CN117482243A - 一种偶联物及其用途 - Google Patents
一种偶联物及其用途 Download PDFInfo
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- CN117482243A CN117482243A CN202310958327.9A CN202310958327A CN117482243A CN 117482243 A CN117482243 A CN 117482243A CN 202310958327 A CN202310958327 A CN 202310958327A CN 117482243 A CN117482243 A CN 117482243A
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- Prior art keywords
- seq
- nucleotide sequence
- alternatively
- heat exchangers
- antisense strand
- Prior art date
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- 238000011160 research Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- HQHCYKULIHKCEB-UHFFFAOYSA-N tetradecanedioic acid Natural products OC(=O)CCCCCCCCCCCCC(O)=O HQHCYKULIHKCEB-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
本发明涉及一种偶联物及包括该偶联物的药物组合物,以及上述偶联物或偶联物的药物组合物在制备用于治疗、抑制或预防PCSK9相关的疾病的药物中的用途。
Description
技术领域
本发明涉及一种偶联物以及偶联物在制备用于治疗、抑制或预防PCSK9相关疾病、失调或病症的药物中的用途。
背景技术
人体血液中有4类脂肪:胆固醇、中性脂肪、游离脂肪酸和磷脂类。胆固醇是一种油油复合体,大部分在肝脏中产生。人体内胆固醇的总量为100到200克,其中三分之二在体内自行合成,三分之一来自食物。胆固醇必须和脂蛋白结合才能运送到体内各部分。脂蛋白又分低密度脂蛋白和高密度脂蛋白。血清中的低密度和高密度脂蛋白的含量是一比二,两者都有重要任务:低密度脂蛋白把胆固醇从肝脏运送到全身组织,高密度脂蛋白将各组织的胆固醇送回肝脏代谢。低密度脂蛋白可被氧化成氧化低密度脂蛋白,当低密度脂蛋白,尤其是氧化修饰的低密度脂蛋白(OX-LDL)过量时,它携带的胆固醇便积存在动脉壁上,久了容易引起动脉硬化。
研究表明,PCSK9(Kexin样前转化酶枯草杆菌蛋白酶家族的第9个成员)介导肝细胞上低密度脂蛋白受体(Low Density Lipoprotein Receptor,LDLR)的降解,调节低密度脂蛋白(Low Density Lipoprotein,LDL),升高胆固醇(LDL-C)水平,使血液中LDL不能清除,从而导致高胆固醇血症或提高冠心病、心肌梗死的患病风险。因此,如何有效抑制PCSK9表达,是值得研究的方向。
发明内容
本发明主要解决的技术问题是提供一种新型偶联物,并通过该新型偶联物实现较好的治疗效果。
本发明披露的偶联物,具有式(I)的结构:
其中,L为载体基团;
R和R*独立地选自不同或相同的天然或非天然氨基酸的侧链;
m和m′独立地选自0至3的整数,当m或m′为1时,结构片段 独立选自不同或相同的氨基酸残基,当m或m′为2或3时,结构片段独立选自不同或相同的寡肽残基;
n和n′独立地选自0至10的整数,且n和n′不同时为0;
A选自以下基团中的一种:
或亚甲基(CH2),
并且当A为亚甲基时,m和m′不同时为0;
R1为细胞受体的生物配体基团;
R2为基因组分,所述基因序列包含:
由核苷酸序列5'-csxusxaxgxaxcxCfxuxGfxuxdTxuxuxgxcxuxuxuxuxgxu-3'组成的正义链和由核苷酸序列5'-VPayxCfyxaxAfxAfxAfxgxCfxaxAfxaxAfxcxAfxgxGfxuxCfxuxaxgsxasxa-3'组成的反义链
优选地,所述基因组分包括由核苷酸序列5'-csxusxaxgxaxcxCfxuxGfxuxdTxuxuxgxcxuxuxuxuxgxu-3'组成的正义链和由核苷酸序列5'-VPasxCfsxaxAfxAfxAfxgxCfxaxAfxaxAfxcxAfxgxGfxuxCfxuxaxgsxasxa-3'组成的反义链。
优选地,所述基因组分包括由核苷酸序列5'-csxusxaxgxaxcxCfxuxGfxuxdTxuxuxgxcxuxuxuxuxgxu-3'组成的正义链和由核苷酸序列5'-VPaxCfxaxAfxAfxAfxgxCfxaxAfxaxAfxcxAfxgxGfxuxCfxuxaxgsxasxa-3'组成的反义链。
其中a、g、c和u分别是2'-O-甲基(2'-OMe)修饰的A、G、C和U核苷酸;Af、Gf、Cf和Uf分别是2'-氟修饰的A、G、C和U核苷酸;VPa是5'-(E)-乙烯基磷酸酯-2'-O-甲基修饰的A;dT是脱氧胸腺嘧啶核苷酸,以及,任意y独立地表示s或不存在,s是硫代磷酸酯键
任意x独立地表示其右侧相邻核苷酸的五位亚甲基上的氢为天然丰度的H或D(氘),具体地,D(氘)可以是一个或两个;
或其右侧相邻核苷酸的五位氧为天然丰度的O或同位素富集的18O;
或其右侧相邻核苷酸的磷酸酯键或硫代磷酸酯键上的氧原子任意的选自天然丰度的O或同位素富集的18O,磷酸酯键或硫代磷酸酯键上的氧原子指的是与磷原子连结的任意氧原子,具体地,可以是以单键与磷原子连接的氧原子,可以是以双键与磷原子连接的氧原子(即P=O键),同位素富集的氧原子可以是一个、两个、三个或四个;
或其右侧相邻核苷酸的五位氧被硫取代;
作为限制地,上述x中的至少一个表示其右侧相邻核苷酸的五位亚甲基上的氢为D(氘)、或其右侧相邻核苷酸的五位氧为同位素富集的18O、或其右侧相邻核苷酸的磷酸酯键或硫代磷酸酯键上的氧原子为同位素富集的18O,或其右侧相邻核苷酸的五位氧被硫取代;
上述正义链通过3'端或5'端的氧原子与式(I)所示的磷原子进行连接。
本发明公开的偶联物,具有很好的生物活性,能够有效的减少PSCK9蛋白的表达,降低血脂水平,或者有效地降低高密度脂蛋白胆固醇(HDL-c)、低密度脂蛋白胆固醇(LDL-c)、总胆固醇(TC)及总甘油三酯(TG)水平中的一种或多种。
在一些实施方式中,基因序列包含:
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:2)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:4)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:6)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:8)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ IDNO:10)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:12)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ IDNO:14)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ IDNO:16)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:18)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:20)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:22)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:24)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:26)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ IDNO:28)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:30)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:122)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:124)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:126)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:128)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQID NO:130)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasa-3'(SEQ ID NO:132)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:134)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:136)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:138)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQID NO:140)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfDDaDDAfcAfgGfuCfuagsasa-3'(SEQ IDNO:142)组成的反义链;或
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:144)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:146)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:148)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:150)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:152)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:154)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:156)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:158)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:160)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:162)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:164)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:166)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:168)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ IDNO:170)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:172)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:174)组成的反义链;或,
由核苷酸序列5'-VPaDDCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:176)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:178)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:180)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:182)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasa-3'(SEQ ID NO:184)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:186)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ IDNO:188)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:190)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:192)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfDDaDDAfcAfgGfuCfuagsasa-3'(SEQ ID NO:194)组成的反义链;或
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:196)组成的反义链;或
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:198)组成的反义链;或
由核苷酸序列5'-VPasCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:200)组成的反义链;或
由核苷酸序列5'-VPaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:202)组成的反义链;
其中,上标DD表示其右侧相邻核苷酸的五位亚甲基为二氘代的亚甲基,即为-CD2-。
在一些实施方式中,基因序列包含:
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:32)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:34)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ ID NO:36)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ ID NO:38)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ IDNO:40)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ IDNO:42)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ IDNO:44)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ IDNO:46)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ IDNO:48)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ IDNO:50)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ IDNO:52)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ IDNO:54)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ IDNO:56)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ IDNO:58)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ IDNO:60)组成的反义链;
其中,上标oa表示其右侧相邻核苷酸的五位氧为18O。
在一些实施方式中,基因序列包含:
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:62)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:64)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ ID NO:66)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ ID NO:68)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ IDNO:70)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ IDNO:72)组成的反义链;或,
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ IDNO:74)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ IDNO:76)组成的反义链;或,
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ IDNO:78)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ IDNO:80)组成的反义链;或,
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ IDNO:82)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ IDNO:84)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ IDNO:86)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ IDNO:88)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ IDNO:90)组成的反义链;或,
其中,上标ob表示其右侧相邻核苷酸的磷酸酯键或硫代磷酸酯键上的氧原子为18O。
在一些实施方式中,基因序列包含:
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:92)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:94)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ ID NO:96)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ ID NO:98)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ IDNO:100)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ IDNO:102)组成的反义链;或,
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ IDNO:104)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ IDNO:106)组成的反义链;或,
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ IDNO:108)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ IDNO:110)组成的反义链;或,
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ IDNO:112)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ IDNO:114)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ IDNO:116)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ IDNO:118)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ IDNO:120)组成的反义链;
其中,上标os表示其右侧相邻核苷酸的五位O被硫取代。
在一些实施方式中,A为亚甲基,偶联物可以是式(II)化合物:
一方面,式(I)或式(II)的氨基酸选自包括(但不限于)瓜氨酸、高瓜氨酸、赖氨酸、高赖氨酸、天冬酰胺、谷氨酰胺、精氨酸、甘氨酸、蛋氨酸、苯丙氨酸、合欢氨酸、缬氨酸,以及其任意组合。
另一方面,本发明公开式(III)和式(IV)所示的偶联物:
其中Y独立地选自氧(O)和氮(NH)。当Y为氧时,分子中的氨基酸残基来自瓜氨酸;当Y为N时,分子中的氨基酸残基来自精氨酸。
一方面,偶联物中的氨基酸残基衍生自天然氨基酸、非天然氨基酸、及其任意组合。
另一方面,偶联物中的氨基酸残基衍生自L-氨基酸、D-氨基酸、DL-氨基酸、及其任意组合。
可选的,氨基酸为L-氨基酸。
在一些实施方式中,氨基酸为瓜氨酸,可选的,瓜氨酸具有L-构型。
一方面,载体基团为含氮杂环衍生的基团。
可选地,含氮杂环可以是四元环、五元环或六元环。
进一步地,载体基团L可选自以下基团之一:
其中,Z选自氧(O)、硫(S)、和氮(NH);R3和R4独立选自氢(H)、羟基(-OH)、或-OR5,其中R5为羟基上的取代基团或保护基团,且R5可选自脂肪烃基、芳香烃基、酰基、膦酰基等。
在一些实施方式中,载体基团含有五元含氮杂环结构。
在另一些实施方式中,含氮五元杂环载体基团为以下结构:
可选地,含氮五元杂环载体基团具有以下立体结构:
在一些实施方式中,本发明公开偶联物所含生物配体基团含有亲脂体,亲脂体选自胆固醇基、胆酸、金刚烷乙酸、1-芘丁酸、二氢睾酮、1,3-双-O(十六烷基)甘油、香叶基氧基己基、十六烷基甘油、冰片、薄荷醇、1,3-丙二醇、十七烷基、棕榈酸、肉豆蔻酸、O-3-(油酰基)石胆酸、O-3-(油酰基)胆烯酸、二甲氧基三苄基和吩噁嗪。
进一步地,生物配体基团含有碳水化合物,碳水化合物选自阿洛糖、阿卓糖、阿拉伯糖、克拉定糖、赤藓糖、赤藓酮糖、果糖、D-岩藻糖醇、L-岩藻糖醇、岩藻糖胺、岩藻糖、墨角藻糖、半乳糖胺、D-半乳糖胺醇、N-乙酰基-半乳糖胺(GalNAc)、半乳糖、葡糖胺、N-乙酰基-葡糖胺、葡糖胺醇、葡萄糖、葡萄糖-6-磷酸酯、古洛糖甘油醛、L-甘油-D-甘露糖-庚糖、甘油、甘油酮、古洛糖、艾杜糖、来苏糖、甘露糖胺、甘露糖、甘露糖-6-磷酸酯、阿洛酮糖、奎诺糖、奎诺糠胺、鼠李糖醇、鼠李糖胺、鼠李糖、核糖、核酮糖、景天庚醛糖、山梨糖、塔格糖、塔罗糖、酒石酸、苏糖、木糖和木酮糖。具体地,生物配体基团为含有N-乙酰基-半乳糖胺(GalNAc)的配体基团。
在另一些实施方式中,本发明公开的偶联物特异性地结合到特定组织的特有受体,从而实现组织特异性靶向。在一些实施方式中,本发明的偶联物特异性地靶向至肝细胞表面受体,从而特异性地靶向至肝组织。在一些实施方式中,本发明的偶联物特异性地靶向至肝细胞表面的去唾液酸糖蛋白受体(asialoglycoprotein receptors,ASGPR)。在一些实施方式中,生物配体基团为含有N-乙酰基-半乳糖胺(GalNAc)的配体基团。
进一步地,生物配体基团包含碳水化合物,具体的,包括以下结构;
具体地,前述偶联物包括但不限于表1中化合物结构实例,表1中所有偶联物的正义链均通过3'端的氧原子连接在磷原子上。
表1.偶联物的实例
本发明所述的化合物或偶合成偶联物的化合物包括但不限于其光学异构体,外消旋化合物物和其它混合物本发明所述的所有偶联物也可以视为一个化合物整体,即,本发明所有的化合物既包括用于偶合成偶联物的各组分,也包括各组分偶合后得到的偶联物整体。在这些情况下,单一对映异构体或非对映异构体,即光学活性的构型,可以通过不对称合成或手性拆分得到。外消旋体的拆分可以例如通过常规方法实现,例如在拆分剂存在下重结晶,或使用如手性高压液相色谱(HPLC)柱色谱法。此外,一些含有碳-碳双键的化合物具有Z-和E-构型(或顺式-和反式-构型)。当本发明所述的化合物存在互变异构时,术语“化合物”(包含偶合物或偶联物)包括化合物的所有互变异构形式。这样的化合物还包括晶体和螯合物。类似地,术语“盐”包括化合物的所有互变异构形式和化合物的晶体形式。
在一些实施方式中,本发明公开的偶联物,其基因组分为双链寡核苷酸,双链寡核苷酸包含正义链和反义链,偶联物的核苷酸序列通过3'端或5'端连接在偶联物上。本文所述的正义链或反义链通过3'端或5'端端连接在偶联物上,即正义链或反义链的3'端或5'端通过磷酸酯键与载体基团连接。在一些实施方式中,双链寡核苷酸通过正义链3'端连接在磷原子上。在一些实施方式中,双链寡核苷酸通过正义链的5'端连接在磷原子上。在一些实施方式中,双链寡核苷酸通过反义链3'端连接在磷原子上。在一些实施方式中,双链寡核苷酸通过反义链5'端连接在磷原子上。
另一方面,双链寡核苷酸为siRNA,siRNA中的每个核苷酸各自独立地为修饰或未修饰的核苷酸。
进一步地,siRNA对应的靶点可以为:ApoB、ApoC、ANGPTL3、PCSK9、SCD1、FVII、p53、HBV、HCV。具体地,siRNA是PCSK9-siRNA。
可选地,siRNA的序列包括表2中任意一种siRNA。
表2一些实施方式中的siRNA序列表
注:S,正义链;AS,反义链;其中a、g、c和u分别是2′-O-甲基(2′-OMe)修饰的A、G、C和U核苷酸;C、G、U、A分别表示胞苷-3′-磷酸酯、鸟苷-3′-磷酸酯、尿苷-3′-磷酸酯、腺苷-3′-磷酸酯;Af、Gf、Cf和Uf分别是2′-氟修饰的A、G、C和U核苷酸;VP表示该字母组合VP右侧的核苷酸序列5'末端上的五位氧被取代为乙烯基磷酸,VPa表示5′-VP-2′-O-甲基修饰的A,VS修饰具体结构参见表3;dT是脱氧胸腺嘧啶核苷酸;s表示字母s左右相邻的两个核苷酸之间的连接为是硫代磷酸酯键;上标ob表示其右侧相邻核苷酸的磷酸酯键为18O代磷酸酯键,即磷酸酯键上的磷氧键(P=O)中氧原子为18O,sob表示该字母sob左右相邻的两个核苷酸之间的连接为硫代-18O代磷酸酯键,即硫代磷酸酯键上的氧原子为18O;dT是脱氧胸腺嘧啶核苷酸;上标DD表示该上标DD右侧相邻的一个核苷酸为5′-二氘代的核苷酸,即五位亚甲基为二氘代的亚甲基;上标oa表示该上标oa右侧相邻的一个核苷酸为5′-18O取代的核苷酸,即其右侧相邻核苷酸的五位氧为18O,soa表示该字母组合soa左右相邻的两个核苷酸之间的连接为是硫代磷酸酯键且右侧相邻的一个核苷酸为5′-18O取代的核苷酸;上标os表示该上标os右侧相邻的一个核苷酸为5′-硫取代的核苷酸,即五位O被硫取代的核苷酸,sos表示该字母组合sos左右相邻的两个核苷酸之间的连接为是硫代磷酸酯键且右侧相邻的一个核苷酸为5′-硫代修饰的核苷酸。上述部分被修饰或取代的核苷酸或磷酸酯键,可参照表3所示结构。
表3部分被修饰或取代的核苷或磷酸酯键
上述
进一步地,偶联物的基因组分是PCSK9-siRNA。因此,该偶联物可用于制备用于治疗或预防PSCK9相关的疾病、失调或病症的药物。PSCK9相关的疾病包括但不限于动脉粥样硬化,高胆固醇血症,高甘油三酯症,急性冠脉综合征,血脂障碍,心肌梗塞,冠状动脉病变,中风,冠状动脉疾病,心血管疾病,糖尿病,高脂血症,二型糖尿病,肾脏疾病。
本发明还提供一种药物组合物,其包含上述任意偶联物或者其药学上可接受的盐和酯,以及药学上可接受的载体,可用于将用本发明的偶联物实际用于对各种相应疾病或病症的预防和/或疗效。
在一些实施方式中,药学上可接受的载体包括乳膏、乳剂、凝胶、脂质体或纳米颗粒。
本发明提供的药物组合物,采用上述任意连接基因组分和生物配体基团的偶联物,能够有效提高基因组分的递送效率,从而提高偶联物及其药物组合物的治疗效果。
附图说明
图1人源PCSK9蛋白水平示意图:I组,空白对照组(生理盐水组);II组,阳性对照组(Inclisiran组);III组,对比偶联物1;偶联物130、偶联物131。
图2人源PCSK9蛋白水平示意图:I组,空白对照组(生理盐水组);II组,阳性对照组(Inclisiran组);III组,对比偶联物1;偶联物132、偶联物133。
具体实施方式
为了对本发明的说明书中所使用的术语提供清楚且一致的理解,在下文中提供一些定义。此外,除了特殊说明,本发明所用的全部技术和科学术语具有同本发明所属领域中普通技术人员通常所理解的相同的含义。
当在权利要求和/或说明书中与术语“包括”结合使用时,词语“一”的使用可以表示“一个”,但它也与“一个或多个”,“至少一个”和“一个或多于一个”的含义已知。类似地,词语“另一个”可以表示至少第二个或者更多个。
如在本说明书和权利要求中所使用的词语“包括”(以及包括的任何形式,诸如“包括”和“包含”),“具有”(以及任何形式的具有,“具有”、“包含”和“含有”)是包括性的和开放式的,并且不排除另外的未列出的要素或处理步骤。术语“约”或“大约”用于表示该值包括在确定该值中所用的仪器和方法带来的误差。
本发明所用的术语“衍生物”应理解为是结构上类似,在一些细微结构上不同的另一种化合物。
本发明中使用的术语“偶联物”(有时亦称为偶联物、偶连物、耦联物、偶联物,有时文献中亦称为缀合物)对应于英语中的"conjugate"或"conjugates"。偶联物是指两个或多个化合物的分子通过具备连接功能的双价或多价化合物分子共价连接(偶联)后所生成的新化合物。偶联物也可以由两个分子直接经偶联或缩合生成。常见的antibody-drugconjugate(ADC)即是偶联物,也称为抗体药物偶联物。本发明中,siRNA分子经连接基团以及双价化合物的连接与生物配体基团偶联在一起所产生的产物,同样是偶联物。
本发明中使用的术语“双价化合物”(bivalent compound),是指一种具备以分子中的两个可以被衍生的位点分别连接(亦称偶联)两个其它化合物基团或残基、从而形成一个新的化合物或偶联物(conjugate)的有机化合物或有机分子。例如,1,12-十二烷二酸就是个典型的双价化合物,它可以用1-位和十二位的两个羧基分别以酰胺或酯将另外两个分子进行连接或偶联,从而生成一个新的化合物,即偶联物。双价化合物中的两个可以被衍生的位点可以不同,也可以相同。
本发明中所用术语“偶联”是指两个或两个以上化合物分子经过某种反应生成新化学键及新分子的化学过程。在一定的上下文中,“偶联”可以与“连接”交替使用或相互代替。
同位素富集是通过改变其给定元素的同位素的相对丰度,使一种特定同位素富集(即增加),并且相应的另一种同位素减少或耗尽的过程。如本发明所用术语“同位素富集的”化合物或衍生物是指化合物中一种或多种特定同位素被增加(即一种或多种特定的同位素元素被富集或增加)。通常,在一个同位素富集的化合物或衍生物中,化合物特定位置的特定同位素元素被富集或增加。然而应当理解,化合物可以有两种或多种同位素元素被富集或增加,包括同一元素的不同同位素以及不同元素的各自同位素。此外,同位素富集的化合物可以是同位素富集的混合形式,即含有多种特定同位素或元素或两者兼有。
通常,氘(D或2H)(质量约为氢的两倍的其稳定同位素),氮-15(15N),碳-13(13C),氧-18(18O)和氧-17(17O)的天然丰度分别为0.016%,0.37%,1.11%,0.204%和0.037%。本发明所用“同位素富集的”化合物或衍生物具有高于该天然丰度的同位素水平。同位素富集的水平取决于特定的同位素本身的天然丰度。在一些实施方案中,化合物或化合物中元素的同位素富集水平可以为约1至约100摩尔百分比(%),例如约2%、约5%、约17%、约30%、约51%、约83%、约90%、约95%、约96%、约97%、约98%、以及大于约98%、约99%或为100%。在一个实施方案中,本发明的同位素富集化合物的同位素富集水平为约5%或更高,或约10%以上。在另一个实施方案中,本发明的同位素富集的化合物的同位素富集水平为约20%或更高,或约50%以上。在另一个实施方案中,本发明的同位素富集的化合物的同位素富集水平为约75%或更高,或约90%或更高。在另一个实施方案中,本发明的同位素富集化合物的同位素富集水平为约95%或更高,或100%。在另一个实施方案中,本发明的同位素富集化合物的同位素富集水平为约98%至100%。值得注意的是,特定化合物或化合物的特定元素的同位素富集的水平将取决于化合物的几种性质包括化学、药代动力学和治疗效果来决定,目的是为了改善化合物的治疗功效、治疗生物分布、生物利用度、代谢、稳定性和/或药代动力学等情况。
本发明所用术语“天然丰度元素”或“自然丰度元素”是指其在自然界中最丰富的原子质量的元素。例如,氢的天然丰度元素为1H,氮的天然丰度元素为14N;氧的天然丰度元素为16O,碳的天然丰度元素为12C等。“非同位素富集”化合物是其中化合物中的所有原子或元素都是天然丰度的同位素的化合物,即所有原子或元素的原子质量是在自然界中最丰富。而同位素富集的化合物指其中一种或多种特定元素以不是天然丰度的同位素的形式富集。非同位素富集的化合物从本发明提供的化合物中排除。
术语“基因组分”是包含修饰或未修饰的核苷酸序列的组分,基因组分可以是单链的核苷酸酸序列,也可以是配对的双链核苷酸序列,所述配对的双链核苷酸序列可是完全配对,也可以是部分配对,双链核苷酸序列的两条链可以全部对齐,也可以部分对齐。在一些实施方式中,基因组分是诸如核糖核酸(RNA)或其衍生物的多核化物。例如,且不限于,基因组分可以是RNA治疗分子,例如小干扰RNA(siRNA)、RNA适配体或反义RNA。在一些实施方式中,基因组分为修饰或未修饰的双链RNA,该双链RNA包括正义链和反义链,其中正义链通过3'端或5'端上五位的氧原子进行偶联,具体地,氧原子连接至式I所示的磷原子上。在一些实施方式中,该双链RNA为两条至少部分配对的寡核苷酸序列,每条寡核苷酸序列上有10-30个修饰或未修饰的核苷酸。
在一些实施方式中,偶联物的基因组分选自表2所示的SEQ ID NO 195/196,其中正义链SEQ ID NO 195通过3'端的氧原子与式(I)所示的磷原子进行连接。在一些实施方式中,偶联物的基因组分选自表2所示的SEQ ID NO 197/198,其中正义链SEQ ID NO 197通过3'端的氧原子与式(I)所示的磷原子进行连接。本发明所有的“/”,当其出现在两个基因序列号之间时,表示“和”的关系,例如,SEQ ID NO 1/2表示SEQ ID NO 1和SEQ ID NO 2组合在一起形成的双链核苷酸。
术语“氨基酸”通常是指同时包含羧酸基团和胺基基团的有机化合物。术语“氨基酸”包括“天然”和“非天然”的氨基酸。另外,术语氨基酸包括O-烷基化或N-烷基化的氨基酸,以及具有含氮、硫或氧的侧链(例如Lys,Cys或Ser)的氨基酸,其中氮、硫或氧原子可以被或不被酰基化或烷基化。氨基酸可以是L-氨基酸,D-氨基酸或L-和D-混合的氨基酸,包括(但不限于)外消旋混合物。
本发明所用术语“天然氨基酸”和等同表达是指通常在天然存在的蛋白质中发现的L-氨基酸。天然氨基酸的实例包括但不限于瓜氨酸(Citn),丙氨酸(Ala),半胱氨酸(Cys),天冬氨酸(Asp),谷氨酸(Glu),苯丙氨酸(Phe),甘氨酸(Gly),组氨酸(His),异亮氨酸(Ile),赖氨酸(Lys),亮氨酸(Leu),甲硫氨酸(Met),天冬酰胺(Asn),脯氨酸(Pro),谷氨酰胺(Gln),精氨酸(Arg),丝氨酸(Ser),苏氨酸(Thr),色氨酸(Trp),酪氨酸(Tyr),β-丙氨酸(β-Ala)和γ-氨基丁酸(GABA)等。
本发明所用术语“非天然氨基酸”是指天然氨基酸的任何衍生物,包括D-型氨基酸及其衍生物,以及α-和β-氨基酸衍生物。应注意的是,在本发明中某些非天然氨基酸的(例如羟脯氨酸)可在自然界中存在于某些生物组织或特定蛋白质中。具有许多不同保护基团、适于固相肽合成中直接应用的氨基酸是可以通过购买得到的。除了二十种最常见的天然氨基酸,可以根据本发明使用如下实例的非天然氨基酸和氨基酸衍生物(括号中为常见的缩写):2-氨基己二酸(Aad),3-氨基己二酸(β-Aad),2-氨基丁酸(2-Abu),α,β-脱氢-2-氨基丁酸(8-AU),1-氨基环丙烷-1-羧酸(ACPC),氨基异丁酸(Aib),3-氨基异丁酸(β-Aib),2-氨基-噻唑啉-4-羧酸,5-氨基戊酸(5-Ava),6-氨基己酸(6-Ahx),2-氨基庚酸(Ahe),8-氨基辛酸(8-Aoc),11-氨基十一烷酸(11-Aun),12-氨基十二烷酸(12-Ado),2-氨基苯甲酸(2-Abz),3-氨基苯甲酸(3-Abz),4-氨基苯甲酸(4-Abz),4-氨基-3-羟基-6-甲基庚酸(Statine,Sta),氨基氧基乙酸(Aoa),2-氨基四氢化萘-2-羧酸(ATC),4-氨基-5-环己基-3-羟基戊酸(ACHPA),对氨基苯丙氨酸(4-NH2-Phe),2-氨基庚二酸(Apm),联苯基丙氨酸(Bip),对溴苯丙氨酸(4-Br-Phe),邻氯苯丙氨酸(2-Cl-Phe),间氯苯丙氨酸(3-Cl-Phe),对氯苯丙氨酸(3-Cl-Phe),间-氯酪氨酸(3-Cl-Tyr),对苯甲酰基苯丙氨酸(Bpa),叔丁基甘氨酸(TLG),环己基丙氨酸(Cha),环己基甘氨酸(Chg),锁链素(Des),2,2-二氨基庚二酸(Dpm),2,3-二氨基丙酸(Dpr),2,4-二氨基丁酸(Dbu),3,4-二氯苯丙氨酸(3,4-Cl2-Phe),3,4-二氟苯丙氨酸(3,4-F2-Phe),3,5-二碘酪氨酸(3,5-I2-Tyr),N-乙基甘氨酸(EtGly),N-乙基天冬酰胺(EtAsn),邻氟苯丙氨酸(2-F-Phe),间氟苯丙氨酸(3-F-Phe),对氟苯丙氨酸(4-F-Phe),间-氟酪氨酸(3-F-Tyr),高丝氨酸(Hse),高苯丙氨酸(Hfe),高酪氨酸羟基赖氨酸(Hyl),异羟基赖氨酸(aHyl),5-羟色氨酸(5-OH-Trp),3-或4-羟基脯氨酸(3-或4-Hyp),对碘苯丙氨酸-异酪氨酸(3-I-Tyr),二氢吲哚-2-羧酸(Idc),异艾杜霉素(Ide),异亮氨酸(α-Ile),异哌啶酸(Inp),N-甲基异亮氨酸(MeLys),间甲基酪氨酸(3-Me-Tyr),N-甲基缬氨酸(MeVal),1-萘基丙氨酸(1-Nal),2-萘基丙氨酸(2-Nal),对硝基苯丙氨酸(4-NO2-Phe),3-硝基酪氨酸(3-NO2-Tyr),正亮氨酸(Nle),正缬氨酸(Nva),鸟氨酸(Orn),邻磷酸酪氨酸(H2PO3-Tyr),八氢吲哚-2-羧酸(Penicillamine),五氟苯丙氨酸(F5-Phe),苯基甘氨酸(Phg),哌啶酸(Pip),炔丙基甘氨酸(Pra),焦谷氨酸(PGLU),肌氨酸(Sar),四氢异喹啉-3-羧酸(Tic),噻唑烷-4-羧酸(硫代脯氨酸,Th)。
本发明所用术语“氨基酸的侧链”是指上述天然氨基酸和非天然氨基酸的侧链。
本发明所用术语“氨基酸残基”是指不完整的氨基酸,即氨基酸分子失去至少一部分后剩余的结构片段。例如,多肽是由多个氨基酸相互之间经肽键连接后形成的;在多肽链中的氨基酸,由于其部分基团参与了肽键的形成,剩余的结构部分则称氨基酸残基。氨基酸残基不限于肽分子中,当氨基酸参与和其它分子连接后形成的不完整氨基酸部分,统称为氨基酸残基。同样,术语“寡肽残基”是指不完整的寡肽。
术语“碳水化合物”是指单糖、二糖、三糖或多糖。
术语“单糖”包括阿洛糖的基团,麦芽糖,阿拉伯糖,克拉定糖,红糖,赤藓糖,果糖,D-岩藻糖醇,L-岩藻糖醇,岩藻糖胺,岩藻糖,半乳糖胺,D-半乳糖胺醇,N-乙酰基-半乳糖胺,半乳糖,葡糖胺,N-乙酰基-葡糖胺,葡糖胺醇,葡萄糖,葡萄糖-6-磷酸酯,葡萄糖甘油醛,L-甘油-D-甘露糖-庚糖,甘油,碘糖,来苏糖,甘露糖胺,甘露糖,甘露糖-6-磷酸酯,阿洛酮糖,异鼠李糖,奎诺糠胺,鼠李糖醇,鼠李糖,核糖,核酮糖,庚糖,山梨糖,塔格糖,塔罗糖,酒石酸,苏糖和木糖。单糖可以是D-或L-构型。单糖还可以是脱氧糖(被氢取代的醇羟基),氨基糖(由氨基取代的醇羟基),硫代糖(被硫醇取代的醇羟基),或由CS取代的CO或由硫取代的环状环氧),硒代糖,碲糖,氮杂糖(环碳被氮取代),亚氨基糖(环氧被氮取代),磷代糖(环氧被磷取代),磷糖(用磷取代的环碳),C-取代的单糖(非末端碳原子上的氢被碳取代),不饱和单糖,糖醇(羰基被CHOH基团取代),醛糖酸(醛基被羧基取代),酮醛糖酸,糖醛酸,醛糖酸等。氨基糖包括氨基单糖,优选半乳糖胺,葡糖胺,甘露糖胺,岩藻糖胺,喹伏糖胺,神经氨酸,胞壁酰胺酸,乳糖二胺,阿考糖胺,芽孢杆菌糖胺,道诺糖胺,去糖胺,福罗沙明,氨基甲酰胺,卡诺糖胺,甘露糖胺,海藻糖,霉胺,过氧化物酶胺,肺炎胺,嘌呤核胺,罗丹胺。应当理解,单糖等可以被进一步取代。
术语“二糖”,“三糖”和“多糖”包括阿贝醌糖的基团,阿克拉波糖,氨基葡萄糖,支链淀粉,直链淀粉,芹菜糖,氨基葡萄糖,子囊糖,抗坏血酸,黄酮糖,纤维二糖,纤维三糖,纤维素,查可三糖,硫醚,甲壳素,胶原蛋白,环糊精,三聚氰胺,糊精,2-脱氧核糖,2-脱氧葡萄糖,二葡萄糖,麦芽糖,数字酮糖,EVALOSE,吴茱萸,低聚果糖,低聚半乳糖,龙胆糖,龙胆二糖,葡聚糖,糖原,金缕梅糖,肝素,菊粉,异吴茱萸皂苷元,异麦芽糖,异麦芽三糖,异戊糖,曲多糖,乳糖,乳糖胺,乳糖二胺,层状阿拉伯糖,左旋葡聚糖,左旋葡聚糖酮,麦芽糖,甘露寡糖,甘露三糖,蜜二糖,胞壁酰胺酸,海藻糖,海藻糖,神经氨酸,黑葡萄糖,诺吉利霉素,槐糖,水苏糖,链球菌糖,蔗糖,海藻糖。此外,应当理解,“二糖”,“三糖”和“多糖”等可以被进一步取代。二糖还包括氨基糖及其衍生物,特别是在C-4′位衍生的霉胺糖或在C-6′位衍生的4-脱氧-3-氨基-葡萄糖。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。理想的化合物的盐(碱性、酸性或带电官能团)可以保留或改善如本发明所定义的母体化合物的生物活性和性质,并且不是生物学上不需要的。
术语“酯”意指衍生自本申请中各个通式化合物的酯,其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
基因组分通过一个磷酸酯键与载体基团相偶联。载体基团一般是优选环状结构。环状结构可以是碳环体系,即所有的环原子都是碳原子,或者是杂环体系,即一个或多个环原子可以是杂原子,例如氮,氧,硫。环状结构可以是单环体系,或者可以包含两个或更多个环,例如稠环。环状结构可以是完全饱和的环体系,或者它可以含有一个或多个双键。
在一实施方式中,基因组分的载体为含氮杂环,优选的,可以是四元环、五元环或六元环,氮杂环上至少有一个含活性官能团的取代基,氮杂环通过取代基上的活性官能团与基因组分相偶联。
在一些实施方式中,基因组分为功能性寡核苷酸,可选地,功能性寡核苷酸选自小干扰RNA、微小RNA、抗微小RNA、微小RNA拮抗剂、微小RNA模拟物、诱饵寡核苷酸、免疫刺激物、G-四极子、可变剪接体、单链RNA、反义核酸、核酸适配体、茎环RNA、mRNA片段、激活RNA或DNA中的一种。在一些实施方式中,功能性寡核苷酸为单链寡核苷酸,载体连接到单链寡核苷酸的端部,单链寡核苷酸的端部指单链寡核苷酸中从一端起算的前4个核苷酸;可选地,载体连接到单链寡核苷酸的末端;可选地,双价化合物连接到单链寡核苷酸的3′末端或5′末端。
在一些实施方式中,功能性寡核苷酸为双链寡核苷酸,双链寡核苷酸包含正义链和反义链,载体连接到所述双链寡核苷酸的端部。在一些实施方式中,双链寡核苷酸为siRNA,该siRNA中的每个核苷酸各自独立地为修饰或未修饰的核苷酸。
在一些实施方式中,偶联物包括直接连接在偶联物上的正义链和与正义链互补的反义链,偶联物作为一个整体的活性分子进入体内后产生治疗效果。
在本发明中可以使用各种羟基保护基团。一般来说,保护基团使化学官能团对特定的反应条件不敏感,并且可以在分子中的该官能团上添加及去除,而不实质上损害分子的其余部分。代表性的羟基保护基团公开于Beaucage等人,Tetrahedron 1992,48,2223-2311,以及Greeneand Wuts,Protective Groups in Organic Synthesis,Chapter 2,2ded,John Wiley&Sons,New York,1991中,本发明以引用的方式将上述文献各自整体并入本文。在一些实施方式中,保护基团在碱性条件下稳定,但可以在酸性条件下脱除。在一些实施方式中,本发明可使用的羟基保护基的非排他性实例包括二甲氧基三苯甲基(DMT)、单甲氧基三苯甲基、9-苯基氧杂蒽-9-基(Pixyl)和9-(对甲氧基苯基)氧杂蒽-9-基(Mox)。在一些实施方式中,本文可使用的羟基保护基的非排他性实例包括三苯甲基(Tr)、4-甲氧基三甲苯基(MMTr)、4,4′-二甲氧基三苯甲基(DMTr)和4,4′,4″-三甲氧基三苯甲基(TMTr)。
在一些实施方式中,本发明的生物配体基团与细胞表面受体结合。为此目的,任何细胞表面受体或者生物标志物或其一部分都被认为是合适的。在一些实施方式中,本发明的生物配体基团特异性地结合到特定组织的特有受体,从而实现组织特异性靶向。在一些实施方式中,本发明的生物配体基团特异性地靶向至肝细胞表面受体,从而特异性地靶向至肝组织。在一些实施方式中,本发明的生物配体基团特异性地靶向至肝细胞特有的细胞表面受体。在一些实施方式中,本发明的生物配体基团包含GalNAc,特异性地靶向至肝细胞表面的去唾液酸糖蛋白受体(asialoglycoprotein receptors,ASGPR)。
在一些实施方式中,本发明的寡核苷酸偶联物具有优异的肝靶向特异性,能够高效地将所偶联的功能性寡核苷酸递送至肝部,从而有效地对肝细胞内特定基因表达进行调控。在一些实施方式中,本发明的寡核苷酸偶联物具有优异生物活性,从而有效地治疗或预防靶向位点的相关疾病。本发明的寡核苷酸偶联物具有广泛的应用前景。
在一些实施方式中,特异性的选择肝脏中表达的内源性基因,siRNA的靶点选自ApoB、ApoC、ANGPTL3、PCSK9、SCD1、FVII、p53、HBV和HCV。
在一些实施方式中,基因组分是针对靶基因的双链siRNA。在一个实施例中,目标基因是PCSK9。在一些实施方式中,基因组分是靶向PCSK9基因的siRNA。
在一些实施方式中,受试者具有由PCSK9表达介导的病症或与PCSK9相关的疾病或病症。
在一些实施方式中,提供了治疗由PCSK9表达介导的疾病的受试者的方法,包括向受试者投予治疗有效量的本文所述化合物或其药物组合物,以使受试者得到治疗。在一些实施方式中,受试者具有高胆固醇血症、血脂异常或高脂血症。在一些实施方式中,在施用本文所述化合物或组合物后,受试者的血清胆固醇水平降低。
本发明还提供一种药物组合物,其包含上述任意一种偶联物或者其药学上可接受的盐和酯,以及药学上可接受的载体,并且其活性分子是PSCK9-siRNA。在一些实施方式中,上述药物组合物可用于制备用于治疗或预防PSCK9相关的疾病、失调或病症的药物。具体的,PSCK9相关的疾病包括动脉粥样硬化,高胆固醇血症,急性冠脉综合征,血脂障碍,心肌梗塞,冠状动脉病变,中风,冠状动脉疾病,心血管疾病,糖尿病,高脂血症,二型糖尿病,肾脏疾病等。
本发明提供了一种抑制细胞中目标基因表达的方法,方法包括将细胞与本发明公开的偶联物或其药物组合物接触,并使细胞维持足够的时间,以获得目标基因的mRNA转录子的降解,从而抑制靶基因在细胞中的表达。在一些实施例中,目标基因的表达被抑制至少30%,至少约40%,至少约50%,至少约60%,或至少70%。
本发明还提供了一种高胆固醇的治疗和预防方法。在一些实施例中,这些方法还包括测定受试者血清胆固醇水平的步骤。血清胆固醇水平可在所述给药之前、期间和/或之后测定。
在本发明提供的治疗和预防方法的一些实施方式中,受试者是哺乳动物,例如灵长类动物、啮齿动物或人类。
在本发明提供的治疗和预防方法的一些实施方式中,以约0.01mg/kg至约10mg/kg、约0.5mg/kg至约50mg/kg或约10mg/kg至约30mg/kg的剂量施用偶联物。
在本发明提供的治疗和预防方法的一些实施方式中,施用本发明的偶联物或药物组合物导致受试者血清胆固醇降低。
在本发明提供的治疗和预防方法的一些实施方式中,化合物或组合物以注射或输注溶液的形式经肠外(例如皮下、肌肉内或静脉内)施用。在一个实施例中,将化合物或组合物皮下施用。
本领域技术人员清楚知晓的是,可以通过使用具有相应修饰的核苷单体来将修饰的核苷酸基团引入本发明所述的siRNA中,制备具有相应修饰的核苷单体的方法及将修饰的核苷酸基团引入siRNA的方法也是本领域技术人员所熟知的。所有修饰的核苷单体均可以商购得到或者采用已知方法制备得到。
本发明所提供的某些基因组分的载体基团是一些由氮杂环衍生而来的载体基团。可以理解的是,载体基团不限于含有氮杂环的基团,而是包括可以用做基因组分载体的各种载体基团。
本发明在一些实施方式中采用了膦酰基将基因组分与载体基团进行连接。可以理解的是,这种双价化合物与基因组分的连接或偶联方式是多样化的,包括但不限于直接偶联和间接偶联、且间接偶联可以通过各种适合于偶联的载体基团及连接方式。
实施例
通过参考以下实施例将更容易理解本发明,所述实施例用于说明本发明,而不应被解释为以任何方式限制本发明的范围。
除非另有定义或上下文另有明确规定,本发明使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。应当理解,与本发明所述类似或等同的任何方法和材料可用于本发明的实践或测试。除非另有说明,否则本发明中所使用的材料和仪器均常规商购所得。
制备例:偶联物的合成
根据下述反应路线来制备偶联物。
步骤1,制备中间体M1
将(s)-2-(((苄氧基)羰基)氨基)-5-脲啶戊酸(0.8g,2.59mmol,1eq.),EDCI(991.60mg,5.17mmol,2eq.),N,N-二异丙基乙胺(1.34g,10.35mmol,1.80mL,4eq.),HOBt(349.47mg,2.59mmol,1eq.)混合于20mL二氯甲烷中,再加入S2A(1.09g,2.60mmol,1eq.)。所得混合物在氮气氛围下于25℃搅拌16h。LC-MS监测新产物生成。反应液用20mL二氯甲烷稀释后,再加入20mL水。静置,分层后得有机相。有机相用无水硫酸钠干燥后,溶剂旋干得粗产物。粗产物经硅胶柱色谱分离得M1(1.2g,收率65.0%)。
步骤2,制备中间体M2
将M1(1.2g,1.69mmol,1eq.)溶于10mL甲醇中,再加入Pd/C(102.52mg)。所得混合物在H2氛围下于25℃搅拌16h。LC-MS监测目标产物生成。反应混合物经过滤,得溶液。溶剂旋干后得M2(860mg),直接用于下一步反应。
步骤3,制备中间体M3
将壬二酸单甲酯(301.61mg,1.49mmol,1eq.),HBTU(1.13g,2.98mmol,2eq.),N,N-二异丙基乙胺(770.94mg,5.97mmol,1.04mL,4eq.)混合于10mL二氯甲烷中,再加入M2(860mg,1.49mmol,1eq.)。所得混合液在氮气氛围下于25℃搅拌16h。LC-MS监测目标产物生成。反应液用20mL二氯甲烷稀释后,再加入20mL水。静置,分层后,得有机相。有机相用无水硫酸钠干燥后,将溶剂旋干,得粗产物。粗产物经硅胶柱色谱分离(甲醇/二氯甲烷=0-6%)得到M3(680mg,收率59.9%)。
步骤4,制备中间体M4
将M3(600mg,788.53μmol,1eq.)溶于10mL甲醇与10mL水,再加入氢氧化锂(188.85mg,7.89mmol,10eq.)。所得混合物于80℃搅拌3h。LC-MS监测目标产物生成。反应液中溶剂旋干后得M4(590mg),直接用于下一步反应。
步骤5,制备中间体M5
将M4(201.43mg,267.57μmol,1.5eq)溶于5mL DMF,再加入HOBT(1eq.),EDCI(2eq.),DIPEA(2eq.)。搅拌0.5h后,再加入M13(320mg,178.38μmol,1eq.)。所得混合液在氮气氛围下于25℃搅拌16h。LC-MS监测目标产物生成。向反应体系中加入15mL水后,再用二氯甲烷萃取(15mLx 3)。有机相合并后,溶剂旋干,得粗产物。粗产物经硅胶柱色谱分离(二氯甲烷(含0.1%三乙胺)/甲醇=90:10,80:20,70:30),得M5(230mg)。
步骤6,制备中间体M6
将M5(230mg,91.17μmol,1eq.)溶于10mL二氯甲烷,再加入DMAP(22.28mg,182.34μmol,2eq.),三乙胺(415.14mg,4.10mmol,570.25μL,45eq.)。冰浴冷却后,向反应体系中加入丁二酸酐(136.85mg,1.37mmol,15eq.)。所得混合液逐渐升温至25℃后,于该条件搅拌16h。LC-MS监测目标产物生成。反应混合液浓缩后,所得粗产物经HPLC制备分离(碳-18色谱柱,乙腈/0.01%氨水),得到M6(33.8mg)。HPLC纯度:99.83%。LCMS(ESI):Cal.forC124H184N14O47:2622.89,Found[M-H]-:2621.7
步骤7,制备中间体M7
(I)将M6(33.8mg,12.89μmol,1eq.)及HBTU(9.77mg,25.77μmol,2eq.)溶于5mL乙腈中,再加入N,N-二异丙基乙胺(6.66mg,51.55μmol,8.98μL,4eq.)。震摇3-4min后,再加入CPG-氨基树脂(386.7mg,50umol/g)。所得混合物在室温条件下于摇床震摇48h。反应混合物经过滤,滤饼用乙腈(25mL)洗涤两次。所得固体在35℃干燥2h,得白色固体(382.6mg)。
(II)将上述所得白色固体与吡啶(4.54mg,57.39μmol,4.62μL,相对于乙酸酐为3eq.)混合于10mL乙腈中,再在冰浴条件下加入乙酸酐(1.95mg,19.13μmol,1.81μL,相对于CPG固载上的游离氨基为1eq.)。所得混合物在室温条件下于摇床震摇0.5h。混合物经过滤,滤饼用乙腈(10mL)洗涤两次。所得固体在40℃干燥2h,得白色固体M7(261.6mg)。负载量:20.5μmol/g。
步骤8,制备偶联物
本申请所用RNA序列均由苏州贝信生物技术有限公司合成。
R2选用SEQ ID NO 195/196,固相负载产物M7经固相合成及脱保护(参照M.J.Damha,K.K.Ogilvie,Methods Mol.Biol.1993,20,81-114.下同),得偶联物130。
R2选用SEQ ID NO 197/198,固相负载产物M7经固相合成及脱保护,得偶联物131。
R2选用SEQ ID NO 199/200,固相负载产物M7经固相合成及脱保护,得偶联物132。
R2选用SEQ ID NO 201/202,固相负载产物M7经固相合成及脱保护,得偶联物133。
R2选用SEQ ID NO 203/204,固相负载产物M7经固相合成及脱保护,得对比偶联物1。
阳性对照物
阳性对照采用Inclisiran,合成步骤参照CN104854242B,其具体结构如下:
生物学测定
1.食蟹猴原代肝细胞自由摄取
由妙通(上海)生物科技有限公司获得食蟹猴原代肝细胞(冷冻保藏)并于37℃和5%CO2气氛的加湿培养箱内的复苏培养基中培养。复苏后,将肝细胞以5x 105细胞/孔的密度接种到经包被培养基包被的96孔板中。贴壁24小时后吸取上清液,添加siRNA(500nM开始,10倍稀释,共2次)并加入维持培养基进行培养。
共培养48小时后,裂解原代肝细胞,并根据实验方案使用DynabeadsTM mRNAPurification Kit进行mRNA提取,逆转录获得cDNA并使用SYBR green法对PCSK9及GAPDHmRNA水平进行检测。使用标准化的PCSK9/GAPDH比值作为PCSK9 mRNA的相对水平作图。
2.PCSK9人源化小鼠检测PCSK9敲低水平
PCSK9人源化小鼠分为七组,A组按照设计剂量(1mg/kg)皮下注射使用生理盐水稀释的偶联物130;B组按照设计剂量(1mg/kg)皮下注射使用生理盐水稀释的偶联物131;C组按照设计剂量(1mg/kg)皮下注射使用生理盐水稀释的偶联物132;D组按照设计剂量(1mg/kg)皮下注射使用生理盐水稀释的偶联物133;I组为空白对照组,皮下注射相同体积的生理盐水;II组为阳性对照组,按照设计剂量(1mg/kg)皮下注射使用生理盐水稀释的选择阳性对照药物Inclisiran,III组为按照设计剂量(1mg/kg)皮下注射使用生理盐水稀释的选择对比偶联物1。按照相应时间点通过眼眶采血100μl,EDTA抗凝后离心获得血浆并于-80℃冻存。待实验结束后,使用ELISA法或生化分析仪对各组小鼠血清中PCSK9的蛋白水平及血脂水平进行检测。
人源PCSK9 ELISA法检测
根据供应商提供实验方案对人源PCSK9蛋白水平进行检测(R&D)。样品充分溶解后使用PBS稀释10倍后加入已包被有捕获抗体的ELISA板中,室温孵育2小时后,清洗并加入生物素化的检测抗体及SA-HRP混合液室温孵育1小时。清洗完成后使用TMB进行显色,并使用m5e多功能酶标仪检测450nm光吸收。标准曲线以四参数拟合后用于样品人源PCSK9蛋白浓度换算。各组人源PCSK9蛋白水平在不同时间点的分析结果。检测结果如图1和图2所示。
血脂水平进行检测
动物血液样品分别于第3、7、14、21、28、35、42、和49天采集,血清样品充分溶解后加入等体积生理盐水进行稀释,并使用相应分析试剂盒进行高密度脂蛋白胆固醇(HDL-c),低密度脂蛋白胆固醇(LDL-c),总胆固醇(TC)及总甘油三酯(TG)水平检测,使用全自动生化分析仪为深圳雷杜生命科技产Chemray 800。全部检测由上海碧云天生物技术有限公司进行。
尽管参照本发明的实施例详细描述了本发明,但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。
Claims (17)
1.一种偶联物或其药学上可接受的盐或酯,所述偶联物具有式(I)的结构:
其中,
L为载体基团;
R和R*独立地选自不同或相同的天然或非天然氨基酸的侧链;
m和m′独立地选自0至3的整数,其中当m或m′为1时,结构片段 独立选自不同或相同的氨基酸残基,当m或m′为2或3时,结构片段独立选自不同或相同的寡肽残基;
n和n′独立地选自0至10的整数,且n和n′不同时为0;
A选自以下基团中的一种:
或亚甲基(CH2),
当A为亚甲基时,m和m′不同时为0;
R1为细胞受体的生物配体基团;
R2为基因组分,所述基因组分包含:
由核苷酸序列5'-csxusxaxgxaxcxCfxuxGfxuxdTxuxuxgxcxuxuxuxuxgxu-3'组成的正义链和由核苷酸序列5'-VPayxCfyxaxAfxAfxAfxgxCfxaxAfxaxAfxcxAfxgxGfxuxCfxuxaxgsxasxa-3'组成的反义链,
其中a、g、c和u分别是2'-O-甲基修饰的A、G、C和U核苷酸,Af、Gf、Cf和Uf分别是2'-氟修饰的A、G、C和U核苷酸,VPa是5'-VP-2'-O-甲基修饰的A,dT是脱氧胸腺嘧啶核苷酸,以及,任意y独立地表示s或不存在,s是硫代磷酸酯键,
任意x独立地表示其右侧相邻核苷酸的五位亚甲基上的氢为天然丰度的H或D(氘)、或其右侧相邻核苷酸的五位氧为天然丰度的O或同位素富集的18O、或其右侧相邻核苷酸的磷酸酯键或硫代磷酸酯键上的氧原子任意的选自天然丰度的O或同位素富集的18O,或其右侧相邻核苷酸的五位氧被硫取代,且所述x中的至少一个表示其右侧相邻核苷酸的五位亚甲基上的氢为D(氘)、或其右侧相邻核苷酸的五位氧为同位素富集的18O、或其右侧相邻核苷酸的磷酸酯键或硫代磷酸酯键上的氧原子为同位素富集的18O,或其右侧相邻核苷酸的五位氧被硫取代;
所述正义链通过3'端或5'端的氧原子与式(I)所示的磷原子进行连接。
2.根据权利要求1所述的偶联物,其中,所述基因组分包含:
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:2)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:4)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:6)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:8)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:10)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:12)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:14)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:16)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:18)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:20)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:22)组成的反义链;或,
由核苷酸序列5'-VPasCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:24)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:26)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:28)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:30)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:122)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:124)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:126)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:128)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:130)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasa-3'(SEQ ID NO:132)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:134)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:136)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:138)组成的反义链;或,
由核苷酸序列5'-VPasDDCfsDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQ IDNO:140)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfDDaDDAfcAfgGfuCfuagsasa-3'(SEQ ID NO:142)组成的反义链;或
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:144)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:146)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:148)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:150)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:152)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:154)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:156)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:158)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:160)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:162)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:164)组成的反义链;或,
由核苷酸序列5'-VPaCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:166)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:168)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasa-3'(SEQ ID NO:170)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:172)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:174)组成的反义链;或,
由核苷酸序列5'-VPaDDCfsaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:176)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:178)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:180)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfDDaAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:182)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasa-3'(SEQ ID NO:184)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:186)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsasDDa-3'(SEQ ID NO:188)组成的反义链;或,
由核苷酸序列5'-VPaDDCfaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:190)组成的反义链;或,
由核苷酸序列5'-VPaDDCfDDaAfAfAfgCfaAfaDDAfcAfgGfuCfuagsDDasDDa-3'(SEQ ID NO:192)组成的反义链;或,
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfDDaDDAfcAfgGfuCfuagsasa-3'(SEQ ID NO:194)组成的反义链;或
由核苷酸序列5'-VPaCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:196)组成的反义链;或
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:198)组成的反义链;或
由核苷酸序列5'-VPasCfaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:200)组成的反义链;或
由核苷酸序列5'-VPaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:202)组成的反义链;
其中,上标DD表示其右侧相邻核苷酸的五位亚甲基为二氘代的亚甲基。
3.根据权利要求1所述的偶联物,其中,所述基因组分包含:
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:32)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:34)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ ID NO:36)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ ID NO:38)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:40)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ ID NO:42)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ ID NO:44)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ ID NO:46)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ ID NO:48)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ ID NO:50)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ ID NO:52)组成的反义链;或,
由核苷酸序列5'-VPasCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ ID NO:54)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoaa-3'(SEQ ID NO:56)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasa-3'(SEQ ID NO:58)组成的反义链;或,
由核苷酸序列5'-VPasoaCfsoaaAfAfAfgCfaAfaAfcAfgGfuCfuagsoaasoaa-3'(SEQ ID NO:60)组成的反义链;
其中,上标oa表示其右侧相邻核苷酸的五位氧为18O。
4.根据权利要求1所述的偶联物,其中,所述基因组分包含:
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:62)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:64)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ ID NO:66)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ ID NO:68)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:70)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ ID NO:72)组成的反义链;或,
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ ID NO:74)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ ID NO:76)组成的反义链;或,
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ ID NO:78)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ ID NO:80)组成的反义链;或,
由核苷酸序列5'-VPasobCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ ID NO:82)组成的反义链;或,
由核苷酸序列5'-VPasCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ ID NO:84)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsasoba-3'(SEQ ID NO:86)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasa-3'(SEQ ID NO:88)组成的反义链;或,
由核苷酸序列5'-VPasobCfsobaAfAfAfgCfaAfaAfcAfgGfuCfuagsobasoba-3'(SEQ ID NO:90)组成的反义链;
其中,上标ob表示其右侧相邻核苷酸的磷酸酯键或硫代磷酸酯键上的氧原子为18O。
5.根据权利要求1所述的偶联物,其中,所述基因组分包含:
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:92)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:94)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ ID NO:96)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ ID NO:98)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3'(SEQ ID NO:100)组成的反义链;或,
由核苷酸序列5'-VPasCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ ID NO:102)组成的反义链;或,
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ ID NO:104)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ ID NO:106)组成的反义链;或,
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ ID NO:108)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ ID NO:110)组成的反义链;或,
由核苷酸序列5'-VPasosCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ ID NO:112)组成的反义链;或,
由核苷酸序列5'-VPasCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ ID NO:114)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsasosa-3'(SEQ ID NO:116)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasa-3'(SEQ ID NO:118)组成的反义链;或,
由核苷酸序列5'-VPasosCfsosaAfAfAfgCfaAfaAfcAfgGfuCfuagsosasosa-3'(SEQ ID NO:120)组成的反义链;
其中,上标os表示其右侧相邻核苷酸的五位O被硫取代。
6.根据权利要求1所述的偶联物,其中,所述天然或非天然氨基酸选自瓜氨酸、高瓜氨酸、赖氨酸、高赖氨酸、天冬酰胺、谷氨酰胺、精氨酸、甘氨酸、蛋氨酸、苯丙氨酸、合欢氨酸、缬氨酸,以及其组合。
7.根据权利要求1所述的偶联物,其中,所述载体基团L为含氮杂环,优选四元含氮杂环、五元含氮杂环或六元含氮杂环。
8.根据权利要求7所述的偶联物,其中,所述载体基团L选自:
其中,Z选自氧(O)、硫(S)、和氮(NH);
R3和R4独立选自氢(H)、羟基(-OH)、或-OR5,其中R5为羟基上的取代基团或保护基团,且R5选自脂肪烃基、芳香烃基、酰基、膦酰基。
9.根据权利要求1至8中任意一项所述的偶联物,其中,所述细胞受体为去唾液酸糖蛋白细胞受体(ASGPR)。
10.根据权利要求1至8中任意一项所述的偶联物,其中,所述生物配体基团含有亲脂体,所述亲脂体选自胆固醇基、胆酸、金刚烷乙酸、1-芘丁酸、二氢睾酮、1,3-双-O(十六烷基)甘油、香叶基氧基己基、十六烷基甘油、冰片、薄荷醇、1,3-丙二醇、十七烷基、棕榈酸、肉豆蔻酸、O-3-(油酰基)石胆酸、O-3-(油酰基)胆烯酸、二甲氧基三苄基和吩噁嗪。
11.根据权利要求1至8中任意一项所述的偶联物,其中,所述生物配体基团含有碳水化合物,所述碳水化合物选自阿洛糖、阿卓糖、阿拉伯糖、克拉定糖、赤藓糖、赤藓酮糖、果糖、D-岩藻糖醇、L-岩藻糖醇、岩藻糖胺、岩藻糖、墨角藻糖、半乳糖胺、D-半乳糖胺醇、N-乙酰基-半乳糖胺(GalNAc)、半乳糖、葡糖胺、N-乙酰基-葡糖胺、葡糖胺醇、葡萄糖、葡萄糖-6-磷酸酯、古洛糖甘油醛、L-甘油-D-甘露糖-庚糖、甘油、甘油酮、古洛糖、艾杜糖、来苏糖、甘露糖胺、甘露糖、甘露糖-6-磷酸酯、阿洛酮糖、奎诺糖、奎诺糠胺、鼠李糖醇、鼠李糖胺、鼠李糖、核糖、核酮糖、景天庚醛糖、山梨糖、塔格糖、塔罗糖、酒石酸、苏糖、木糖和木酮糖;优选地,其中所述生物配体基团为含有N-乙酰基-半乳糖胺(GalNAc)的配体基团。
12.根据权利要求1至8中任意一项所述的偶联物,其中,所述R1为以下结构中的一种:
13.根据权利要求1到12中任意一项所述的偶联物,其中,所述正义链通过3'端的氧原子与式(I)所示的磷原子进行连接。
14.根据权利要求1到13中任意一项所述的偶联物,其中,所述偶联物选自如下:
或其药学上可接受的盐和酯,上述偶联物的正义链通过3'端的氧原子与式(I)所示的磷原子进行连接。
15.一种药物组合物,其包含如权利要求1至14中任意一项所述的偶联物或者其药学上可接受的盐或酯,以及药学上可接受的载体。
16.权利要求1至14中任意一项所述的偶联物或者权利要求15所述的药物组合物在制备用于治疗或预防PCSK9相关的疾病、失调或病症的药物中的应用。
17.根据权利要求16所述的应用,其中,PCSK9相关的疾病、失调或病症包括动脉粥样硬化,高胆固醇血症,高胆固醇血症,急性冠脉综合征,血脂障碍,心肌梗塞,冠状动脉病变,中风,冠状动脉疾病,心血管疾病,糖尿病,高脂血症,二型糖尿病,及肾脏疾病。
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