CN113365649A - 含有能够刺激gprc6a依赖性信号传导通路的肽的组合物 - Google Patents

含有能够刺激gprc6a依赖性信号传导通路的肽的组合物 Download PDF

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CN113365649A
CN113365649A CN202080008448.1A CN202080008448A CN113365649A CN 113365649 A CN113365649 A CN 113365649A CN 202080008448 A CN202080008448 A CN 202080008448A CN 113365649 A CN113365649 A CN 113365649A
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C·福雷斯塔
L·德托尼
A·迪尼西欧
M·德罗克蓬塞
A·焦里
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Abstract

本文公开了药物组合物或营养组合物，其包含与合适的赋形剂混合的肽或含有所述肽的提取物，所述肽具有序列NMYLPPVPPP PVVPTF。

Description

含有能够刺激GPRC6A依赖性信号传导通路的肽的组合物
本发明涉及药物组合物或营养组合物，其包含与合适的赋形剂混合的肽或含有所述肽的提取物，所述肽具有序列NMYLPPVPPP PVVPTF。根据本发明的组合物可用于治疗或辅助治疗受益于刺激GPRC6A依赖性信号传导通路的病症。此类病症的示例包括男性性腺机能减退、骨质减少/骨质疏松症、勃起功能障碍和代谢综合征。
背景技术
骨组织作为内分泌器官的作用是近十年来引起科学界极大兴趣的课题。对动物模型的初步研究表明，骨钙素(OCN)，一种源自成骨细胞的小蛋白，通常以其γ-羧化形式参与细胞外骨基质的矿化，在脱羧后可能表现出全身作用。特别是，未羧化的骨钙素(ucOCN)似乎是胰岛释放胰岛素的直接刺激物，是维持激素的主要靶器官(如脂肪组织和肌肉)对胰岛素敏感性的保护性因子，并且是通过控制睾丸中的Leydig细胞产生和释放睾酮(T)调节骨质量和雄性生育力的调节物[Lee Cell.2007；Ferron Proc Natl Acad Sci USA.2008；PiPLoS One.2008；Rached J Clin Invest.2010；Ferron Cell.2010；Oury Cell.2011]。体外和体内研究确定了GPRC6A受体是ucOCN全身活性的介质[Pi J Biol Chem.2005；Pi J BoneMiner Res.2011；Wei Diabetes.2014]。随后的研究表明了ucOCN通过GPRC6A受体的内分泌作用也在人类中保留了，证实了这种新型多器官内分泌轴的作用[Foresta J ClinEndocrinol Metab.2010；Oury.J Clin Invest.2013；De Toni Endocrinology.2014；DeToni J Clin Endocrinol Metab.2016；Di Nisio Clin Endocrinol(Oxf).2017；Parker JBone Miner Res.2018]。
GPRC6A的关键特征是它是一种代谢型受体，即可以被一系列代谢目的小分子激活，例如碱性氨基酸(例如精氨酸和鸟氨酸)和金属阳离子(例如钙和镁)[Pi J BiolChem.2005]。2010年代初期进行的体外研究表明GPRC6A可以代表T膜受体，即雄激素的“非基因组”或快速作用的介质[Pi J Biol Chem.2010；Pi Mol Endocrinol.2015]。该假设的正确性随后在以GPRC6A组成型表达为特征的细胞系和原代细胞培养物的大量体外研究中得到证实[Ko.J Biol Chem.2014；Pi Mol Endocrinol.2015；O’Hara FASEB J.2015]。
根据一些作者的说法，GPRC6A代表一些化学上高度不同的实体(例如氨基酸、金属阳离子和类固醇)的共同分子靶标的假说构成了一种生物模型，其具有某些高度关键的环节[Clemmensen Br J Pharmacol.2014]。在这方面，应该记住，大部分T以与称为“性激素结合球蛋白”(SHBG)的血清球蛋白的复合物的形式存在于外周循环中[Mean Clin ChimActa.1977]。此外，大量研究表明，低血浆水平的SHBG与代谢改变的临床症状(例如增加的胰岛素抗性和增加的2型糖尿病风险)之间存在显著相关性[Birkeland J ClinEndocrinol Metab.1993；Tsai Diabetes Care.2004；Muller J Clin EndocrinolMetab.2005；Pitteloud Diabetes Care.2005；Ding N Engl J Med.2009]。这些因素，加上ucOCN和SHBG都是蛋白质这一事实，表明SHBG可能在T和GPRC6A之间的相互作用中充当介质。该假设在最近的一项研究中得到证实，其中使用集成的计算实验方法，在GPRC6A的细胞外结构域中鉴定了一个与ucOCN和SHBG相互作用的共同结合位点[De Toni Endocrinology2016]。WO2009073544提出了能够调节GPRC6A水平和/或活性的试剂的可能治疗用途，特别是用于治疗肥胖症和糖尿病。
发明内容
现在已经发现，一种氨基酸序列与SHBG的结构域141-161(SHBG141-161)表现出密切的同源性(62.5％的氨基酸同一性；75％的结构相似性)，所述SHBG的结构域141-161对应于具有高度柔性的蛋白质环，负责ucOCN和GPRC6A之间的相互作用。
还发现所述肽序列(NMYLPPVPPPPVVPTF,SEQ ID 1,P80762)在细胞系培养物的实验模型中刺激胰岛素和睾酮释放。
因此，本发明的目的是药物组合物或营养组合物，其包含与合适的赋形剂混合d分离形式的具有序列NMYLPPVPPP PVVPTF的肽、或含有所述序列的分离蛋白质、或含有所述序列或分离蛋白质的提取物。
根据本发明的组合物可用于治疗受益于刺激GPRC6A依赖性信号传导通路的病症。此类病症的示例包括男性性腺机能减退、骨质减少/骨质疏松症、勃起功能障碍和代谢综合征。
除了具有所示序列的肽之外，本发明还包括使用与序列P80762(SEQ ID 1)相比，显示至少75％、优选至少80％、更优选至少90％同源性的肽。例如，根据本发明，可以使用这样的肽，其中序列
Figure BDA0003153853730000031
已被氨基酸的保守取代和/或1-4个氨基酸的缺失修饰。
肽
Figure BDA0003153853730000032
及其同源物可以通过常规肽合成方法制备。或者，可以使用含有所述肽的天然来源，特别是含有所述物种的蛋白质级分的菜豆(Phaseolus vulgaris)提取物。
提取物可以从各品种的菜豆获得，所述菜豆经过合适的酶水解过程，然后用水或醇基溶剂提取。
根据本发明的组合物可以口服、经皮或肠胃外施用。
合适的施用形式的例子包括胶囊、片剂、溶液、悬浮液、凝胶、透皮贴剂等。菜豆提取物中所含的肽可以与具有互补或其他有用活性的其他成分组合，所述其他成分如维生素、氨基酸和抗氧化剂、矿物质如锌和镁盐、以及植物治疗提取物(如人参(Panaxginseng)、银杏(Ginkgo biloba)、绿茶、葡萄(Vitis vinifera)、欧洲越橘(Vacciniummyrtillus)、锯棕榈(Serenoa repens)、芦荟(Aloe vera)、菜蓟(Cynara scolymus)、枳实(Citrus aurantium)和生姜(Zingiber officinalis)。
肽的有效剂量将由技术人员在临床前和临床试验的基础上确定。剂量将取决于各种因素，例如患者疾患或病症的类型和严重程度，以及患者的体重、性别和年龄。然而，平均日剂量范围为10到1000mg的肽，或含有其的提取物的等同量。
可以从使用商业来源的芸豆粉，在INS-1大鼠胰岛瘤和MA-10小鼠Leydig细胞肿瘤细胞系上进行的体外研究中推断出根据本发明的制剂的功效。在下面的实验部分中报告的结果表明了胰岛素(图2)和睾酮(图1和3)的释放。在两种细胞系中都证实了GPRC6A的表达[Brar Diabetes.2017；De Toni Endocrinology.2014]。
以下实施例更详细地说明本发明。
实施例1从MA-10小鼠Leydig细胞肿瘤细胞培养物中释放睾酮
根据已验证的方案，使用不同的激动剂在无菌条件下、在37℃下刺激在24孔多孔板中培养至90％汇合的MA-10小鼠Leydig细胞肿瘤细胞12小时[Cormier Cell BiolToxicol.2018]。对照(CTRL)不含激动剂。结果涉及睾酮释放，表示为每μg从细胞提取物中获得的总蛋白质中睾酮(T)的ng。柱状图显示未羧化的骨钙素(OCN，3ng/mL)和肽SEQ ID1(肽，10-6M)对睾酮释放的作用。显著性：*＝P<0.05vs.CTRL。
实施例2从INS-1鼠胰岛瘤细胞培养物中释放胰岛素
根据已验证的方案，使用不同的促分泌素激动剂的组合在无菌条件下、在37℃下刺激在24孔多孔板中培养至90％汇合的INS-1大鼠胰岛瘤细胞2小时[HohmeierDiabetes.2000]。结果涉及胰岛素释放，表示为基线对照下低浓度葡萄糖(Gluc 3mM)的归一化变化。用磷酸二酯酶抑制剂IBMX(Gluc 1mM+IBMX)的刺激代表最大的促分泌素刺激和实验的阳性对照。图2a中的四个柱状图显示精氨酸(Arg，浓度范围为2.5至20mM)(一种已知的GPRC6A激动剂)对胰岛素释放的作用，而三种菜豆提取物(Ph1400179、Ph31721和Ph32046，浓度范围为0.0005至5mg/mL)的释放分别显示在图2b-d中。显著性：*、**和***＝P<0.05、0.01和0.001，分别与基线对照相比。
实施例3从MA-10小鼠Leydig细胞肿瘤细胞培养物中释放睾酮
根据已验证的方案，使用不同的激动剂在无菌条件下、在37℃下刺激在24孔多孔板中培养至90％汇合的MA-10小鼠Leydig细胞肿瘤细胞12小时[Cormier Cell BiolToxicol.2018]。对照(CTRL)不含激动剂。结果涉及睾酮释放，表示为相对于CTRL的归一化变化。图3a中的四个柱状图显示精氨酸(Arg，浓度范围为2.5至20mM)(一种已知的GPRC6A激动剂)对睾酮释放的作用，而三种菜豆提取物(Ph1400179、Ph31721和Ph32046，浓度范围为0.0005至5mg/mL)的释放分别显示在图3b-d中。显著性：*、＊＊和＊＊*＝P＜0.05、0.01和0.001，分别与基线对照相比。
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Figure IDA0003153853800000011

Claims (5)

1.药物组合物或营养组合物，其包含分离形式的具有序列NMYLPPVPPP PVVPTF的肽、或含有所述序列的分离蛋白质、或含有所述序列或分离蛋白质的提取物。
2.根据权利要求1所述的组合物，其中所述肽包含在菜豆(Phaseolus vulgaris)的提取物中。
3.根据权利要求1或2所述的组合物，进一步包含具有互补或协同活性的其他活性成分。
4.根据权利要求1-3所述的组合物，其用于治疗受益于刺激GPRC6A依赖性信号传导通路的病症的用途。
5.根据权利要求4所述的用途的组合物，其中所述病症包括男性性腺机能减退、骨质减少/骨质疏松症、勃起功能障碍和代谢综合征。
CN202080008448.1A 2019-01-10 2020-01-07 含有能够刺激gprc6a依赖性信号传导通路的肽的组合物 Pending CN113365649A (zh)

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