CN104105499A - 芳香族阳离子肽及其用途 - Google Patents
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- CN104105499A CN104105499A CN201280066416.2A CN201280066416A CN104105499A CN 104105499 A CN104105499 A CN 104105499A CN 201280066416 A CN201280066416 A CN 201280066416A CN 104105499 A CN104105499 A CN 104105499A
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Classifications
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Abstract
本公开内容提供了涉及芳香族阳离子肽的组合物和方法。该方法包括给有此需要的受试者施用有效量的芳香族阳离子肽。例如,该肽可施用于需要线粒体靶向抗氧化剂的受试者。
Description
与相关申请的交叉参考
本专利申请要求于2011年12月9日提交的美国临时申请号61/569,120的优先权和利益,所述美国临时申请全文以引用方式并入本文。
技术领域
本技术总体涉及预防或治疗疾病的组合物和方法。特别地,该方法涉及给有此需要的受试者施用芳香族阳离子肽。
背景技术
本文公开的芳香族阳离子肽可用于涉及氧化损伤和细胞死亡的治疗应用中。当施用于有此需要的哺乳动物时,该肽定位至线粒体且改善该细胞器的完整性和功能。该肽对有此需要的受试者的施用减少经历线粒体通透性转变的线粒体数目,减少对细胞和组织的氧化损伤水平,并且增加线粒体ATP合成率。
发明内容
在一个方面,本发明提供了芳香族阳离子肽或其药学可接受的盐。在一些实施例中,该盐包含三氟乙酸盐或乙酸盐。在一些实施例中,该肽选自下述:
6-丁酸CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
6-癸酸CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
Arg-Arg-Dmt-Phe |
Arg-Cha-Lys |
Arg-Dmt |
Arg-Dmt-Arg |
Arg-Dmt-Lys |
Arg-Dmt-Lys-Phe |
Arg-Dmt-Lys-Phe-Cys |
Arg-Dmt-Phe |
Arg-Dmt-Phe-Lys |
Arg-Lys-Dmt-Phe |
Arg-Lys-Phe-Dmt |
Arg-Phe-Dmt-Lys |
Arg-Phe-Lys |
Arg-Trp-Lys |
Arg-Tyr-Lys |
Arg-Tyr-Lys-Phe |
D-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
D-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
D-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
D-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
D-Arg-Dmt-D-Lys-NH2 |
D-Arg-Dmt-D-Lys-Phe-NH2 |
D-Arg-Dmt-Lys-D-Phe-NH2 |
D-Arg-Dmt–Lys-NH2 |
D-Arg-Dmt-Lys-Phe-Cys |
D-Arg-Dmt-NH2 |
D-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
D-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
D-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
D-Arg-Phe-Lys-NH2 |
D-Arg-Trp-Lys-NH2 |
D-Arg-Tyr-Lys-NH2 |
Dmt-Arg |
Dmt-Lys |
Dmt-Lys-D-Phe-NH2 |
Dmt-Lys-NH2 |
Dmt-Lys-Phe |
Dmt-Lys-Phe |
Dmt-Lys-Phe-NH2 |
Dmt-Phe-Arg-Lys |
H-Arg-D-Dmt-Arg-NH2 |
H-Arg-D-Dmt-Lys-NH2 |
H-Arg-D-Dmt-Lys-Phe-NH2 |
H-Arg-D-Dmt-NH2 |
H-Arg-Dmt-Lys-Phe-NH2 |
H-D-Arg-2,6-二氯-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二氯酪氨酸-Lys-Phe-NH2 |
H-D-Arg-2,6-二氟-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二氟酪氨酸-Lys-Phe-NH2 |
H-D-Arg-2,6-二甲基-L-苯丙氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二甲基苯丙氨酸-Lys-Phe-NH2 |
H-D-Arg-4-甲氧基-2,6-二甲基-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-4-甲氧基-2,6-二甲基酪氨酸-Lys-Phe-NH2 |
H-D-Arg-Arg-Dmt-Phe-NH2 |
H-D-Arg-Cha-Lys-NH2 |
H-D-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
H-D-Arg-D-Dmt-Lys-Phe-NH2 |
H-D-Arg-D-Dmt-NH2 |
H-D-Arg-Dmt-D-Lys-D-Phe-NH2 |
H-D-Arg-Dmt-Lys-2,6-二甲基苯丙氨酸-NH2 |
H-D-Arg-Dmt-Lys-3-羟基苯丙氨酸-NH2 |
H-D-Arg-Dmt-Lys-NH2 |
H-D-Arg-Dmt-Lys-OH |
H-D-Arg-Dmt-Lys-Phe-OH |
H-D-Arg-Dmt-N6-乙酰基赖氨酸-Phe-NH2 |
H-D-Arg-Dmt-OH |
H-D-Arg-Dmt-Phe-Lys-NH2 |
H-D-Arg-Dmt-Phe-NH2 |
H-D-Arg-D-Phe-L-Lys-L-Phe-NH2 |
H-D-Arg-D-Trp-L-Lys-L-Phe-NH2 |
H-D-Arg-D-Tyr-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Dmt-L-Lys-2,6-二甲基-L-苯丙氨酸-NH2 |
H-D-Arg-L-Dmt-L-Lys-3-羟基-L-苯丙氨酸-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Trp-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Tyr-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Trp-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Tyr-NH2 |
H-D-Arg-L-Dmt-L-Phe-L-Lys-NH2 |
H-D-Arg-L-Dmt-N6-乙酰基-L-赖氨酸-L-Phe-NH2 |
H-D-Arg-L-Lys-L-Dmt-L-Phe-NH2 |
H-D-Arg-L-Lys-L-Phe-L-Dmt-NH2 |
H-D-Arg-L-Phe-L-Dmt-L-Lys-NH2 |
H-D-Arg-L-Phe-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Phe-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Trp-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Tyr-L-Lys-L-Phe-NH2 |
H-D-Arg-Lys-Dmt-Phe-NH2 |
H-D-Arg-Lys-Phe-Dmt-NH2 |
H-D-Arg-Phe-Dmt-Lys-NH2 |
H-D-Arg-Phe-Lys-Dmt-NH2 |
H-D-Arg-Tyr-Lys-Phe-NH2 |
H-D-Dmt-Arg-NH2 |
H-D-His-L-Dmt-L-Lys-L-Phe-NH2 |
H-D-Lys-L-Dmt-L-Lys-L-Phe-NH2 |
H-Dmt-D-Arg-Lys-Phe-NH2 |
H-Dmt-D-Arg-NH2 |
H-Dmt-D-Arg-Phe-Lys-NH2 |
H-Dmt-D-Phe-Arg-Lys-NH2 |
H-Dmt-Lys-D-Arg-Phe-NH2 |
H-Dmt-Lys-Phe-D-Arg-NH2 |
H-Dmt-Phe-D-Arg-Lys-NH2 |
H-Dmt-Phe-Lys-D-Arg-NH2 |
H-D-N2-乙酰基精氨酸-Dmt-Lys-Phe-NH2 |
H-D-N8-乙酰基精氨酸-Dmt-Lys-Phe-NH2 |
H-D-Phe-D-Arg-D-Phe-D-Lys-NH2 |
H-L-Dmt-D-Arg-L-Lys-L-Phe-NH2 |
H-L-Dmt-D-Arg-L-Phe-L-Lys-NH2 |
H-L-Dmt-L-Lys-D-Arg-L-Phe-NH2 |
H-L-Dmt-L-Lys-L-Phe-D-Arg-NH2 |
H-L-Dmt-L-Phe-D-Arg-L-Lys-NH2 |
H-L-Dmt-L-Phe-L-Lys-D-Arg-NH2 |
H-L-His-L-Dmt-L-Lys-L-Phe-NH2 |
H-L-Lys-D-Arg-L-Dmt-L-Phe-NH2 |
H-L-Lys-D-Arg-L-Phe-L-Dmt-NH2 |
H-L-Lys-L-Dmt-D-Arg-L-Phe-NH2 |
H-L-Lys-L-Dmt-L-Lys-L-Phe-NH2 |
H-L-Lys-L-Dmt-L-Phe-D-Arg-NH2 |
H-L-Lys-L-Phe-D-Arg-L-Dmt-NH2 |
H-L-Lys-L-Phe-L-Dmt-D-Arg-NH2 |
H-L-Phe-D-Arg-L-Dmt-L-Lys-NH2 |
H-L-Phe-D-Arg-L-Lys-L-Dmt-NH2 |
H-L-Phe-L-Dmt-D-Arg-L-Lys-NH2 |
H-L-Phe-L-Dmt-L-Lys-D-Arg-NH2 |
H-L-Phe-L-Lys-D-Arg-L-Dmt-NH2 |
H-L-Phe-L-Lys-L-Dmt-D-Arg-NH2 |
H-Lys-D-Arg-Dmt-Phe-NH2 |
H-Lys-D-Arg-Phe-Dmt-NH2 |
H-Lys-Dmt-D-Arg-Phe-NH2 |
H-Lys-Dmt-Phe-D-Arg-NH2 |
H-Lys-D-Phe-Arg-Dmt-NH2 |
H-Lys-Phe-D-Arg-Dmt-NH2 |
H-Lys-Phe-Dmt-D-Arg-NH2 |
H-N2-乙酰基-D-精氨酸-L-Dmt-L-Lys-L-Phe-NH2 |
H-N7-乙酰基-D-精氨酸-Dmt-Lys-Phe-NH2 |
H-Phe(d5)-D-Arg-Phe(d5)-Lys-NH2 |
H-Phe-Arg-Phe-Lys-NH2 |
H-Phe-D-Arg-Dmt-Lys-NH2 |
H-Phe-D-Arg-Dmt-Lys-NH2 |
H-Phe-D-Arg-D-Phe-Lys-NH2 |
H-Phe-D-Arg-Lys-Dmt-NH2 |
H-Phe-D-Arg-Phe-D-Lys-NH2 |
H-Phe-D-Arg-Phe-Lys-Glu-Cys-Gly-NH2 |
H-Phe-D-Dmt-Arg-Lys-NH2 |
H-Phe-Dmt-D-Arg-Lys-NH2 |
H-Phe-Dmt-Lys-D-Arg-NH2 |
H-Phe-Lys-D-Arg-Dmt-NH2 |
H-Phe-Lys-Dmt-D-Arg-NH2 |
L-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-L-Phe-NH2 |
Lys-Dmt-Arf |
Lys-Dmt-D-Arg-NH2 |
Lys-Phe |
Lys-Phe-Arg-Dmt |
Lys-Phe-NH2 |
Lys-Trp-Arg |
Lys-Trp-D-Arg-NH2 |
Phe-Arg-Dmt-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys-Glu-Cys-Gly |
Phe-Dmt-Arg-Lys |
Phe-Lys-Dmt |
Phe-Lys-Dmt-NH2 |
琥珀酸单酯CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
其中Cha是环己基丙氨酸。
在一个实施例中,该肽由式I限定:
其中R1和R2独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)其中m=1-3
(iv)
(v)
R3、R4、R5、R6、R7、R8、R9、R10、R11和R12各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)C1-C6烷氧基;
(iv)氨基;
(v)C1-C4烷基氨基;
(vi)C1-C4二烷基氨基;
(vii)硝基;
(viii)羟基;
(ix)卤素,其中“卤素”包含氯、氟、溴和碘;和
n为1-5的整数。
在特定实施例中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11和R12均为氢;并且n为4。在另一个实施例中,R1、R2、R3、R4、R5、R6、R7、R8、R9和R11均为氢;R8和R12为甲基;R10为羟基;并且n为4。
在一个实施例中,该肽由式II限定:
其中R1和R2各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)其中m=1-3;
(iv)
(v)
R3和R4各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)C1-C6烷氧基;
(iv)氨基;
(v)C1-C4烷基氨基;
(vi)C1-C4二烷基氨基;
(vii)硝基;
(viii)羟基;
(ix)卤素,其中“卤素”包含氯、氟、溴和碘;和
R5、R6、R7、R8和R9各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)C1-C6烷氧基;
(iv)氨基;
(v)C1-C4烷基氨基;
(vi)C1-C4二烷基氨基;
(vii)硝基;
(viii)羟基;
(ix)卤素,其中“卤素”包含氯、氟、溴和碘;和
n为1-5的整数。
在特定实施例中,R1和R2为氢;R3和R4为甲基;R5、R6、R7、R8和R9均为氢;并且n为4。
在一个实施例中,芳香族阳离子肽具有交替的芳香族和阳离子氨基酸的核心结构基序。例如,该肽可以是由下文所示式III-VI中的任一个限定的四肽:
芳香族的-阳离子的-芳香族的-阳离子的(式III)
阳离子的-芳香族的-阳离子的-芳香族的(式IV)
芳香族的-芳香族的-阳离子的-阳离子的(式V)
阳离子的-阳离子的-芳香族的-芳香族的(式VI)
其中,芳香族的是选自下述的残基:Phe(F)、Tyr(Y)、Trp(W)和环己基丙氨酸(Cha);并且阳离子的是选自下述的残基:Arg(R)、Lys(K)、正亮氨酸(Nle)和2-氨基-庚酸(Ahe)。
在一些实施例中,该肽由式VII限定:
在一些实施例中,该肽是式VII的同分异构体,其中式III的手性中心定义为H-(R)-Arg-(S)-DMT-(S)-Lys-(S)-Phe-NH2,并且其中立体异构体由下式描述
R-S-S-S
S-R-R-R
S-S-S-S
R-R-R-R
R-R-S-S
S-S-R-R
S-R-S-S
R-S-R-R
R-S-R-S
S-R-S-R
R-R-S-R
S-S-R-S
R-R-R-S
S-S-S-R
R-S-S-R
S-R-R-S
在一些实施例中,该肽是选自下述的式VII的组成成分同分异构体:
Arg-Dmt-Lys-Phe-NH2
Phe-Dmt-Arg-Lys-NH2
Phe-Lys-Dmt-Arg-NH2
Dmt-Arg-Lys-Phe-NH2
Lys-Dmt-Arg-Phe-NH2
Phe-Dmt-Lys-Arg-NH2
Arg-Lys-Dmt-Phe-NH2
Arg-Dmt-Phe-Lys-NH2
在一些实施例中,该肽由式VIII限定:
其中R选自
(i)OMe,和
(ii)H。
在一些实施例中,该肽由式IX限定:
其中R选自
(i)F,
(ii)Cl,和
(iii)H。
在一些实施例中,该肽由式X限定:
其中R1-R4选自
(i)Ac,(ii)H,(iii)H,(iv)H,
(i)H,(ii)Ac,(iii)H,(iv)H,
(i)H,(ii)H,(iii)Ac,(iv)H,和
(i)H,(ii)H,(iii)H,(iv)OH。
在一些实施例中,该肽由式XI限定:
在一些方面,本文提供了药物组合物。在一些实施例中,药物组合物包含一种或多种芳香族阳离子肽或其药学可接受的盐,例如乙酸盐或三氟乙酸盐。在一些实施例中,药物组合物包括一种或多种药学可接受的载体。
在一个方面,本公开内容提供了减少有此需要的哺乳动物中经历线粒体通透性转变(MPT)的线粒体数目或预防有此需要的哺乳动物中线粒体通透性转变的方法,该方法包括给哺乳动物施用有效量的本文描述的一种或多种芳香族阳离子肽,或其药学可接受的盐例如乙酸盐或三氟乙酸盐。在另一个方面,本公开内容提供了用于增加有此需要的哺乳动物中的ATP合成率的方法,该方法包括给哺乳动物施用有效量本文描述的一种或多种芳香族阳离子肽,或其药学可接受的盐例如乙酸盐或三氟乙酸盐。在另外一个方面,本公开内容提供了用于减少有此需要的哺乳动物中的氧化损伤的方法,该方法包括给哺乳动物施用有效量本文描述的一种或多种芳香族阳离子肽,或其药学可接受的盐例如乙酸盐或三氟乙酸盐。
在一些方面,提供了用于测定受试者中芳香族阳离子肽的存在或存在的芳香族阳离子肽量的方法。通常,该方法包括检测来自受试者的生物样品中的该肽。在一些实施例中,该肽在将该肽施用于受试者的过程中进行检测;在一些实施例中,该肽在将该肽施用于受试者后进行检测。在一些实施例中,检测包括HPLC例如反相HPLC或离子交换HPLC。在一些实施例中,检测包括质谱法。
在一些实施例中,生物样品包含流体;在一些实施例中,生物样品包含细胞。在一些实施例中,生物样品包含组织。在其他实施例中,生物样品包含活组织检查样本(biopsy)。
在一些实施例中,检测的芳香族阳离子肽选自下述中的一种或多种:
D-Arg-Dmt-Lys-Phe-NH2 |
Dmt-D-Arg-Phe-Lys-NH2 |
Phe-D-Arg-Dmt-Lys-NH2 |
6-丁酸CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
6-癸酸CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
Arg-Arg-Dmt-Phe |
Arg-Cha-Lys |
Arg-Dmt |
Arg-Dmt-Arg |
Arg-Dmt-Lys |
Arg-Dmt-Lys-Phe |
Arg-Dmt-Lys-Phe-Cys |
Arg-Dmt-Phe |
Arg-Dmt-Phe-Lys |
Arg-Lys-Dmt-Phe |
Arg-Lys-Phe-Dmt |
Arg-Phe-Dmt-Lys |
Arg-Phe-Lys |
Arg-Trp-Lys |
Arg-Tyr-Lys |
Arg-Tyr-Lys-Phe |
D-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
D-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
D-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
D-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
D-Arg-Dmt-D-Lys-NH2 |
D-Arg-Dmt-D-Lys-Phe-NH2 |
D-Arg-Dmt-Lys-D-Phe-NH2 |
D-Arg-Dmt–Lys-NH2 |
D-Arg-Dmt-Lys-Phe-Cys |
D-Arg-Dmt-NH2 |
D-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
D-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
D-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
D-Arg-Phe-Lys-NH2 |
D-Arg-Trp-Lys-NH2 |
D-Arg-Tyr-Lys-NH2 |
Dmt-Arg |
Dmt-Lys |
Dmt-Lys-D-Phe-NH2 |
Dmt-Lys-NH2 |
Dmt-Lys-Phe |
Dmt-Lys-Phe |
Dmt-Lys-Phe-NH2 |
Dmt-Phe-Arg-Lys |
H-Arg-D-Dmt-Arg-NH2 |
H-Arg-D-Dmt-Lys-NH2 |
H-Arg-D-Dmt-Lys-Phe-NH2 |
H-Arg-D-Dmt-NH2 |
H-Arg-Dmt-Lys-Phe-NH2 |
H-D-Arg-2,6-二氯-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二氯酪氨酸-Lys-Phe-NH2 |
H-D-Arg-2,6-二氟-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二氟酪氨酸-Lys-Phe-NH2 |
H-D-Arg-2,6-二甲基-L-苯丙氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二甲基苯丙氨酸-Lys-Phe-NH2 |
H-D-Arg-4-甲氧基-2,6-二甲基-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-4-甲氧基-2,6-二甲基酪氨酸-Lys-Phe-NH2 |
H-D-Arg-Arg-Dmt-Phe-NH2 |
H-D-Arg-Cha-Lys-NH2 |
H-D-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
H-D-Arg-D-Dmt-Lys-Phe-NH2 |
H-D-Arg-D-Dmt-NH2 |
H-D-Arg-Dmt-D-Lys-D-Phe-NH2 |
H-D-Arg-Dmt-Lys-2,6-二甲基苯丙氨酸-NH2 |
H-D-Arg-Dmt-Lys-3-羟基苯丙氨酸-NH2 |
H-D-Arg-Dmt-Lys-NH2 |
H-D-Arg-Dmt-Lys-OH |
H-D-Arg-Dmt-Lys-Phe-OH |
H-D-Arg-Dmt-N6-乙酰基赖氨酸-Phe-NH2 |
H-D-Arg-Dmt-OH |
H-D-Arg-Dmt-Phe-Lys-NH2 |
H-D-Arg-Dmt-Phe-NH2 |
H-D-Arg-D-Phe-L-Lys-L-Phe-NH2 |
H-D-Arg-D-Trp-L-Lys-L-Phe-NH2 |
H-D-Arg-D-Tyr-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Dmt-L-Lys-2,6-二甲基-L-苯丙氨酸-NH2 |
H-D-Arg-L-Dmt-L-Lys-3-羟基-L-苯丙氨酸-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Trp-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Tyr-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Trp-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Tyr-NH2 |
H-D-Arg-L-Dmt-L-Phe-L-Lys-NH2 |
H-D-Arg-L-Dmt-N6-乙酰基-L-赖氨酸-L-Phe-NH2 |
H-D-Arg-L-Lys-L-Dmt-L-Phe-NH2 |
H-D-Arg-L-Lys-L-Phe-L-Dmt-NH2 |
H-D-Arg-L-Phe-L-Dmt-L-Lys-NH2 |
H-D-Arg-L-Phe-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Phe-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Trp-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Tyr-L-Lys-L-Phe-NH2 |
H-D-Arg-Lys-Dmt-Phe-NH2 |
H-D-Arg-Lys-Phe-Dmt-NH2 |
H-D-Arg-Phe-Dmt-Lys-NH2 |
H-D-Arg-Phe-Lys-Dmt-NH2 |
H-D-Arg-Tyr-Lys-Phe-NH2 |
H-D-Dmt-Arg-NH2 |
H-D-His-L-Dmt-L-Lys-L-Phe-NH2 |
H-D-Lys-L-Dmt-L-Lys-L-Phe-NH2 |
H-Dmt-D-Arg-Lys-Phe-NH2 |
H-Dmt-D-Arg-NH2 |
H-Dmt-D-Arg-Phe-Lys-NH2 |
H-Dmt-D-Phe-Arg-Lys-NH2 |
H-Dmt-Lys-D-Arg-Phe-NH2 |
H-Dmt-Lys-Phe-D-Arg-NH2 |
H-Dmt-Phe-D-Arg-Lys-NH2 |
H-Dmt-Phe-Lys-D-Arg-NH2 |
H-D-N2-乙酰基精氨酸-Dmt-Lys-Phe-NH2 |
H-D-N8-乙酰基精氨酸-Dmt-Lys-Phe-NH2 |
H-D-Phe-D-Arg-D-Phe-D-Lys-NH2 |
H-L-Dmt-D-Arg-L-Lys-L-Phe-NH2 |
H-L-Dmt-D-Arg-L-Phe-L-Lys-NH2 |
H-L-Dmt-L-Lys-D-Arg-L-Phe-NH2 |
H-L-Dmt-L-Lys-L-Phe-D-Arg-NH2 |
H-L-Dmt-L-Phe-D-Arg-L-Lys-NH2 |
H-L-Dmt-L-Phe-L-Lys-D-Arg-NH2 |
H-L-His-L-Dmt-L-Lys-L-Phe-NH2 |
H-L-Lys-D-Arg-L-Dmt-L-Phe-NH2 |
H-L-Lys-D-Arg-L-Phe-L-Dmt-NH2 |
H-L-Lys-L-Dmt-D-Arg-L-Phe-NH2 |
H-L-Lys-L-Dmt-L-Lys-L-Phe-NH2 |
H-L-Lys-L-Dmt-L-Phe-D-Arg-NH2 |
H-L-Lys-L-Phe-D-Arg-L-Dmt-NH2 |
H-L-Lys-L-Phe-L-Dmt-D-Arg-NH2 |
H-L-Phe-D-Arg-L-Dmt-L-Lys-NH2 |
H-L-Phe-D-Arg-L-Lys-L-Dmt-NH2 |
H-L-Phe-L-Dmt-D-Arg-L-Lys-NH2 |
H-L-Phe-L-Dmt-L-Lys-D-Arg-NH2 |
H-L-Phe-L-Lys-D-Arg-L-Dmt-NH2 |
H-L-Phe-L-Lys-L-Dmt-D-Arg-NH2 |
H-Lys-D-Arg-Dmt-Phe-NH2 |
H-Lys-D-Arg-Phe-Dmt-NH2 |
H-Lys-Dmt-D-Arg-Phe-NH2 |
H-Lys-Dmt-Phe-D-Arg-NH2 |
H-Lys-D-Phe-Arg-Dmt-NH2 |
H-Lys-Phe-D-Arg-Dmt-NH2 |
H-Lys-Phe-Dmt-D-Arg-NH2 |
H-N2-乙酰基-D-精氨酸-L-Dmt-L-Lys-L-Phe-NH2 |
H-N7-乙酰基-D-精氨酸-Dmt-Lys-Phe-NH2 |
H-Phe(d5)-D-Arg-Phe(d5)-Lys-NH2 |
H-Phe-Arg-Phe-Lys-NH2 |
H-Phe-D-Arg-Dmt-Lys-NH2 |
H-Phe-D-Arg-Dmt-Lys-NH2 |
H-Phe-D-Arg-D-Phe-Lys-NH2 |
H-Phe-D-Arg-Lys-Dmt-NH2 |
H-Phe-D-Arg-Phe-D-Lys-NH2 |
H-Phe-D-Arg-Phe-Lys-Glu-Cys-Gly-NH2 |
H-Phe-D-Dmt-Arg-Lys-NH2 |
H-Phe-Dmt-D-Arg-Lys-NH2 |
H-Phe-Dmt-Lys-D-Arg-NH2 |
H-Phe-Lys-D-Arg-Dmt-NH2 |
H-Phe-Lys-Dmt-D-Arg-NH2 |
L-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-L-Phe-NH2 |
Lys-Dmt-Arf |
Lys-Dmt-D-Arg-NH2 |
Lys-Phe |
Lys-Phe-Arg-Dmt |
Lys-Phe-NH2 |
Lys-Trp-Arg |
Lys-Trp-D-Arg-NH2 |
Phe-Arg-Dmt-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys-Glu-Cys-Gly |
Phe-Dmt-Arg-Lys |
Phe-Lys-Dmt |
Phe-Lys-Dmt-NH2 |
琥珀酸单酯CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
其中Cha是环己基丙氨酸。
在一些方面,提供了用于检测芳香族阳离子肽的试剂盒。在一些实施例中,该试剂盒包括收集来自受试者的样品的生物样品收集器,和用于保存生物样品的样品贮存装置。在一些实施例中,生物样品包含流体。在一些实施例中,生物样品包含细胞。在一些实施例中,生物样品包含组织。在其他实施例中,生物样品包含活组织检查样本。
具体实施方式
应当理解本发明的某些方面、模式、实施例、变化和特点在下文以不同的详细水平描述,以便提供本发明的基本理解。
在实践本发明中,使用分子生物学、蛋白质生物化学、细胞生物学、免疫学、微生物学和重组DNA的许多常规技术。这些技术是众所周知的,并且分别在例如下述中说明:Current Protocols in Molecular Biology,第I-III卷,Ausubel,编辑(1997);Sambrook等人,Molecular Cloning:A Laboratory Manual,第二版(Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,1989);DNA Cloning:A Practical Approach,第I和II卷,Glover,编辑(1985);Oligonucleotide Synthesis,Gait,编辑(1984);Nucleic Acid Hybridization,Hames&Higgins,编辑(1985);Transcription and Translation,Hames&Higgins,编辑(1984);Animal Cell Culture,Freshney,编辑(1986);Immobilized Cells andEnzymes(IRL Press,1986);Perbal,A Practical Guide to Molecular Cloning;系列,Meth.Enzymol.,(Academic Press,Inc.,1984);Gene Transfer Vectors forMammalian Cells,Miller&Calos,编辑(Cold Spring Harbor Laboratory,NY,1987);和Meth.Enzymol.,第154和155卷,Wu&Grossman和Wu,编辑。
如本说明书中使用的某些术语的定义在下文提供。除非另有定义,本文使用的所有技术和科学术语一般具有与本发明所属领域普通技术人员通常理解相同的含义。
如本说明书和所附权利要求中使用的,除非内容另有明确说明,单数形式“一个”、“一种”和“该/所述”包括复数指代物。例如,提及“一个(种)细胞”包括两个(种)或更多个(种)细胞的组合等等。
如本文使用的,试剂、药物或肽对受试者的“施用”包括将化合物引入或递送至受试者以执行其预期功能的任何途径。施用可通过任何合适途径执行,包括经口、鼻内、肠胃外(静脉内、肌内、腹膜内或皮下)或局部。施用包括自施用和通过另一者的施用。
如本文使用的,术语“氨基酸”包括天然存在的氨基酸和合成氨基酸,以及氨基酸类似物和氨基酸模拟物,其以类似于天然存在的氨基酸的方式起作用。天然存在的氨基酸是由遗传密码编码的氨基酸,以及以后修饰的氨基酸,例如羟脯氨酸、γ-羧基谷氨酸盐和O-磷酸丝氨酸。氨基酸类似物指这样的化合物,其具有与天然存在的氨基酸相同的基本化学结构,即与氢、羧基、氨基和R基结合的α-碳,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。此类类似物具有经修饰的R基(例如正亮氨酸)或经修饰的肽主链,但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物指这样的化学化合物,其具有不同于氨基酸的一般化学结构的结构,但以类似于天然存在的氨基酸的方式起作用。氨基酸在本文中可由其通常已知的三字母符号或由IUPAC-IUB生物化学命名委员会推荐的单字母符号提及。
如本文使用的,术语“生物样品”指源自活细胞或由活细胞接触的材料。该术语包含从受试者中分离的组织、细胞和生物流体,以及存在于受试者内的组织、细胞和流体。生物样品包括但不限于全血、分馏血液、***、唾液、泪、尿、粪便材料、汗、颊、皮肤、脑脊髓液和毛发。生物样品还包括内脏和癌症的活组织检查样本。生物样品可得自受试者用于诊断或研究,或可得自未患病的个体,作为对照或用于基础研究。
如本文使用的,术语“有效量”指足以实现所需治疗和/或预防效应的数量。在治疗或预防应用的背景下,施用于受试者的组合物量将取决于疾病的类型和严重性,以及个体的特征,例如一般健康、年龄、性别、体重和对药物的耐受。它还将取决于疾病的程度、严重性和类型。取决于这些及其他因素,技术人员将能够测定适当剂量。组合物还可与一种或多种另外的治疗化合物组合施用。
“分离的”或“纯化的”多肽或肽基本上不含来自试剂源自其的细胞或组织来源的细胞材料或其他污染多肽,或当化学合成时,基本上不含化学前体或其他化学品。例如,分离的芳香族阳离子肽将不含干扰试剂的诊断或治疗用途的材料。此类干扰材料可包括酶、激素及其他蛋白质性和非蛋白质性溶质。
如本文使用的,术语“多肽”、“肽”和“蛋白质”在本文中可互换使用,以意指包含通过肽键或经修饰的肽键彼此连接的两个或更多个氨基酸的聚合物,即肽等排物。多肽指通常被称为肽、糖肽或寡聚物的短链,和一般被称为蛋白质的更长链两者。多肽可含有20种基因编码的氨基酸以外的氨基酸。多肽包括通过天然过程例如翻译后加工、或通过本领域众所周知的化学修饰技术进行修饰的氨基酸序列。
如本文使用的,术语“处理”或“治疗”或“减轻”指治疗性处理和预防或防止措施两者,其中目的是预防或减慢(减轻)靶向病理学病症或障碍。还应当理解如所述的医学病症的多种治疗或预防模式意指“基本的”,其包括完全治疗或预防以及少于完全治疗或预防,并且其中达到一些生物学或医学相关结果。
如本文使用的,障碍或病症的“预防”或“防止”指这样的化合物,相对于未经处理的对照样品,其在统计样品中减少经处理的样品中的障碍或病症的出现,或者相对于未经处理的对照样品,延迟障碍或病症的一种或多种症状的发作或降低障碍或病症的一种或多种症状的严重性。
预防或治疗方法
本技术涉及通过施用某些芳香族阳离子肽的疾病治疗或预防。
芳香族阳离子肽是水溶性和高度极性的。尽管有这些特性,该肽仍可容易地穿透细胞膜。芳香族阳离子肽通常包括由肽键共价连接的最少两个或三个氨基酸或最少四个氨基酸。芳香族阳离子肽中存在的氨基酸的最大数目是由肽键共价连接的约二十个氨基酸。适当地,氨基酸的最大数目是约十二、更优选约九且最优选约六。
芳香族阳离子肽的氨基酸可以是任意氨基酸。如本文使用的,术语“氨基酸”用于指含有至少一个氨基和至少一个羧基的任何有机分子。通常,至少一个氨基在相对于羧基的α位置处。氨基酸可以是天然存在的。天然存在的氨基酸包括例如在哺乳动物蛋白质中通常发现的二十种最常见的左旋(L)氨基酸,即丙氨酸(Ala)、精氨酸(Arg)、天冬酰胺(Asn)、天冬氨酸(Asp)、半胱氨酸(Cys)、谷氨酰胺(Gln)、谷氨酸(Glu)、甘氨酸(Gly)、组氨酸(His)、异亮氨酸(Ile)、亮氨酸(Leu)、赖氨酸(Lys)、甲硫氨酸(Met)、苯丙氨酸(Phe)、脯氨酸(Pro)、丝氨酸(Ser)、苏氨酸(Thr)、色氨酸(Trp)、酪氨酸(Tyr)和缬氨酸(Val)。其他天然存在的氨基酸包括例如在与蛋白质合成不相关的代谢过程中合成的氨基酸。例如,氨基酸鸟氨酸和瓜氨酸在尿素生产过程中的哺乳动物代谢中合成。天然存在的氨基酸的另一个例子包括羟脯氨酸(Hyp)。
该肽任选含有一种或多种非天然存在的氨基酸。最佳地,该肽不具有天然存在的氨基酸。天然存在的氨基酸可以是左旋的(L-)、右旋的(D-)或其混合物。非天然存在的氨基酸是这样的氨基酸,其通常在活生物体中的正常代谢过程中未合成,并且在蛋白质中未天然存在。另外,天然存在的氨基酸适当地也不由常见蛋白酶识别。天然存在的氨基酸可存在于肽中的任何位置处。例如,非天然存在的氨基酸可在N末端、C末端或N末端和C末端之间的任何位置处。
非天然氨基酸可例如包含在天然氨基酸中未发现的烷基、芳基或烷基芳基。非天然烷基氨基酸的一些例子包括α-氨基丁酸、β-氨基丁酸、γ-氨基丁酸、δ-氨基戊酸和ε-氨基己酸。非天然芳基氨基酸的一些例子包括邻、间和对氨基苯甲酸。非天然烷基芳基氨基酸的一些例子包括邻、间和对氨基苯乙酸和γ-苯基-β-氨基丁酸。非天然存在的氨基酸包括天然存在的氨基酸的衍生物。天然存在的氨基酸的衍生物可例如包括一个或多个化学基团对天然存在的氨基酸的添加。
例如,一个或多个化学基团可加入苯丙氨酸或酪氨酸残基的芳环的2′、3′、4′、5′或6′位置或者色氨酸残基的苯并环的4′、5′、6′或7′位置中的一个或多个。基团可以是可加入芳环的任何化学基团。此类基团的一些例子包括分支或未分支的C1-C4烷基,例如甲基、乙基、正丙基、异丙基、丁基、异丁基或叔丁基、C1-C4烷基氧基(即烷氧基)、氨基、C1-C4烷基氨基和C1-C4二烷基氨基(例如甲基氨基、二甲氨基)、硝基、羟基、卤素(即氟、氯、溴或碘)。天然存在的氨基酸的非天然存在的衍生物的一些具体例子包括正缬氨酸(Nva)和正亮氨酸(Nle)。
肽中的氨基酸修饰的另一个例子是肽的天冬氨酸或谷氨酸残基的羧基的衍生化。一个衍生化例子是由氨或者由伯胺或仲胺酰胺化,所述伯胺或仲胺例如甲胺、乙胺、二甲胺或二乙胺。另一个衍生化例子包括由例如甲醇或乙醇酯化。另一种此类修饰包括赖氨酸、精氨酸或组氨酸残基的氨基的衍生化。例如,此类氨基可以是酰化的。一些合适的酰基包括例如苯甲酰基或包含上文提及的C1-C4烷基中的任一个的烷酰基例如乙酰基或丙酰基。
非天然存在的氨基酸优选对常见蛋白酶是抗性,并且更优选对常见蛋白酶是不敏感的。对蛋白酶抗性或不敏感的非天然存在的氨基酸的例子包括右旋(D-)形式的上述天然存在的L-氨基酸中的任一个,以及L-和/或D-非天然存在的氨基酸。D-氨基酸通常不存在于蛋白质中,尽管它们在某些肽抗生素中发现,所述肽抗生素由细胞的正常核糖体蛋白合成机制以外的方法合成。如本文使用的,D-氨基酸视为非天然存在的氨基酸。
为了使蛋白酶敏感性降到最低,该肽应具有由常见蛋白酶识别的小于五个、优选小于四个、更优选小于三个且最优选小于两个邻接L-氨基酸,与氨基酸是天然存在的还是非天然存在的无关。最佳地,该肽仅具有D-氨基酸,且不具有L-氨基酸。如果该肽含有蛋白酶敏感的氨基酸序列,则氨基酸中的至少一个优选是非天然存在的D-氨基酸,由此赋予蛋白酶抗性。蛋白酶敏感序列的例子包括由常见蛋白酶例如内肽酶和胰蛋白酶容易切割的两个或更多个邻接的碱性氨基酸。碱性氨基酸的例子包括精氨酸、赖氨酸和组氨酸。
与肽中的氨基酸残基总数目相比较,芳香族阳离子肽应在生理pH下具有最小数目的净正电荷。在生理pH下的净正电荷的最小数目在下文将被称为(pm)。肽中的氨基酸残基总数目在下文将被称为(r)。下文讨论的净正电荷的最小数目均在生理pH下。如本文使用的术语“生理pH”指在哺乳动物机体的组织和器官的细胞中的正常pH。例如,人的生理pH通常为大约7.4,但哺乳动物中的正常生理pH可以是约7.0-约7.8的任何pH。
如本文使用的“净电荷”指由肽中存在的氨基酸携带的正电荷数目和负电荷数目的平衡。在本说明书中,应当理解净电荷在生理pH下测量。在生理pH下带正电的天然存在的氨基酸包括L-赖氨酸、L-精氨酸和L-组氨酸。在生理pH下带负电的天然存在的氨基酸包括L-天冬氨酸和L-谷氨酸。
通常,肽具有带正电的N末端氨基和带负电的C末端羧基。电荷在生理pH下彼此抵消。作为计算净电荷的例子,肽Tyr-Arg-Phe-Lys-Glu-His-Trp-D-Arg具有一个带负电的氨基酸(即Glu)和四个带正电的氨基酸(即两个Arg残基、一个Lys和一个His)。因此,上述肽具有净正电荷三。
在一个实施例中,该肽由式I限定:
其中R1和R2独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)w其he中remm==1-31;-3;
(iv)
(v)
R3、R4、R5、R6、R7、R8、R9、R10、R11和R12各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)C1-C6烷氧基;
(iv)氨基;
(v)C1-C4烷基氨基;
(vi)C1-C4二烷基氨基;
(vii)硝基;
(viii)羟基;
(ix)卤素,其中“卤素”包含氯、氟、溴和碘;和
n为1-5的整数。
在特定实施例中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11和R12均为氢;并且n为4。在另一个实施例中,R1、R2、R3、R4、R5、R6、R7、R8、R9和R11均为氢;R8和R12为甲基;R10为羟基;并且n为4。
在一个实施例中,该肽由式II限定:
其中R1和R2各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)其中m=1-3;
(iv)
(v)
R3和R4各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)C1-C6烷氧基;
(iv)氨基;
(v)C1-C4烷基氨基;
(vi)C1-C4二烷基氨基;
(vii)硝基;
(viii)羟基;
(ix)卤素,其中“卤素”包含氯、氟、溴和碘;和
R5、R6、R7、R8和R9各自独立地选自
(i)氢;
(ii)线性或分支C1-C6烷基;
(iii)C1-C6烷氧基;
(iv)氨基;
(v)C1-C4烷基氨基;
(vi)C1-C4二烷基氨基;
(vii)硝基;
(viii)羟基;
(ix)卤素,其中“卤素”包含氯、氟、溴和碘;和
n为1-5的整数。
在特定实施例中,R1和R2为氢;R3和R4为甲基;R5、R6、R7、R8和R9均为氢;并且n为4。
在一个实施例中,芳香族阳离子肽具有交替的芳香族和阳离子氨基酸的核心结构基序。例如,该肽可以是由下文所示式III-VI中的任一个限定的四肽:
芳香族的-阳离子的-芳香族的-阳离子的(式III)
阳离子的-芳香族的-阳离子的-芳香族的(式IV)
芳香族的-芳香族的-阳离子的-阳离子的(式V)
阳离子的-阳离子的-芳香族的-芳香族的(式VI)
其中,芳香族的是选自下述的残基:Phe(F)、Tyr(Y)、Trp(W)和环己基丙氨酸(Cha);并且阳离子的是选自下述的残基:Arg(R)、Lys(K)、正亮氨酸(Nle)和2-氨基-庚酸(Ahe)。
在一个方面,本公开内容提供了减少有此需要的哺乳动物中经历线粒体通透性转变(MPT)的线粒体数目或预防有此需要的哺乳动物中线粒体通透性转变的方法,该方法包括给哺乳动物施用有效量的本文描述的一种或多种芳香族阳离子肽。在另一个方面,本公开内容提供了用于增加有此需要的哺乳动物中的ATP合成率的方法,该方法包括给哺乳动物施用有效量本文描述的一种或多种芳香族阳离子肽。在另外一个方面,本公开内容提供了用于减少有此需要的哺乳动物中的氧化损伤的方法,该方法包括给哺乳动物施用有效量本文描述的一种或多种芳香族阳离子肽。
在一个实施例中,芳香族阳离子肽具有的在生理pH下的净正电荷的最小数目(pm)和氨基酸残基的总数目(r)之间的关系为:其中3pm是小于或等于r+1的最大数。在该实施例中,净正电荷的最小数目(pm)和氨基酸残基总数目(r)之间的关系如下:
表1.氨基酸数目和净正电荷(3pm≤p+1)
(r) | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(pm) | 1 | 1 | 2 | 2 | 2 | 3 | 3 | 3 | 4 | 4 | 4 | 5 | 5 | 5 | 6 | 6 | 6 | 7 |
在另一个实施例中,芳香族阳离子肽具有的在净正电荷的最小数目(pm)和氨基酸残基的总数目(r)之间的关系为:其中2pm是小于或等于r+1的最大数。在该实施例中,净正电荷的最小数目(pm)和氨基酸残基总数目(r)之间的关系如下:
表2.氨基酸数目和净正电荷(2pm≤p+1)
(r) | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(pm) | 2 | 2 | 3 | 3 | 4 | 4 | 5 | 5 | 6 | 6 | 7 | 7 | 8 | 8 | 9 | 9 | 10 | 10 |
在一个实施例中,净正电荷的最小数目(pm)和氨基酸残基的总数目(r)相等。在另一个实施例中,该肽具有三个或四个氨基酸残基和最少一个净正电荷、适当地最少二个净正电荷和更优选地最少三个净正电荷。
还重要的是,芳香族阳离子肽具有与净正电荷的总数目(pt)相比较最小数目的芳香族基团。芳香族基团的最小数目在下文将被称为(a)。具有芳香族基团的天然存在的氨基酸包括氨基酸组氨酸、色氨酸、酪氨酸和苯丙氨酸。例如,六肽Lys-Gln-Tyr-D-Arg-Phe-Trp具有净正电荷二(由赖氨酸残基和精氨酸残基贡献)以及三个芳香族基团(由酪氨酸、苯丙氨酸和色氨酸残基贡献)。
芳香族阳离子肽还应具有的在芳香族基团的最小数目(a)和在生理pH下的净正电荷的总数目(pt)之间的关系为:其中3a是小于或等于pt+1的最大数,除了当pt是1时,a也可以是1之外。在该实施例中,芳香族基团的最小数目(a)和净正电荷的总数目(pt)之间的关系如下:
表3.芳香族基团和净正电荷(3a≤pt+1或a=pt=1)
(pt) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(a) | 1 | 1 | 1 | 1 | 2 | 2 | 2 | 3 | 3 | 3 | 4 | 4 | 4 | 5 | 5 | 5 | 6 | 6 | 6 | 7 |
在另一个实施例中,芳香族阳离子肽具有的在芳香族基团的最小数目(a)和净正电荷的总数目(pt)之间的关系为:其中2a是小于或等于pt+1的最大数。在该实施例中,芳香族氨基酸残基的最小数目(a)和净正电荷的总数目(pt)之间的关系如下:
表4.芳香族基团和净正电荷(2a≤pt+1或a=pt=1)
(pt) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 |
(a) | 1 | 1 | 2 | 2 | 3 | 3 | 4 | 4 | 5 | 5 | 6 | 6 | 7 | 7 | 8 | 8 | 9 | 9 | 10 | 10 |
在另一个实施例中,芳香族基团的数目(a)和净正电荷的总数目(pt)相等。在一个实施例中,芳香族阳离子肽可具有
(a)至少一个净正电荷;
(b)最少三个氨基酸;
(c)最多约二十个氨基酸;
(d)净正电荷的最小数目(pm)和氨基酸残基的总数目(r)之间的关系为:其中3pm是小于或等于r+1的最大数;和
(e)芳香族基团的最小数目(a)和净正电荷的总数目(pt)之间的关系为:其中3a是小于或等于pt+1的最大数,除了当a是1时,pt也可以是1之外。
羧基且尤其是C末端氨基酸的末端羧基适当地由例如氨酰胺化,以形成C末端酰胺。作为另外一种选择,C末端氨基酸的末端羧基可由任一伯胺或仲胺酰胺化。所述伯胺或仲胺可以例如是烷基胺,尤其是分支的或无分支的C1-C4烷基胺或者芳基胺。相应地,在肽的C末端处的氨基酸可转化为酰胺基、N-甲基酰胺基、N-乙基酰胺基、N,N-二甲基酰胺基、N,N-二乙基酰胺基、N-甲基-N-乙基酰胺基、N-苯基酰胺基或N-苯基-N-乙基酰胺基。未存在于芳香族阳离子肽的C末端处的天冬酰胺、谷氨酰胺、天冬氨酸和谷氨酸残基的游离羧酸基也可被酰胺化,不论它们是否存在于肽内。在这些内部位置处的酰胺化可以是由氨或者上述伯胺或仲胺中的任一个进行。
芳香族阳离子肽包括但不限于下述示例性肽:
6-丁酸CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
6-癸酸CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
Arg-Arg-Dmt-Phe |
Arg-Cha-Lys |
Arg-Dmt |
Arg-Dmt-Arg |
Arg-Dmt-Lys |
Arg-Dmt-Lys-Phe |
Arg-Dmt-Lys-Phe-Cys |
Arg-Dmt-Phe |
Arg-Dmt-Phe-Lys |
Arg-Lys-Dmt-Phe |
Arg-Lys-Phe-Dmt |
Arg-Phe-Dmt-Lys |
Arg-Phe-Lys |
Arg-Trp-Lys |
Arg-Tyr-Lys |
Arg-Tyr-Lys-Phe |
D-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
D-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
D-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
D-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
D-Arg-Dmt-D-Lys-NH2 |
D-Arg-Dmt-D-Lys-Phe-NH2 |
D-Arg-Dmt-Lys-D-Phe-NH2 |
D-Arg-Dmt–Lys-NH2 |
D-Arg-Dmt-Lys-Phe-Cys |
D-Arg-Dmt-NH2 |
D-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
D-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
D-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
D-Arg-Phe-Lys-NH2 |
D-Arg-Trp-Lys-NH2 |
D-Arg-Tyr-Lys-NH2 |
Dmt-Arg |
Dmt-Lys |
Dmt-Lys-D-Phe-NH2 |
Dmt-Lys-NH2 |
Dmt-Lys-Phe |
Dmt-Lys-Phe |
Dmt-Lys-Phe-NH2 |
Dmt-Phe-Arg-Lys |
H-Arg-D-Dmt-Arg-NH2 |
H-Arg-D-Dmt-Lys-NH2 |
H-Arg-D-Dmt-Lys-Phe-NH2 |
H-Arg-D-Dmt-NH2 |
H-Arg-Dmt-Lys-Phe-NH2 |
H-D-Arg-2,6-二氯-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二氯酪氨酸-Lys-Phe-NH2 |
H-D-Arg-2,6-二氟-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二氟酪氨酸-Lys-Phe-NH2 |
H-D-Arg-2,6-二甲基-L-苯丙氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-2,6-二甲基苯丙氨酸-Lys-Phe-NH2 |
H-D-Arg-4-甲氧基-2,6-二甲基-L-酪氨酸-L-Lys-L-Phe-NH2 |
H-D-Arg-4-甲氧基-2,6-二甲基酪氨酸-Lys-Phe-NH2 |
H-D-Arg-Arg-Dmt-Phe-NH2 |
H-D-Arg-Cha-Lys-NH2 |
H-D-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
H-D-Arg-D-Dmt-Lys-Phe-NH2 |
H-D-Arg-D-Dmt-NH2 |
H-D-Arg-Dmt-D-Lys-D-Phe-NH2 |
H-D-Arg-Dmt-Lys-2,6-二甲基苯丙氨酸-NH2 |
H-D-Arg-Dmt-Lys-3-羟基苯丙氨酸-NH2 |
H-D-Arg-Dmt-Lys-NH2 |
H-D-Arg-Dmt-Lys-OH |
H-D-Arg-Dmt-Lys-Phe-OH |
H-D-Arg-Dmt-N6-乙酰基赖氨酸-Phe-NH2 |
H-D-Arg-Dmt-OH |
H-D-Arg-Dmt-Phe-Lys-NH2 |
H-D-Arg-Dmt-Phe-NH2 |
H-D-Arg-D-Phe-L-Lys-L-Phe-NH2 |
H-D-Arg-D-Trp-L-Lys-L-Phe-NH2 |
H-D-Arg-D-Tyr-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Dmt-L-Lys-2,6-二甲基-L-苯丙氨酸-NH2 |
H-D-Arg-L-Dmt-L-Lys-3-羟基-L-苯丙氨酸-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Trp-NH2 |
H-D-Arg-L-Dmt-L-Lys-D-Tyr-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Trp-NH2 |
H-D-Arg-L-Dmt-L-Lys-L-Tyr-NH2 |
H-D-Arg-L-Dmt-L-Phe-L-Lys-NH2 |
H-D-Arg-L-Dmt-N6-乙酰基-L-赖氨酸-L-Phe-NH2 |
H-D-Arg-L-Lys-L-Dmt-L-Phe-NH2 |
H-D-Arg-L-Lys-L-Phe-L-Dmt-NH2 |
H-D-Arg-L-Phe-L-Dmt-L-Lys-NH2 |
H-D-Arg-L-Phe-L-Lys-L-Dmt-NH2 |
H-D-Arg-L-Phe-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Trp-L-Lys-L-Phe-NH2 |
H-D-Arg-L-Tyr-L-Lys-L-Phe-NH2 |
H-D-Arg-Lys-Dmt-Phe-NH2 |
H-D-Arg-Lys-Phe-Dmt-NH2 |
H-D-Arg-Phe-Dmt-Lys-NH2 |
H-D-Arg-Phe-Lys-Dmt-NH2 |
H-D-Arg-Tyr-Lys-Phe-NH2 |
H-D-Dmt-Arg-NH2 |
H-D-His-L-Dmt-L-Lys-L-Phe-NH2 |
H-D-Lys-L-Dmt-L-Lys-L-Phe-NH2 |
H-Dmt-D-Arg-Lys-Phe-NH2 |
H-Dmt-D-Arg-NH2 |
H-Dmt-D-Arg-Phe-Lys-NH2 |
H-Dmt-D-Phe-Arg-Lys-NH2 |
H-Dmt-Lys-D-Arg-Phe-NH2 |
H-Dmt-Lys-Phe-D-Arg-NH2 |
H-Dmt-Phe-D-Arg-Lys-NH2 |
H-Dmt-Phe-Lys-D-Arg-NH2 |
H-D-N2-乙酰基精氨酸-Dmt-Lys-Phe-NH2 |
H-D-N8-乙酰基精氨酸-Dmt-Lys-Phe-NH2 |
H-D-Phe-D-Arg-D-Phe-D-Lys-NH2 |
H-L-Dmt-D-Arg-L-Lys-L-Phe-NH2 |
H-L-Dmt-D-Arg-L-Phe-L-Lys-NH2 |
H-L-Dmt-L-Lys-D-Arg-L-Phe-NH2 |
H-L-Dmt-L-Lys-L-Phe-D-Arg-NH2 |
H-L-Dmt-L-Phe-D-Arg-L-Lys-NH2 |
H-L-Dmt-L-Phe-L-Lys-D-Arg-NH2 |
H-L-His-L-Dmt-L-Lys-L-Phe-NH2 |
H-L-Lys-D-Arg-L-Dmt-L-Phe-NH2 |
H-L-Lys-D-Arg-L-Phe-L-Dmt-NH2 |
H-L-Lys-L-Dmt-D-Arg-L-Phe-NH2 |
H-L-Lys-L-Dmt-L-Lys-L-Phe-NH2 |
H-L-Lys-L-Dmt-L-Phe-D-Arg-NH2 |
H-L-Lys-L-Phe-D-Arg-L-Dmt-NH2 |
H-L-Lys-L-Phe-L-Dmt-D-Arg-NH2 |
H-L-Phe-D-Arg-L-Dmt-L-Lys-NH2 |
H-L-Phe-D-Arg-L-Lys-L-Dmt-NH2 |
H-L-Phe-L-Dmt-D-Arg-L-Lys-NH2 |
H-L-Phe-L-Dmt-L-Lys-D-Arg-NH2 |
H-L-Phe-L-Lys-D-Arg-L-Dmt-NH2 |
H-L-Phe-L-Lys-L-Dmt-D-Arg-NH2 |
H-Lys-D-Arg-Dmt-Phe-NH2 |
H-Lys-D-Arg-Phe-Dmt-NH2 |
H-Lys-Dmt-D-Arg-Phe-NH2 |
H-Lys-Dmt-Phe-D-Arg-NH2 |
H-Lys-D-Phe-Arg-Dmt-NH2 |
H-Lys-Phe-D-Arg-Dmt-NH2 |
H-Lys-Phe-Dmt-D-Arg-NH2 |
H-N2-乙酰基-D-精氨酸-L-Dmt-L-Lys-L-Phe-NH2 |
H-N7-乙酰基-D-精氨酸-Dmt-Lys-Phe-NH2 |
H-Phe(d5)-D-Arg-Phe(d5)-Lys-NH2 |
H-Phe-Arg-Phe-Lys-NH2 |
H-Phe-D-Arg-Dmt-Lys-NH2 |
H-Phe-D-Arg-Dmt-Lys-NH2 |
H-Phe-D-Arg-D-Phe-Lys-NH2 |
H-Phe-D-Arg-Lys-Dmt-NH2 |
H-Phe-D-Arg-Phe-D-Lys-NH2 |
H-Phe-D-Arg-Phe-Lys-Glu-Cys-Gly-NH2 |
H-Phe-D-Dmt-Arg-Lys-NH2 |
H-Phe-Dmt-D-Arg-Lys-NH2 |
H-Phe-Dmt-Lys-D-Arg-NH2 |
H-Phe-Lys-D-Arg-Dmt-NH2 |
H-Phe-Lys-Dmt-D-Arg-NH2 |
L-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-D-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-D-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-D-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-L-Phe-NH2 |
L-Arg-L-Dmt-L-Lys-L-Phe-NH2 |
Lys-Dmt-Arf |
Lys-Dmt-D-Arg-NH2 |
Lys-Phe |
Lys-Phe-Arg-Dmt |
Lys-Phe-NH2 |
Lys-Trp-Arg |
Lys-Trp-D-Arg-NH2 |
Phe-Arg-Dmt-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys |
Phe-Arg-Phe-Lys-Glu-Cys-Gly |
Phe-Dmt-Arg-Lys |
Phe-Lys-Dmt |
Phe-Lys-Dmt-NH2 |
琥珀酸单酯CoQ0-Phe-D-Arg-Phe-Lys-NH2 |
其中Cha是环己基丙氨酸。
在一个实施方式中,该肽具有μ型阿片样(mu-opioid)受体激动剂活性(即,它们活化μ型阿片样受体)。通过与克隆的μ型阿片样受体的放射性配体结合或通过利用豚鼠回肠的生物测定可评估μ型阿片样的活性(Schiller等人,Eur J Med Chem,35:895-901,2000;Zhao等人,J Pharmacol Exp Ther,307:947-954,2003)。μ型阿片样受体的活化通常引发镇痛作用。在某些情况下,具有μ型阿片样受体激动剂活性的芳香族阳离子肽是优选的。例如,在短期治疗过程中,例如在急性病或病症中,使用活化μ型阿片样受体的芳香族阳离子肽可以是有利的。此类急性病和病症通常与中等疼痛或严重疼痛有关。在这些情况下,芳香族阳离子肽的镇痛作用在人患者或其他哺乳动物的治疗方案中可以是有利的。然而,不活化μ型阿片样受体的芳香族阳离子肽也可根据临床需要连同或不连同镇痛药一起使用。具有μ型阿片样受体激动剂活性的肽通常是在N末端(即,第一氨基酸位置)处具有酪氨酸残基或酪氨酸衍生物的那些肽。
作为另外一种选择,在其他情况下,不具有μ型阿片样受体激动剂活性的芳香族阳离子肽是优选的。例如,在长期治疗过程中,例如在慢性疾病状态或病症中,活化μ型阿片样受体的芳香族阳离子肽的使用可能是禁忌的。在这些情况下,芳香族阳离子肽的潜在副作用或上瘾作用可排除活化μ型阿片样受体的芳香族阳离子肽在人患者或其他哺乳动物的治疗方案中的使用。潜在的副作用可包括镇静、便秘和呼吸抑制。在此类情况下,不活化μ型阿片样受体的芳香族阳离子肽可以是适当的治疗。不具有μ阿片样受体激动剂活性的肽通常在N末端(即氨基酸位置1)处不具有酪氨酸残基或酪氨酸衍生物。在N末端处的氨基酸可以是与酪氨酸不同的任何天然存在的氨基酸或非天然存在的氨基酸。在一个实施例中,在N末端处的氨基酸是苯丙氨酸或其衍生物。苯丙氨酸的示例性衍生物包括2′-甲基苯丙氨酸(Mmp)、2′,6′-二甲基苯丙氨酸(2′,6′-Dmp)、N,2′,6′-三甲基苯丙氨酸(Tmp)和2′-羟基-6′-甲基苯丙氨酸(Hmp)。
本文提及的肽及其衍生物还可包括功能变体。如果变体具有与所述肽相同的功能,则肽视为功能变体。类似物例如可以是肽的置换变体,其中一个或多个氨基酸由另一个氨基酸置换。适当的肽置换变体包括保守氨基酸置换。氨基酸可根据其物理化学特征如下分组:
(a)非极性氨基酸:Ala(A)Ser(S)Thr(T)Pro(P)Gly(G)Cys(C);
(b)酸性氨基酸:Asn(N)Asp(D)Glu(E)Gln(Q);
(c)碱性氨基酸:His(H)Arg(R)Lys(K);
(d)疏水氨基酸:Met(M)Leu(L)Ile(I)Val(V);和
(e)芳香族氨基酸:Phe(F)Tyr(Y)Trp(W)His(H)。
肽中的氨基酸由相同组的另一种氨基酸的置换被称为保守置换,并且可保存初始肽的物理化学特征。相比之下,肽中的氨基酸由不同组的另一种氨基酸的置换一般更可能改变初始肽的特征。
在一些实施例中,本文公开的肽源自前体,例如肽前体。例如,在一些实施例中,前体包含其也是治疗试剂或药物的芳香族阳离子肽。
芳香族阳离子肽的合成
可通过本领域众所周知的方法的任一种来合成本文公开的芳香族阳离子肽。用于化学方式合成蛋白质的合适方法包括例如液相和固相合成,以及由Stuart和Young在Solid Phase Peptide Synthesis,第二版,PierceChemical Company(1984)和在Methods Enzymol.,289,Academic Press,Inc,New York(1997)中描述的那些方法。可使用分子生物学、蛋白质生物化学、细胞生物学和微生物学中的常规技术生成重组肽,所述技术例如下述中分别所述的那些:Current Protocols in Molecular Biology,第I-III卷,Ausubel,编辑(1997);Sambrook等人,Molecular Cloning:A Laboratory Manual,第二版(Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,1989);DNACloning:A Practical Approach,第I和II卷,Glover,编辑(1985);Oligonucleotide Synthesis,Gait,编辑(1984);Nucleic Acid Hybridization,Hames&Higgins,编辑(1985);Transcription and Translation,Hames&Higgins,编辑(1984);Animal Cell Culture,Freshney,编辑(1986);Immobilized Cells andEnzymes(IRL Press,1986);Perbal,A Practical Guide to Molecular Cloning;系列,Meth.Enzymol.,(Academic Press,Inc.,1984);Gene Transfer Vectors forMammalian Cells,Miller&Calos,编辑(Cold Spring Harbor Laboratory,NY,1987);和Meth.Enzymol.,第154和155卷,Wu&Grossman和Wu,编辑。
芳香族阳离子肽的检测和表征
本文描述的芳香族阳离子肽可使用本领域已知的方法进行检测和/或表征。样品中的肽可例如使用高效液相色谱法(HPLC)方法进行检测,所述HPLC方法例如Aguilar,HPLC of Peptides and Proteins:Methods andProtocols,Humana Press,New Jersey(2004)中所述的那些。肽可例如使用反相HPLC(RP-HPLC)或离子交换HPLC进行检测。高效液相色谱法(或高压液相色谱法,HPLC)是这样的色谱技术,其可分离化合物的混合物,并且用于生物化学和分析化学中,以鉴定、定量且纯化混合物的各个组分。HPLC通常利用不同类型的静止相,移动一种或多种流动相和分析物通过柱的泵,和提供分析物的特征性保留时间的检测器。该检测器还可提供关于分析物的另外的信息(例如如果如此配备,则分析物的紫外/可见光谱数据)。分析物保留时间取决于其与静止相的相互作用强度、使用的一种或多种溶剂的比/组成和流动相的流速而改变。通常,对于HPLC,泵(而不是重力)提供移动流动相和分析物通过相对致密填充的柱所需的更高压。增加的密度起于较小的粒子大小。当与普通柱色谱法相比较时,这允许在更短长度的柱上的更佳分离。
在一些实施例中,肽使用反相HPLC(RP-HPLC)进行检测和/或表征。反相HPLC(RP-HPLC或RPC)通常包括非极性静止相和水性、中等极性的流动相。一种常见静止相是已用RMe2SiCl处理的二氧化硅,其中R是直链烷基例如C18H37或C8H17。对于这些静止相,保留时间对于较少极性的分子更长,而极性分子更容易洗脱。
在一些实施例中,肽使用离子交换HPLC进行检测和/或表征。通常,在离子交换色谱法中,保留基于溶质离子和与静止相结合的荷电位点之间的吸引。排除相同电荷的离子。通常类型的离子交换剂包括但不限于下述。聚苯乙烯树脂。这些树脂允许增加链的稳定性的交联。一般而言,更高的交联降低转弯(swerving),这增加平衡时间且最终改善选择性。纤维素和右旋糖酐离子交换剂(凝胶):这些具有更大的孔径和低电荷密度,使得它们适合于蛋白质分离。可控孔度玻璃或多孔二氧化硅。
一般而言,离子交换剂有利于更高电荷和更小半径的离子的结合。通常,反离子(就树脂中的官能团而言)浓度的增加减少保留时间。通常,pH的增加减少阳离子交换中的保留时间,而pH的降低减少阴离子交换中的保留时间。
另外,样品中的肽可例如使用质谱法(MS)的方法进行表征。关于质谱法的方法的一般参考文献是Sparkman,Mass Spectrometry Desk Reference,Pittsburgh:Global View Pub(2000)。
本领域技术人员应当理解本文描述的芳香族阳离子肽可使用本领域已知的任何常规生物化学方法进行检测和/或表征。本文描述的HPLC和MS法是举例说明性的,而不应以任何方式解释为限制性的。
芳香族阳离子肽的预防和治疗用途
本文中描述的芳香族阳离子肽可用于预防或治疗疾病。具体地,公开内容提供了通过施用本文描述的芳香族阳离子肽来治疗处于疾病的危险中(或易受疾病影响)的受试者的预防和治疗方法。因此,本方法提供了通过将有效量的芳香族阳离子肽施用于有此需要的受试者来预防和/或治疗受试者中的疾病。
在一个实施例中,上文描述的肽可用于治疗与线粒体通透性转变(MPT)相关的任何疾病或病症。减少经历MPT的线粒体数目和预防MPT是重要的,因为MPT与哺乳动物中的几种常见疾病和病症相关。此类疾病和病症包括但不限于组织或器官的缺血和/或再灌注、缺氧和神经退行性疾病等。需要治疗或预防MPT的哺乳动物是那些患有这些疾病或病症的哺乳动物。
哺乳动物的组织或器官中的缺血是多方面的病理状态,其由氧剥夺(缺氧)和/或葡萄糖(例如底物)剥夺引起。组织或器官的细胞中的氧和/或葡萄糖剥夺导致能量生成能力的减少或全部丧失,和后续跨越细胞膜的离子主动转运功能的丧失。氧和/或葡萄糖剥夺还导致其他细胞膜中的病理变化,包括线粒体膜中的通透性转变。另外,其他分子,例如通常在线粒体内区室化的细胞凋亡蛋白质,可泄漏到细胞质内且引起细胞凋亡性细胞死亡。显著的缺血可导致坏死性细胞死亡。特定组织或器官中的缺血或缺氧可由对该组织或器官的血液供应的丧失或严重减少引起。血液供应中的丧失或严重减少可以例如是由于血栓栓塞性中风、冠状动脉粥样硬化或周围血管疾病导致。受缺血或缺氧影响的组织通常为肌肉,例如心肌、骨骼肌或平滑肌。受缺血或缺氧影响的器官可以是遭受缺血或缺氧的任何器官。受缺血或缺氧影响的器官的例子包括脑、心脏、肾和***。例如,心肌缺血或缺氧通常由动脉粥样硬化或血栓性堵塞引起,其导致由心脏动脉和毛细血管血液供应对心脏组织的氧输送的减少或丧失。此类心肌缺血或缺氧可引起受累心肌的疼痛和坏死,且最终可导致心力衰竭。骨骼肌或平滑肌中的缺血或缺氧可起于相似原因。例如,肠平滑肌或四肢骨骼肌中的缺血或缺氧也可由动脉粥样硬化或血栓性堵塞引起。
再灌注是对其中血流降低或阻塞的任何器官或组织的血流恢复。例如,血流可恢复至受缺血或缺氧影响的任何器官或组织。血流的恢复(再灌注)可通过本领域技术人员已知的任何方法发生。例如,缺血性心脏组织的再灌注可起于血管成形术、冠状动脉旁路移植术或溶栓药的使用。
本文描述的方法还可用于治疗或预防与MPT相关的神经退行性疾病。与MPT相关的神经退行性疾病包括例如帕金森氏病、阿尔茨海默氏病、亨廷顿氏病和肌萎缩侧索硬化(ALS,也称为葛雷克氏病)。本文公开的方法可用于延迟这些及其他与MPT相关的神经退行性疾病的发作,或减慢这些及其他与MPT相关的神经退行性疾病的进展。本文公开的方法可特别用于治疗患有早期与MPT相关的神经退行性疾病的人和易患这些疾病的人。
上文描述的芳香族阳离子肽还可用于预防或治疗胰岛素抗性、代谢综合征、烧伤和继发并发症、心力衰竭、糖尿病并发症(例如糖尿病性视网膜病变)、眼病症(例如脉络膜新生血管化、视网膜变性和氧诱导的视网膜病变)。
上文描述的芳香族阳离子肽还可用于降低有此需要的哺乳动物中的氧化损伤。需要降低氧化损伤的哺乳动物是患有与氧化损伤相关的疾病、病症或治疗的哺乳动物。通常,通过例如活性氧(ROS)和/或活性氮(RNS)的自由基导致氧化损伤。ROS和RNS的例子包括羟基自由基(HO·)、超氧阴离子自由基(O2 -)、一氧化氮(NO·)、过氧化氢(H2O2)、次氯酸(HOCl)和过氧亚硝酸盐阴离子(ONOO-)。在一个实施例中,有此需要的哺乳动物可以是经历与氧化损伤相关的治疗的哺乳动物。例如,哺乳动物可经历再灌注、缺血或缺氧。
在另一个实施例中,芳香族阳离子肽可用于就疾病或病症预防与氧化损伤相关的脂质过氧化和/或炎症过程。脂质过氧化指脂质的氧化修饰。脂质可存在于细胞的膜中。这种膜脂质修饰通常导致细胞膜功能的改变和/或损害。另外,脂质过氧化还可在细胞外源性的脂质或脂蛋白中发生。例如,低密度脂蛋白对脂质过氧化是敏感的。与脂质过氧化相关的病症的例子是动脉粥样硬化。减少与动脉粥样硬化相关的氧化损伤是重要的,因为动脉粥样硬化牵涉例如心脏病发作和冠状动脉疾病。
炎症过程包括免疫***的活化。通常,免疫***由抗原物质活化。抗原物质可以是由免疫***识别的任何物质,并且包括自衍生的颗粒和外源衍生的颗粒。由针对自衍生颗粒的炎症过程发生的疾病或病症的例子包括关节炎和多发性硬化。外源颗粒的例子包括病毒和细菌。病毒可以是任何病毒,其活化炎症过程,并且与氧化损伤相关。病毒的例子包括甲型、乙型或丙型肝炎病毒,人免疫缺陷病毒,流感病毒和牛腹泻病毒。例如,肝炎病毒可引发炎症过程和自由基的形成,由此损害肝。细菌可以是任何细菌,并且包括革兰氏阴性菌或革兰氏阳性菌。革兰氏阴性菌含有在细菌壁中的脂多糖。革兰氏阴性菌的例子包括大肠杆菌(Escherichia coli)、肺炎克雷伯氏菌(Klebsiellapneumoniae)、变形杆菌属(Proteus)物种、铜绿假单胞菌(Pseudomonasaeruginosa)、沙雷氏菌属(Serratia)和拟杆菌属(Bacteroides)。革兰氏阳性菌的例子包括肺炎球菌和链球菌。与由细菌引起的氧化性应激相关的炎症过程的例子是脓毒症。通常,当革兰氏阴性菌进入血流时,发生脓毒症。
由毒性试剂引起的肝损害是与炎症过程和氧化性应激相关的另一种病症。毒性试剂可以是对肝引起损害的任何试剂。例如,毒性试剂可引起肝细胞的细胞凋亡和/或坏死。此类试剂的例子包括酒精和药剂,例如为治疗疾病或病症而服用的处方药和非处方药。
本文公开的方法还可用于降低与任何神经变性疾病或病症相关的氧化损伤。神经变性疾病可影响中枢神经***和周围神经***的任何细胞、组织或器官。此类细胞、组织和器官的例子包括脑、脊髓、神经元、神经节、许旺细胞、星形细胞、少突胶质细胞和小神经胶质细胞。神经变性病症可以是急性病症例如中风或脑创伤或脊髓损伤。在另一个实施例中,神经变性疾病或病症可以是慢性神经变性病症。在慢性神经变性病症中,自由基例如可引起对蛋白质的损伤。此类蛋白质的例子为β淀粉样蛋白。与通过自由基的损伤相关的慢性神经变性疾病的例子包括帕金森氏病、阿尔茨海默氏病、亨廷顿氏病和肌萎缩侧索硬化(也称为葛雷克氏病)。
测定基于芳香族阳离子肽的治疗剂的生物效应。在多个实施例中,进行合适的体外测定或体内测定,来测定特定的基于芳香族阳离子肽的治疗剂的效应以及其施用是否适于治疗。在多个实施例中,可对代表性动物模型进行体外测定,以测定给定的基于芳香族阳离子肽的治疗剂是否在预防或治疗疾病或医学病症方面发挥所需效应。在人受试者中的测试之前,可在合适的动物模型***中测试用于治疗的化合物,所述动物模型***包括但不限于大鼠、小鼠、鸡、猪、牛、猴、兔等等。类似地,对于体内测试,在施用于人受试者之前,可使用本领域已知的动物模型***中的任一种。
预防方法。在一个方面,本发明提供了通过将预防病症起始或进展的芳香族阳离子肽施用于受试者来预防受试者中的疾病的方法。在预防应用中,将芳香族阳离子肽的药物组合物或药剂施用于易遭受疾病或病症或者另外处于疾病或病症的危险中的受试者,其量足以消除或降低疾病的危险、减轻疾病的严重性或延迟疾病的发作,包括疾病的生物化学、组织学和/或行为症状、其并发症和在该疾病发展过程中呈现的中间病理表型。预防性芳香族阳离子肽的施用可在反常的症状特征体现之前发生,使得疾病或障碍得到预防或可替代地延迟其进展。可基于上文描述的筛选测定来测定适当的化合物。
治疗方法。该技术的另一个方面包括为了治疗目的治疗受试者中的疾病的方法。在治疗应用中,将组合物或药剂施用于疑似患有此类疾病或已患有此类疾病的受试者,其量足以治愈或至少部分地阻止该疾病的症状,包括其并发症和在该疾病发展过程中的中间病理表型。像这样,本发明提供了治疗患有疾病或医学病症的个体的方法。
施用模式和有效剂量
可采用本领域的技术人员已知的用于使细胞、器官或组织与肽接触的任何方法。合适方法包括体外、离体或体内方法。体内方法通常包括将芳香族阳离子肽(例如上文描述的芳香族阳离子肽)施用于哺乳动物、适当的人。当在体内用于治疗时,芳香族阳离子肽可以有效量(即具有所需疗效的量)施用于受试者。剂量和给药方案将取决于受试者中的损伤的程度、所使用的特定的芳香族阳离子肽的特征(例如其治疗指数)、受试者以及受试者的病史。
可在临床前试验和临床试验过程中通过医生和临床医生熟悉的方法来测定有效量。在所述方法中有用的肽的有效量可通过用于施用药物组合物的多种众所周知方法中的任一种施用于有此需要的哺乳动物。肽可全身或局部施用。
该肽可配制成药学可接受的盐。术语“药学可接受的盐”意指由适于施用于患者例如哺乳动物的碱或酸制备成的盐(例如对于给定的给药方案,具有可接受的哺乳动物安全性的盐)。然而,应当理解,所述盐无需是药学可接受的盐,例如不预期施用于患者的中间化合物的盐。药学可接受的盐可源自药学可接受的无机碱或有机碱以及药学可接受的无机酸或有机酸。另外,当肽包含碱性部分(例如胺、吡啶或咪唑)和酸性部分(例如羧酸或四唑)两者时,可形成两性离子,且包括在如本文使用的术语“盐”中。源自药学可接受的无机碱的盐包括铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐和锌盐等等。源自药学可接受的有机碱的盐包括伯胺盐、仲胺盐和叔胺盐,包括取代胺盐、环胺盐、天然存在的胺盐等等,所述胺例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄乙烯二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴青霉素(hydrabamine)、异丙胺、赖氨酸、葡甲胺、吗啉、哌嗪、哌啶(piperadine)、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等等。源自药学可接受的无机酸的盐包括硼酸盐、碳酸盐、氢卤酸(氢溴酸、盐酸、氢氟酸或氢碘酸)盐、硝酸盐、磷酸盐、氨基磺酸盐和硫酸盐。源自药学可接受的有机酸的盐包括脂肪族羟基酸(例如柠檬酸、葡糖酸、乙醇酸、乳酸、乳糖酸、苹果酸和酒石酸)盐、脂肪族单羧酸(例如乙酸、丁酸、甲酸、丙酸和三氟乙酸)盐、氨基酸(例如天冬氨酸和谷氨酸)盐、芳香族羧酸(例如苯甲酸、对氯苯甲酸、二苯乙酸、龙胆酸、马尿酸和三苯基乙酸)盐、芳香族羟基酸(例如邻羟基苯甲酸、对羟基苯甲酸、1-羟基萘-2-羧酸和3-羟基萘-2-羧酸)盐、抗坏血酸盐、二羧酸(例如富马酸、马来酸、草酸和琥珀酸)盐、葡糖醛酸盐、扁桃酸盐、粘酸盐、烟酸盐、乳清酸盐、扑酸盐、泛酸盐、磺酸(例如苯磺酸、樟脑磺酸、乙二磺酸(edisylic acid)、乙磺酸、羟乙磺酸、甲磺酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸和对甲苯磺酸)的盐、辛那酸盐等等。在一些实施例中,该盐包含三氟乙酸盐或乙酸盐。
本文描述的芳香族阳离子肽或其药学可接受的盐例如乙酸盐或三氟乙酸盐,可掺入药物组合物内用于单独或组合施用于受试者,以治疗或预防本文描述的疾病或医学病症。此类组合物通常包括活性剂和药学可接受的载体。如本文使用的,术语“药学可接受的载体”包括与药物施用相容的盐水、溶剂、分散介质、涂层、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。补充性活性化合物也可掺入组合物内。
通常将药物组合物配制成与其预期施用途径相容。施用途径的例子包括肠胃外(例如,静脉内、皮内、腹膜内或皮下)、经口、吸入、经皮(局部)、眼内、电离子透入和经粘膜施用。用于肠胃外、皮内或皮下应用的溶液或悬浮液可包括下述组分:无菌稀释剂,例如注射用水、盐水溶液、不挥发油、聚乙二醇、丙三醇、丙二醇或其他合成溶剂;抗菌剂,例如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐以及用于调节张度的试剂,例如氯化钠或右旋糖。可用酸或碱例如盐酸或氢氧化钠来调节pH。肠胃外制剂可封装在玻璃或塑料制成的安瓿瓶、一次性注射器或多剂量小瓶中。为了患者或治疗医生的方便,剂量制剂可在试剂盒中提供,所述试剂盒含有治疗过程(例如治疗7天)所需的所有设备(例如,药物小瓶、稀释小瓶、注射器和针)。
适合于注射用途的药物组合物可包括无菌水溶液(在水溶性的情况下)或者用于临时制备无菌注射液或分散体的分散体和无菌粉末。对于静脉内施用,合适的载体包括生理盐水、抑菌水、Cremophor ELTM(BASF,Parsippany,N.J.)或磷酸盐缓冲盐水(PBS)。在所有情况下,用于肠胃外施用的组合物必须是无菌的,且应流动至存在容易注射性的程度。它在制造和储存条件下应是稳定的,且必须针对微生物例如细菌和真菌的污染作用进行防腐。
芳香族阳离子肽组合物或其药学可接受的盐例如乙酸盐或三氟乙酸盐可包括载体,该载体可以是含有例如水、乙醇、多元醇(例如,丙三醇、丙二醇和液态聚乙二醇等等)及其合适混合物的溶剂或分散介质。可通过例如下述来保持适当的流动性:使用涂层例如卵磷脂,在分散体的情况下维持所需粒子大小,和使用表面活性剂。可通过多种抗菌剂和抗真菌剂来实现微生物作用的预防,所述抗菌剂和抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等等。可包括谷胱甘肽及其他抗氧化剂以防止氧化。在许多情况下,将优选在组合物中包括等渗剂,例如糖、多元醇例如甘露醇、山梨糖醇或氯化钠。可通过在组合物中包括延迟吸收的制剂来造成可注射组合物的延长吸收,所述延迟吸收的制剂例如单硬脂酸铝或明胶。
可通过将所需量的活性化合物掺入具有上文列举的成分之一或组合的适当溶剂中,根据需要随后过滤灭菌来制备无菌可注射溶液。一般地,通过将活性化合物掺入无菌媒介物中来制备分散体,所述无菌媒介物含有基本分散介质和来自上文列举的所需其他成分。在用于制备无菌可注射溶液的无菌粉末的情况下,典型的制备方法包括真空干燥和冷冻干燥,其可获得活性成分加上来自其先前灭菌过滤的溶液的任何另外所需成分的粉末。
口服组合物一般包括惰性稀释剂或可食用载体。为了经口治疗施用的目的,活性化合物可与赋形剂一起掺入,并以片剂、锭剂或胶囊例如明胶胶囊的形式使用。还可使用流体载体制备口服组合物,以用作漱口剂。药学相容的粘合剂和/或辅助材料可被包括作为该组合物的一部分。片剂、丸剂、胶囊、锭剂等等可含有下述成分或具有相似性质的化合物中的任一种:粘合剂,例如微晶纤维素、黄蓍胶或明胶;赋形剂,例如淀粉或乳糖;崩解剂,例如海藻酸、羧甲淀粉钠(Primogel)或玉米淀粉;润滑剂,例如硬脂酸镁或Sterotes;助流剂,例如胶态二氧化硅;甜味剂,例如蔗糖或糖精;或调味剂,例如薄荷、水杨酸甲酯或橙调味料。
关于通过吸入施用,化合物可以来自含有合适推进剂(例如气体,例如二氧化碳)的加压容器或分配器或者喷雾器的气溶胶喷雾形式进行递送。此类方法包括美国专利号6,468,798中描述的方法。
如本文描述的治疗化合物的全身施用还可通过经粘膜或经皮方法来进行。对于经粘膜或经皮施用,适合于待渗透的屏障的渗透剂用于制剂中。此类渗透剂一般是本技术领域已知的,并且对于经粘膜施用,包括例如去污剂、胆汁盐和夫西地酸衍生物。可通过使用鼻腔喷雾来完成经粘膜施用。对于经皮施用,将活性化合物配制成本领域一般已知的软膏、药膏、凝胶或乳膏。在一个实施例中,经皮施用可通过电离子透入来进行。
治疗肽或其药学可接受的盐例如乙酸盐或三氟乙酸盐可在载体***中进行配制。该载体可以是胶态***。该胶态***可以是脂质体、磷脂双层媒介物。在一个实施例中,治疗肽包封在脂质体中,同时维持肽完整性。如本领域技术人员理解的,存在多种制备脂质体的方法。(参见Lichtenberg等人,Methods Biochem.Anal.,33:337-462(1988);Anselem等人,LiposomeTechnology,CRC Press(1993))。脂质体制剂可延迟清除并增加细胞摄取(参见Reddy,Ann.Pharmacother.,34(7-8):915-923(2000))。活性剂还可装载到由药学可接受的成分制备的颗粒内,所述药学可接受的成分包括但不限于可溶、不可溶、可渗透、不可渗透、生物可降解或胃滞留的聚合物或脂质体。此类颗粒包括但不限于纳米颗粒、生物可降解的纳米颗粒、微粒、生物可降解的微粒、纳米球、生物可降解的纳米球、微球、生物可降解的微球、胶囊、乳剂、脂质体、胶粒以及病毒载体***。
该载体还可以是聚合物,例如生物可降解、生物相容的聚合物基质。在一个实施例中,治疗肽可嵌入到聚合物基质中,同时维持蛋白质完整性。聚合物可以是天然的,例如多肽、蛋白质或多糖;或合成的,例如聚α-羟酸。例子包括由例如下述物质制成的载体:胶原蛋白、纤连蛋白、弹性蛋白、乙酸纤维素、硝酸纤维素、多糖、纤维蛋白、明胶及其组合。在一个实施例中,聚合物是聚乳酸(PLA)或乳酸/乙醇酸共聚物(PGLA)。聚合物基质可以多种形式和大小进行制备并分离,包括微球和纳米球。聚合物制剂可导致疗效的延长持续时间(参见Reddy,Ann.Pharmacother.,34(7-8):915-923(2000))。用于人生长激素(hGH)的聚合物制剂已用在临床试验中。(参见Kozarich和Rich,Chemical Biology,2:548-552(1998))。
聚合物微球持续释放制剂的例子在PCT公开WO99/15154(Tracy等人)、美国专利号5,674,534和5,716,644(两者均属于Zale等人)、PCT公开WO96/40073(Zale等人)和PCT公开WO00/38651(Shah等人)中进行描述。美国专利号5,674,534和5,716,644以及PCT公开WO96/40073描述了含有***颗粒的聚合物基质,所述***颗粒用盐针对聚集进行稳定。
在一些实施例中,治疗化合物与保护该治疗化合物不受从机体快速消除的载体一起制备,所述载体例如控制释放制剂,包括埋植剂和装入微胶囊的递送***。可使用生物可降解、生物相容的聚合物,例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。可使用已知技术来制备此类制剂。还可例如从Alza Corporation and Nova Pharmaceuticals,Inc.商购获得材料。脂质体悬浮液(包括靶向具有针对细胞特异性抗原的单克隆抗体的特定细胞的脂质体)也可用作药学可接受的载体。这些可根据本领域技术人员已知的方法进行制备,例如如美国专利号4,522,811中描述的。
治疗化合物还可配制为增强细胞内递送。例如,脂质体递送***是本领域已知的,参见例如Chonn和Cullis,“Recent Advances in Liposome DrugDelivery Systems,”Current Opinion in Biotechnology6:698-708(1995);Weiner,“Liposomes for Protein Delivery:Selecting Manufacture and DevelopmentProcesses,”Immunomethods,4(3):201-9(1994);和Gregoriadis,“EngineeringLiposomes for Drug Delivery:Progress and Problems,”Trends Biotechnol.,13(12):527-37(1995)。Mizguchi等人,Cancer Lett.,100:63-69(1996)描述了使用膜融合脂质体在体内和在体外将蛋白质递送至细胞。
可通过细胞培养或实验动物中的标准药学程序来测定治疗剂的剂量、毒性和治疗效果,例如,用于测定LD50(对50%群体致命的剂量)和ED50(在50%群体中治疗有效的剂量)。毒性和疗效之间的剂量比是治疗指数,并且它可表示为比率LD50/ED50。显示出高治疗指数的化合物是优选的。尽管可使用显示出毒性副作用的化合物,但应当小心设计递送***,该递送***将此类化合物靶向受累组织部位,以便使对未感染细胞的潜在损伤降到最低,且由此降低副作用。
得自细胞培养测定和动物研究的数据可用于配制在人中使用的剂量范围中。此类化合物的剂量优选位于包括具有很少毒性或无毒性的ED50的循环浓度的范围中。取决于采用的剂型和利用的施用途径,剂量可在该范围内变化。对于该方法中使用的任何化合物,可最初由细胞培养测定来估计治疗有效剂量。可在动物模型中配制剂量来实现循环血浆浓度范围,其包括如在细胞培养中测定的IC50(即,实现症状的半数最大抑制的测试化合物浓度)。此类制剂可用于更准确地测定人中的有用剂量。可例如通过高效液相色谱法测量血浆水平。
剂量还可通过检测来自受试者的生物样品中的芳香族阳离子肽凭经验进行测定。得自已施用芳香族阳离子肽的受试者的生物样品可实施HPLC和/或MS,以检测且表征受试者的体液和组织中存在的芳香族阳离子肽。生物样品包括源自活细胞或由活细胞接触的任何材料。生物样品的例子包括但不限于全血、分馏血液、***、唾液、泪、尿、粪便材料、汗、颊、皮肤、脑脊髓液和毛发。生物样品还包括内脏活组织检查样本、因移植或癌症而摘除的器官。通过比较对于参考样品获得的数据例如实例6中提供的那些,确定生物样品中的芳香族阳离子肽的存在。样品中存在的芳香族阳离子肽的水平可充当基础,以增加或降低对给定受试者施用的芳香族阳离子肽或其前体的剂量,其中该前体可以是其也是治疗试剂或药物的芳香族阳离子肽。
通常,足以实现治疗或预防效应的芳香族阳离子肽的有效量范围为约0.000001mg/千克体重/天-约10,000mg/千克体重/天。优选地,剂量范围为约0.0001mg/千克体重/天-约100mg/千克体重/天。例如,剂量可以是每天、每两天或每三天1mg/kg体重或10mg/kg体重,或者在每周、每两周或每三周1-10mg/kg的范围内。在一个实施例中,肽的单次剂量范围为0.1-10,000毫克/kg体重。在一个实施例中,在载体中的芳香族阳离子肽浓度范围为0.2-2000毫克/递送的毫升。示例性治疗方案需要每天一次或每周一次的施用。在治疗应用中,在相对短的间隔中相对高的剂量有时是需要的,直到疾病的进展降低或终止,且优选直到受试者显示疾病症状的部分或完全改善。其后,可对患者施用预防方案。
在一些实施例中,芳香族阳离子肽的治疗有效量可限定为在靶标组织处10-11-10-6摩尔、例如大约10-7摩尔的肽浓度。该浓度可通过0.01-100mg/kg的全身剂量或体表面积的等效剂量来递送。最佳化剂量的时间表,以维持在靶标组织处的治疗浓度,最优选通过每天或每周单次施用,但也包括连续施用(例如,肠胃外输注或经皮应用)。
在一些实施例中,芳香族阳离子肽的剂量以“低”、“中”或“高”剂量水平提供。在一个实施例中,低剂量由约0.001-约0.5mg/kg/h、适当地约0.01-约0.1mg/kg/h提供。在一个实施例中,中剂量由约0.1-约1.0mg/kg/h、适当地约0.1-约0.5mg/kg/h的剂量提供。在一个实施例中,高剂量由约0.5-约10mg/kg/h、适当地约0.5-约2mg/kg/h的剂量提供。
本领域技术人员应当理解,某些因素可影响有效治疗受试者所需的剂量和时机,包括但不限于疾病或障碍的严重性、先前治疗、受试者的一般健康和/或年龄以及存在的其他疾病。此外,使用本文描述的治疗有效量的治疗组合物治疗受试者可包括单次治疗或一系列治疗。
在一些实施例中,将多个剂量或不同量的芳香族阳离子肽施用于受试者。在一些实施例中,在操作(例如手术)过程自始至终或者在疾病或病症过程自始至终施用多个剂量或不同量的肽。例如,在一些实施例中,该肽例如在手术过程中静脉内施用,并且给受试者提供的肽量在操作过程中进行调整。在其他实施例中,约每10分钟、15分钟、30分钟、1小时、2小时、4小时、6小时、8小时、10小时、12小时一次,每天一次,每隔一天一次或每周一次给受试者施用肽剂量(例如经口或通过注射,例如真皮内、皮下、肌内、静脉内、骨内和腹膜内)。在一些实施例中,监控受试者中存在的肽量(受试者的肽水平),以测定维持受试者中的所需肽水平所需的适当剂量和时间表。在一些实施例中,肽水平在施用过程中定期测定,和/或在施用后的一个或多个时间点测定。例如,在一些实施例中,肽水平在施用数分钟内,施用后约10分钟、15分钟、30分钟、1小时、2小时、4小时、6小时、8小时、10小时、12小时、24小时、二天、3天5天、7天或14天进行测定。在其他实施例中,对于预定时间例如在手术操作过程中,每10分钟、15分钟、20分钟、30分钟、每小时、每二小时、每4小时、每6小时或每12小时测定受试者肽水平。取决于测定的肽水平,可提供一个或多个另外的剂量,以实现维持疗效的所需肽水平。在一些实施例中,肽水平可能发现足以延迟另外的一个或多个剂量。
在一些实施例中,检测到的芳香族阳离子肽水平与健康对照受试者(例如已经由基本上相同的施用途径施用基本上相同的肽剂量的受试者)中的芳香族阳离子肽水平相比较。另外或可替代地,在一些实施例中,肽水平在受试者的不同器官、***和/或流体中进行测定。在一些实施例中,肽水平在受试者的不同器官、***和/或流体中进行测定,并且与对照受试者的可比较***、器官和流体中的肽水平相比较。在一些实施例中,此类分析提供关于肽的可用性和与对照相比较肽在受试者身体各处的转运的信息。例如,施用途径可对于特定受试者改变,以优化对特定组织或器官的肽递送(例如以实现更局限性的肽分布)。另外或可替代地,施用途径可对于特定受试者改变,以用于更全身的肽分布。
用于鉴定且测定受试者样品中的芳香族阳离子肽的存在或量(水平)的方法是本领域已知的,并且包括但不限于HPLC和质谱法。
如先前指出的,在一些实施例中,肽水平在来自受试者的生物样品中进行测定,并且包括但不限于血样、组织样品(例如器官或肿瘤活组织检查样品)、尿和唾液。
本文还公开的是用于检测芳香族阳离子肽的试剂盒。在一些实施例中,该试剂盒包括收集来自受试者的样品的样品收集装置,和用于保存生物样品的样品贮存装置。取决于预期的检测方法,将样品贮存于也在试剂盒中提供的适当缓冲液或防腐剂中。在一些实施例中,样品收集器包括液体容器,例如小瓶或管(例如用于血液、血液制品、尿)。在其他实施例中,样品收集器是吸收性材料,例如无菌棉签(例如以收集颊样品、唾液、鼻拭子等)、载玻片、无菌纸、卡、注射器等。样品贮存装置可以是将包围样品且在运输、装运和/或贮存过程中保护样品的任何装置。例如,在一些实施例中,样品贮存装置是可密封管。
在一些实施例中,该试剂盒还包括用于获得样品且适当贮存样品直至分析时的说明书。在一些实施例中,样品包括体液、一种或多种细胞、组织或器官的一部分、活组织检查样品和/或肿瘤的一部分。
依照本方法治疗的哺乳动物可以是任何哺乳动物,包括例如农场动物,例如绵羊、猪、牛和马;宠物动物,例如犬和猫;实验室动物,例如大鼠、小鼠和兔。在合适实施例中,哺乳动物是人。
实例
通过下述实例进一步举例说明本发明,所述实例不应解释为以任何方式限制本发明。
实例1–本技术的芳香族阳离子肽抑制通过分离的线粒体的H
2
O
2
生成
在本实例中,研究本发明的芳香族阳离子肽对通过分离的线粒体的H2O2生成的作用。H2O2使用如Y.Li,H.Zhu,M.A.Trush,Biochim.Biophys.Acta1428,1-12(1999))中所述的鲁米诺化学发光进行测量。简言之,在芳香族阳离子肽的不存在或存在下,将0.1mg线粒体蛋白质加入0.5ml磷酸钾缓冲液(100mM,pH8.0)中。加入鲁米诺(25mM)和0.7IU辣根过氧化物酶,并且用Chronolog型号560凝聚计(Havertown,Pa.)在37℃下监控化学发光共20分钟。产生的H2O2量定量为经过20分钟的曲线下面积(AUC),并且所有数据针对由单独的线粒体产生的AUC标准化。
预测芳香族阳离子肽将减少通过分离的线粒体的自发H2O2产生。像这样,芳香族阳离子肽可用于减少氧化损伤,并且可用于治疗或预防涉及氧化损伤的疾病或病症。
实例2–本技术的芳香族阳离子肽减少细胞内ROS且增加细胞存活
为了显示请求保护的肽当施加于全细胞时是有效的抗氧化剂,将神经元N2A细胞以1x104/孔的密度在96孔板中铺平板,并且允许生长2天,然后用tBHP(0.5或1mM)处理40分钟。将细胞洗涤两次,并且替换为单独的培养基或含有不同浓度的芳香族阳离子肽(10-12M至10-9M)的培养基共4小时。细胞内ROS通过羧基-H2DCFDA(Molecular Probes,Portland,Oreg.)进行测量。细胞死亡通过细胞增殖测定(MTS assay,Promega,Madison,Wis.)进行评价。
与tBHP一起温育将导致细胞内ROS的增加和细胞活力的降低。然而,预测这些细胞与芳香族阳离子肽一起温育将减少细胞内ROS且增加细胞存活。像这样,芳香族阳离子肽可用于减少氧化损伤,并且可用于治疗或预防涉及氧化损伤的疾病或病症。
实例3–本技术的芳香族阳离子肽保护不受由Ca
2+
和3-硝基丙酸诱导的
MPT
为了从小鼠肝中分离线粒体,通过断头术处死小鼠。取出肝且快速置于致冷的肝匀浆化介质中。使用剪刀将肝精细绞碎,并且随后使用玻璃匀浆器手动匀浆化。匀浆物以1000g在4℃下离心10分钟。将上清液抽吸且转移至聚碳酸酯管中,并且再次在3000g、4℃下离心10分钟。去除所得的上清液,并且小心擦掉在管的侧壁上的脂肪脂质。将团块重悬浮于肝匀浆介质中,并且将匀浆化重复两次。将最后纯化的线粒体团块重悬浮于介质中。通过Bradford操作测定线粒体制剂中的蛋白质浓度。
为了研究本发明的芳香族阳离子肽的定位,将在400μl缓冲液中的约1.5mg线粒体与标记的芳香族阳离子肽一起在37℃下温育5-30分钟。随后将线粒体向下离心,并且测量在线粒体级分和缓冲液级分中的标记量。假定0.7μl/mg蛋白质的线粒体基质体积(Lim等人,J Physiol545:961-974,2002),可测定线粒体中的肽浓度。预测与缓冲液级分相比较,请求保护的芳香族阳离子肽在线粒体中将更浓缩。
为了研究本发明的芳香族阳离子肽对线粒体膜电位的作用,使分离的小鼠肝线粒体与100-200μM芳香族阳离子肽一起温育。使用四甲基罗丹明甲酯(TMRM)测量线粒体膜电位。线粒体的添加导致TMRM信号的立即猝灭,所述猝灭容易地通过添加FCCP逆转,从而指示线粒体去极化。Ca2+(150μM)的添加导致立即去极化,随后为进行性的猝灭丧失,这指示MPT。芳香族阳离子肽单独(即使以200μM)的添加也不预测引起线粒体去极化或MPT。还预测芳香族阳离子肽将不改变线粒体功能,包括在状态3或状态4过程中的耗氧量或呼吸比(状态3/状态4)。
为了显示请求保护的肽有效保护不受由Ca2过负荷诱导的MPT,在添加Ca2+前,分离的线粒体用芳香族阳离子肽(10μM)预处理2分钟。预测本发明的芳香族阳离子肽将增加线粒体对累积的Ca2+攻击的耐受。
3-硝基丙酸(3NP)是电子传递链的复合物II中的琥珀酸脱氢酶的不可逆抑制剂。3NP(1mM)对分离的线粒体的添加引起线粒体电位的消散和MPT的发作。线粒体用本发明的芳香族阳离子肽的预处理预测延迟由3NP诱导的MPT的发作。
为了证实本发明的芳香族阳离子肽可穿透细胞膜且保护不受由3NP引发的线粒体去极化,在芳香族阳离子肽的不存在或存在下,将Caco-2细胞用3NP(10mM)处理4小时,并且随后与TMRM一起温育且在LSCM下检查。在对照细胞中,线粒体明确显现为在细胞质各处的细条纹。在用3NP处理的细胞中,TMRM荧光大幅减少,从而指示泛发的去极化。相比之下,预测用本发明的芳香族阳离子肽的同时处理将保护不受由3NP引起的线粒体去极化。
像这样,芳香族阳离子肽可用于预防MPT,并且可用于治疗或预防涉及MPT的疾病或病症。
实例4–本技术的芳香族阳离子肽保护不受线粒体肿胀和细胞色素c释
放
MPT孔打开导致线粒体肿胀。本实例通过测量在540nm处的吸光度(A540)的减少,检查本发明的芳香族阳离子肽对线粒体肿胀的作用。一旦测量吸光度,随后就使线粒体悬浮液离心,并且通过商购可得的ELISA试剂盒测定线粒体团块和上清液中的细胞色素c。预测用本发明的芳香族阳离子肽预处理分离的线粒体,将抑制由Ca2+过负荷诱导的肿胀和细胞色素c释放。除预防由Ca2+过负荷诱导的MPT之外,预测本发明的芳香族阳离子肽还将预防由MPP+(1-甲基-4-苯基吡啶鎓离子)诱导的线粒体肿胀,所述MPP+是线粒体电子传递链的复合物I的抑制剂。
像这样,芳香族阳离子肽可用于预防MPT,并且可用于治疗或预防涉及MPT的疾病或病症。
实例5–本技术的肽增加分离的线粒体中的ATP合成率。
本实例将证实本技术的肽对线粒体ATP合成率的影响。
通过测量在添加400mM ADP后1分钟从分离的线粒体收集的呼吸缓冲液中的ATP,来测定线粒体ATP合成率。ATP将通过HPLC进行测定。所有实验将一式三份进行,其中n=3。预测本技术的肽对分离的线粒体的添加将以剂量依赖性方式增加ATP合成率。
该结果将证实本技术的肽可用于增加线粒体ATP合成率的方法和组合物中。
实例6–芳香族阳离子肽的表征
本技术的芳香族阳离子肽可使用固相合成进行合成,并且使用HPLC和MS进行表征。示例性HPLC和MS方法在下文实例7和8中提供。
实例7–生物样品中的芳香族阳离子肽的检测
本实例证实通过HPLC检测生物样品中的芳香族阳离子肽。取决于样品的性质,以合适方式从受试者中收集生物样品。生物样品包括源自活细胞或由活细胞接触的任何材料。生物样品的例子包括但不限于全血、分馏血液、***、唾液、泪、尿、粪便材料、汗、颊、皮肤、脑脊髓液和毛发。生物样品还包括内脏或癌症活组织检查样本。一旦获得,生物样品就以与检测方法相容的方式贮存,直至执行该方法时,以确保样品中存在的芳香族阳离子肽的保存。
将样品装载到250x4.6(i.d.)mm C185μm柱上,并且根据下述方案实施在乙腈中的0.1%三氟乙酸(溶液A)和在HPLC级别水中的0.1%三氟乙酸(溶液B)的梯度:
通过比较对于参考样品获得的数据例如实例6中提供的那些,确定生物样品中的芳香族阳离子肽的存在。
前述方法仅是举例说明性的,并且不应以任何方式解释为限制性的。本领域技术人员应当理解,本文描述的芳香族阳离子肽可通过多种HPLC方法进行分析,所述HPLC方法例如Aguilar,HPLC of Peptides and Proteins:Methods and Protocols,Humana Press,New Jersey(2004)中所述的那些。
实例8通过MS检测生物样品中的芳香族阳离子肽
该实例证实通过MS检测生物样品中的芳香族阳离子肽。取决于样品的性质,以合适方式从受试者中收集生物样品。生物样品包括源自活细胞或由活细胞接触的任何材料。生物样品的例子包括但不限于全血、分馏血液、***、唾液、泪、尿、粪便材料、汗、颊、皮肤、脑脊髓液和毛发。生物样品还包括内脏或癌症活组织检查样本。一旦获得,生物样品就以与检测方法相容的方式贮存,直至执行该方法时,以确保样品中存在的芳香族阳离子肽的保存。
样品在20μl体积中装载且在下述示例性条件下分析。
本领域技术人员应当理解,本文描述的芳香族阳离子肽可通过多种MS方法进行分析,所述MS方法例如Sparkman,Mass Spectrometry DeskReference,Pittsburgh:Global View Pub(2000)中所述的那些。
本发明并不限于在本申请中描述的特定实施例,所述特定实施例预期用作本发明的单个方面单独举例说明。如对于本领域技术人员显而易见的,可作出本发明的多种修改和变化而不背离其精神和范围。根据上述说明书,除本文中列举的之外,在本发明范围内的功能上等价的方法和仪器对于本领域的技术人员将是显而易见的。此类修改和变化预期落入所附权利要求的范围内。本发明仅受所附权利要求书连同此类权利要求书赋予权力的等价物的全部范围限制。应当理解,本发明并不限于特定的方法、试剂、化合物、组合物或生物***,当然,所述方法、试剂、组合物或生物***可变化。还应理解,本文中使用的术语仅用于描述特定实施例,并不预期是限制性的。
另外,当公开内容的特征或方面按照Markush组进行描述时,本领域技术人员将认识到公开内容由此也按照Markush组的任何个别成员或成员亚组进行描述。
如本领域的技术人员应当理解的,为了任何和所有目的,特别是在提供书面说明书方面,本文公开的所有范围还涵盖任何和所有可能的子范围及其子范围的组合。任何列出的范围可容易地视为充分描述并使相同范围能够分解成至少相等的二分之一、三分之一、四分之一、五分之一、十分之一等。作为非限制性实例,本文讨论的每个范围可容易地分解成下三分之一、中三分之一和上三分之一等。如本领域技术人员还应理解的,所有的语言例如“上至”、“至少”、“大于“、“小于”等等包括所述数目,并且指随后可分解成如上文讨论的子范围的范围。最后,如本领域的技术人员应当理解的,范围包括每一个别成员。因此,例如,具有1-3个单元的组指具有1、2或3个单元的组。类似地,具有1-5个单元的组指具有1、2、3、4或5个单元的组等等。
本文提及或引用的所有专利、专利申请、临时申请和出版物包括所有附图和表格全文以引用的方式并入,到它们不与本说明书的明确教导相矛盾的程度。
在下述权利要求中阐述了其他实施例。
Claims (23)
1.一种芳香族阳离子肽,所述芳香族阳离子肽选自下述:
2.一种药物组合物,所述药物组合物包括根据权利要求1所述的一种或多种芳香族阳离子肽及其药学可接受的盐。
3.根据权利要求2所述的药物组合物,所述药物组合物还包含药学可接受的载体。
4.一种减少有此需要的哺乳动物中经历线粒体通透性转变(MPT)的线粒体数目或预防有此需要的哺乳动物中线粒体通透性转变的方法,所述方法包括给所述哺乳动物施用有效量的根据权利要求1所述的一种或多种芳香族阳离子肽。
5.一种用于减少有此需要的哺乳动物中的氧化损伤的方法,所述方法包括给所述哺乳动物施用有效量的根据权利要求1所述的一种或多种芳香族阳离子肽。
6.一种用于增加有此需要的哺乳动物中的ATP合成率的方法,所述方法包括给所述哺乳动物施用有效量的根据权利要求1所述的一种或多种芳香族阳离子肽。
7.一种用于测定受试者中施用的芳香族阳离子肽的存在或量的方法,所述方法包括:检测来自所述受试者的生物样品中的所述施用的芳香族阳离子肽,其中所述芳香族阳离子肽选自下述:
8.根据权利要求7所述的方法,其中检测在所述肽的施用过程中执行。
9.根据权利要求7所述的方法,其中检测在所述肽的施用后执行。
10.根据权利要求7中任一项所述的方法,其中检测包括HPLC。
11.根据权利要求10所述的方法,其中所述HPLC包括反相HPLC。
12.根据权利要求10所述的方法,其中所述HPLC包括离子交换HPLC。
13.根据权利要求7所述的方法,其中检测包括质谱法。
14.根据权利要求7所述的方法,其中所述生物样品包含流体。
15.根据权利要求7所述的方法,其中所述生物样品包含细胞。
16.根据权利要求7所述的方法,其中所述生物样品包含组织。
17.根据权利要求7中任一项所述的方法,其中所述生物样品包含活组织检查样本。
18.一种芳香族阳离子肽,所述芳香族阳离子肽包含式VII或其立体异构体
其中所述式III的手性中心定义为H-(R)-Arg-(S)-DMT-(S)-Lys-(S)-Phe-NH2,并且其中立体异构体由下式描述:R-S-S-S、S-R-R-R、S-S-S-S、R-R-R-R、R-R-S-S、S-S-R-R、S-R-S-S、R-S-R-R、R-S-R-S、S-R-S-R、R-R-S-R、S-S-R-S、R-R-R-S、S-S-S-R、R-S-S-R和S-R-R-S。
19.一种芳香族阳离子肽,所述芳香族阳离子肽包含式VII或其选自下述的组成成分:
Arg-Dmt-Lys-Phe-NH2、Phe-Dmt-Arg-Lys-NH2、Phe-Lys-Dmt-Arg-NH2、Dmt-Arg-Lys-Phe-NH2、Lys-Dmt-Arg-Phe-NH2、Phe-Dmt-Lys-Arg-NH2、Arg-Lys-Dmt-Phe-NH2、或Arg-Dmt-Phe-Lys-NH2。
20.一种芳香族阳离子肽,所述芳香族阳离子肽包含式VIII
其中R选自
(i)OMe,和
(ii)H。
21.一种芳香族阳离子肽,所述芳香族阳离子肽包含式IX
其中R选自
(i)F,
(ii)Cl,和
(iii)H。
22.一种芳香族阳离子肽,所述芳香族阳离子肽包含式X
其中R1-R4选自
(i)Ac,(ii)H,(iii)H,(iv)H,
(i)H,(ii)Ac,(iii)H,(iv)H,
(i)H,(ii)H,(iii)Ac,(iv)H,和
(i)H,(ii)H,(iii)H,(iv)OH。
23.一种芳香族阳离子肽,所述芳香族阳离子肽包含式XI
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2012
- 2012-12-05 EP EP15177562.4A patent/EP3009141A1/en not_active Withdrawn
- 2012-12-05 CN CN201280066416.2A patent/CN104105499A/zh active Pending
- 2012-12-05 US US14/363,035 patent/US20140294796A1/en not_active Abandoned
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- 2012-12-05 EP EP19202295.2A patent/EP3656394A1/en not_active Withdrawn
- 2012-12-05 CN CN201810783561.1A patent/CN109160936A/zh not_active Withdrawn
- 2012-12-05 EP EP18190582.9A patent/EP3466439A1/en not_active Withdrawn
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- 2012-12-05 JP JP2014546031A patent/JP2015507611A/ja active Pending
- 2012-12-05 WO PCT/US2012/067984 patent/WO2013086020A1/en active Application Filing
- 2012-12-05 AU AU2012347931A patent/AU2012347931A1/en not_active Abandoned
- 2012-12-05 CN CN201710524414.8A patent/CN107312066A/zh active Pending
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2016
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2017
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2018
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2019
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2020
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JP2019137691A (ja) | 2019-08-22 |
EP3009141A1 (en) | 2016-04-20 |
WO2013086020A1 (en) | 2013-06-13 |
CN109160936A (zh) | 2019-01-08 |
EP3656394A1 (en) | 2020-05-27 |
HK1223550A1 (zh) | 2017-08-04 |
EP2788013A4 (en) | 2015-08-19 |
JP2018035190A (ja) | 2018-03-08 |
AU2012347931A1 (en) | 2014-07-03 |
AU2019264653A1 (en) | 2019-12-05 |
CA2858550A1 (en) | 2013-06-13 |
CN107312066A (zh) | 2017-11-03 |
EP2788013A1 (en) | 2014-10-15 |
US20140294796A1 (en) | 2014-10-02 |
US20210040149A1 (en) | 2021-02-11 |
JP2015507611A (ja) | 2015-03-12 |
US20180362579A1 (en) | 2018-12-20 |
EP3466439A1 (en) | 2019-04-10 |
AU2017276158A1 (en) | 2018-01-04 |
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