(HOOC(CH₂)₁₄CO)-γ-Glu)]PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-40：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRC(S-马来酰亚胺-(CH₂)₁₅-COOH)GGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-41：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRC[S-CH₂-CONH-(CH₂CH₂O)₂-(CH₂)₂-NH-(N^α-(HOOC(CH₂)₁₄CO)-γ-Glu)]GGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-42：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVC(S-马来酰亚胺-(CH₂)₁₇-COOH)ITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-43：

HGEGTFTSDVSSYLEEQAAC[S-CH₂-CONH-(CH₂CH₂O)₂-(CH₂)₂-NH-(N^α-(HOOC(CH₂)₁₄CO)-γ-Glu)]EFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-45：

HGEGTFTSDC[S-CH₂-CONH-(CH₂CH₂O)₂-(CH₂)₂-NH-(N^α-(HOOC(CH₂)₁₄CO-γ-Glu-N-

γ-Glu)]SSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-47：

HGEGTFTSDVSSYLEEQAAKEFIAWLVC[S-CH₂-CONH-(CH₂CH₂O)₂-(CH₂)₂-NH-(N^α-(HOOC(CH₂)₁₄CO)-γ-Glu)]GRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-48：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVC[S-CH₂-CONH-(CH₂CH₂O)₄-(CH₂)₂-NH-(N^α-(HOOC(CH₂)₁₆CO)-γ-Glu)]ITDLSENRKQDKRFAFIRSDSGPTTSFESAASPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-49：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC(S-马来酰亚胺-(CH₂)₁₅-COOH)PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)；

G-50：

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRGGGGSGGGGSRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAAC[S-CH₂-CONH-(CH₂CH₂O)₂-(CH₂)₂-NH-(N^α-(HOOC(CH₂)₁₄CO)-γ-Glu)]PGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(S是半胱氨酸侧链的硫原子)。