CN115554403A - 类固醇激素dhea作为受体adgrg2激动剂配体的应用 - Google Patents
类固醇激素dhea作为受体adgrg2激动剂配体的应用 Download PDFInfo
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Abstract
本发明提供类固醇激素DHEA作为受体ADGRG2激动剂配体的应用,属于生物工程和生物医药技术领域。本发明通过研究发现,类固醇激素DHEA可作为孤儿受体ADGRG2的内源性配体,从而有效激活ADGRG2产生Gs信号,表明类固醇激素DHEA可构成开发男性生殖***疾病诊断和/或治疗药的基础,因此具有良好的实际应用之价值。
Description
技术领域
本发明属于生物工程和生物医药技术领域,具体涉及类固醇激素DHEA作为受体ADGRG2激动剂配体的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
G蛋白偶联受体是人类基因组中最大的膜受体家族和药物靶点,约有30%被批准的药物是通过结合GPCR并调控细胞内信号起作用的。其中粘附类G蛋白偶联受体(aGPCRs)是GPCR中的第二大家族,一共有33个成员。所有的aGPCRs除了具有经典的七次跨膜结构,还有一些独特的特征,都具有很长且具有粘附类潜力的N端,N端都包括一个经诱导的可自水解的近膜结构域(Hamann et al.,2015)。粘附类受体的突变与许多人类疾病相关,比如粘附类受体ADGRV1和LPHN2/3分别对耳蜗毛细胞存活和兴奋性突触形成至关重要,ADGRF5通过Gq信号介导肺泡表面活性剂稳态,ADGRG6通过下游的Gs信号调控骨骼发育等。aGPCR已经与各种不同疾病联系在一起,并调节整个身体的许多重要生理过程,因此aGPCR家族在药物发现方面具有巨大的潜力。
ADGRG2(粘附类G蛋白偶联受体G2),也被称为GPR64或人附睾特异性蛋白6(HE6),ADGRG2在人和小鼠的附睾和输出小管高表达,并且在调节雄性生殖功能方面具有重要作用。文献报道,ADGRG2的敲除可导致输出小管中液体重吸收失调,从而导致雄性不育(Davies et al.,2004)。张道来的研究进一步阐明了ADGRG2和Gq在β-arrestin-1的帮助下与阴离子通道CFTR共定位在输出小管的特异性结构顶膜上,形成区域性信号转导复合物,并构成了快速的GPCR-离子通道的偶联,从而精确调控非纤毛细胞的氯离子电流以及小管的重吸收过程。在体外过表达ADGRG2可以引起Gs和Gq组成性活力。然而ADGRG2的内源性配体目前并未发现。
脱氢表雄酮(DHEA)是一种天然产生的C-19肾上腺类固醇(5-雄甾烷-3β-ol-17-1),来源于胆固醇(Webb et al.,2006)。脱氢表雄酮主要由人类和其他灵长类动物肾上腺皮质的网状带分泌。肾上腺皮质每天分泌75-90%的脱氢表雄酮,其余的由睾丸和卵巢产生。DHEA 3β-硫酸脱氢表雄酮(DHEA-S)是一种亲水存储形式,在血液中循环(Baulieu,2002)。DHEAS可以通过脱氢表雄酮磺基转移酶和羟类固醇硫酸盐酶与脱氢表雄酮相互转化(Baulieu,2002)。DHEA和DHEAS是人体最丰富的固醇类激素,在血液中的浓度高于其他类固醇,是一种潜在的雄激素。目前DHEA被越来越多地用于体外受精(IVF)低卵巢功能妇女的治疗,有报道称它能有效提高妊娠率和胚胎质量,同时降低流产率(Arlt et al.,1999;shohatt-tal等人,2015;杨等,2020a)。然而对DHEA的生理活性有待进一步研究。
发明内容
针对现有技术存在的问题,本发明提供类固醇激素DHEA作为受体ADGRG2激动剂配体的应用。本发明通过研究发现,类固醇激素DHEA可作为孤儿受体ADGRG2的内源性配体,从而有效激活ADGRG2产生Gs信号,表明类固醇激素DHEA可构成开发男性生殖***疾病诊断和/或治疗药的基础,因此具有良好的实际应用之价值。
具体的,本发明涉及以下技术方案:
本发明的第一个方面,提供ADGRG2调节化合物在制备诊断和/或治疗男性生殖***相关疾病药物中的用途。
所述男性生殖***相关疾病包括但不限于弱精症、死精症、附睾淤积症、伴***和男性不育。
其中,所述ADGRG2调节化合物是受体ADGRG2激动剂或受体ADGRG2诱导表达剂。
进一步的,所述ADGRG2激动剂包括激活ADGRG2的配体、多肽、抗体或小分子化合物。
所述配体包括类固醇激素DHEA。
本发明的第二个方面,提供脱氢表雄酮在作为受体ADGRG2激动剂配体中的应用。
本发明的第三个方面,提供一种药物组合物,其包含上述脱氢表雄酮或其溶剂化物或其药学上可接受的盐。
以及,一种药物制剂,其包含上述脱氢表雄酮或其溶剂化物或其药学上可接受的盐,和至少一种药学上可接受的辅料和/或载体。
本发明的第四个方面,提供上述DHEA或其溶剂化物或其药学上可接受的盐或者上述药物组合物或药物制剂在制备ADGRG2激活剂药物或试剂中的应用。
本发明的第五个方面,提供上述DHEA或其溶剂化物或其药学上可接受的盐或者上述药物组合物或药物制剂在制备与ADGRG2异常表达相关疾病的药物或试剂中的应用。
本发明的第六个方面,提供一种治疗ADGRG2异常表达相关疾病的方法,其包括向受试者施用治疗有效量的DHEA或所述药物组合物或药物制剂。
以上一个或多个技术方案的有益技术效果:
1.现有研究提供了粘附类受体ADGRG2对调控雄性生殖***输出小管液体重吸收,为***不育地治疗提供了潜在的药物靶点。上述技术方案研究结果揭示了粘附类受体ADGRG2与男性生殖***疾病在机制层面的关系,为黏附类受体作为男性生殖***疾病治疗靶点的应用提供了可靠的依据。
2.上述技术方案提供了粘附类受体ADGRG2的内源性配体类固醇激素的名称和化合物结构式,通过与ADGRG2的特异性结合并介导了Gs信号通路,提供了较为明确的调控机制,为类固醇激素在男性生殖***疾病中的应用提供了相应的指导作用,同时具有良好的实际应用之价值。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明实施例1中类固醇激素DHEA诱导的粘附类受体ADGRG2的胞外端构型变化dose曲线效果图;
图2为本发明实施例1中类固醇激素DHEA诱导的粘附类受体ADGRG2的胞外端构型变化程度效果图;
图3为本发明实施例1中类固醇激素DHEA激活鼠源和人源粘附类受体ADGRG2的Gs信号通路效果图;
图4为本发明实施例1中类固醇激素DHEA诱导的粘附类受体ADGRG2介导的野生型和ADGRG2敲除小鼠的输出小管原代细胞CFTR电流升高图。
图5为本发明实施例1中类固醇激素DHEA诱导的过表达粘附类受体ADGRG2和CFTR或单独表达CFTR的HEK293细胞的CFTR电流升高图。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本申请提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本申请的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。下列具体实施方式中如果未注明具体条件的实验方法,通常按照本领域技术内的分子生物学的常规方法和条件,这种技术和条件在文献中有完整解释。参见例如Sambrook等人,《分子克隆:实验手册》中所述的技术和条件,或按照制造厂商所建议的条件。
如前所述,粘附类受体ADGRG2在输出小管和附睾中特异性高表达,对男性生殖***功能具有重要调节作用。发明人前期研究表明粘附类受体ADGRG2在小鼠输出小管上与CFTR偶联,调控小管内液重吸收。
有鉴于此,本发明提供一种类固醇激素DHEA,该激素可作为粘附类受体ADGRG2的内源性配体,能够有效激活ADGRG2产生Gs信号,有希望成为男性生殖***疾病的治疗药物。
本发明的一个具体实施方式中,提供ADGRG2调节化合物在制备诊断和/或治疗男性生殖***相关疾病药物中的用途。
本发明的又一具体实施方式中,所述男性生殖***相关疾病包括但不限于弱精症、死精症、附睾淤积症、伴***和男性不育。
本发明的又一具体实施方式中,所述ADGRG2调节化合物是受体ADGRG2激动剂或受体ADGRG2诱导表达剂。
本发明的又一具体实施方式中,所述ADGRG2激动剂包括激活ADGRG2的配体、多肽、抗体或小分子化合物。
本发明的又一具体实施方式中,所述配体包括类固醇激素DHEA。
本发明的又一具体实施方式中,提供脱氢表雄酮在作为受体ADGRG2激动剂配体中的应用。
本发明的又一具体实施方式中,提供一种药物组合物,其包含上述脱氢表雄酮或其溶剂化物或其药学上可接受的盐。
以及,一种药物制剂,其包含上述脱氢表雄酮或其溶剂化物或其药学上可接受的盐,和至少一种药学上可接受的辅料和/或载体。
本发明所述辅料是指药物组合物或药物制剂中除有效成分之外的成分,其对受试者无毒。本领域常用的辅料比如缓冲剂、稳定剂、防腐剂或赋型剂,常用的赋形剂例如粘合剂、填充剂、润湿剂、崩解剂等。
作为示例,本发明的所述制剂中可选用的赋形剂包括但不限于:所述赋形剂选自磷酸钙、硬脂酸镁、滑石粉、糊精、淀粉、凝胶纤维素、甲基纤维素、羧甲基纤维素钠盐和聚乙烯吡咯烷酮。
本发明所述药物载体可以是药学上可接受的溶剂、悬浮剂、囊泡、纳米材料等,用于将递送至动物或人体内。载体可以是液体或固体,并按照计划的给药方式进行选择,同时,蛋白和脂质体也是药物载体。
本领域技术人员可采用公知的技术将本发明的化合物配制成药物组合物或制剂。比如将本发明上述DHEA与药用辅料混合,然后如果需要,使所得混合物形成所需的形状。以及,除本发明提到的以外,合适的药用辅料是本领域已知的,例如参见2005年版的药用辅料手册(原著第四版),作者(英)R.C.罗(RaymondCRowe)(美)P.J.舍斯基(PaulJSheskey)。
本发明的又一具体实施方式中,提供上述DHEA或其溶剂化物或其药学上可接受的盐或者上述药物组合物或药物制剂在制备ADGRG2激活剂药物或试剂中的应用。
本发明的又一具体实施方式中,提供上述DHEA或其溶剂化物或其药学上可接受的盐或者上述药物组合物或药物制剂在制备与ADGRG2异常表达相关疾病的药物或试剂中的应用。
本发明的又一具体实施方式中,所述ADGRG2异常表达相关疾病包括男性生殖***相关疾病,进一步包括包括但不限于弱精症、死精症、附睾淤积症、伴***和男性不育。
本发明的又一具体实施方式中,提供一种治疗ADGRG2异常表达相关疾病的方法,其包括向受试者施用治疗有效量的DHEA或所述药物组合物或药物制剂。
本发明所述受试者是指已经是治疗、观察或实验的对象的动物,优选指哺乳动物,最优选指人,所述受试者为雄(男)性。
本发明所述治疗有效量是指包括本发明化合物在内的活性化合物或药物制剂的量,该量可引起研究者、兽医、医生或其他医疗人员所追求的组织***、动物或人的生物学或医学响应,所述响应包括减轻或部分减轻所述治疗疾病、综合征、病症或障碍的症状。
本领域的研究者、兽医、医生或其他医疗人员可根据临床试验或者本领域其他公知的手段获知可使用的治疗有效量的范围。
所述ADGRG2异常表达相关疾病包括男性生殖***相关疾病,进一步包括包括但不限于弱精症、死精症、附睾淤积症、伴***和男性不育。
以下通过实施例对本发明做进一步解释说明,但不构成对本发明的限制。应理解这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1类固醇激素DHEA特异性结合ADGRG2并激活ADGRG2下游信号通路,并调控ADGRG2在输出小管中的功能实验步骤:
1.从阿拉丁试剂官网购买商业化类固醇激素DHEA。
2.采用分子生物学方法,构建基因重组的鼠源ADGRG2重组质粒,以HEK293细胞过表达鼠ADGRG2,给予DHEA刺激,利用ADGRG2N端的Nluc基团和胞外环上的Flash基团的生物发光共振能量转移方法可以检测DHEA诱导的ADGRG2自身构型变化程度,以生物发光功能能量转移的程度反映DHEA与ADGRG2的特异性结合。
3.以HEK293细胞过表达人源或鼠源ADGRG2,利用Glosensor方法可以检测第二信使cAMP的原理,以激动剂DHEA刺激细胞检测胞内cAMP的浓度,以引起细胞内cAMP浓度增加的程度来表征ADGRG2激活Gs信号通路的情况。
4.前期研究证明粘附类受体ADGRG2和囊性纤维化跨膜传导调节因子(CFTR)在输出小管非纤毛细胞顶膜共定位,并且ADGRG2介导CFTR的电流。分离野生鼠和敲除鼠的输出小管单细胞并用腺病毒ADGRG2-promoter-RFP-labeled病毒感染。给予不同浓度的DHEA刺激原代细胞,电生理手段记录ADGRG2-promoter-RFP-labeled细胞的电流。
5.HEK293细胞过表达人源或鼠源ADGRG2与CFTR或单独过表达CFTR,用不同浓度的DHEA刺激,电生理手段记录两种细胞的全细胞电流。
将DHEA用PBS配制成工作浓度为10-8M、10-7M、10-6M、10-5.5M、10-5M、10-4.5M、10-4M,在过表达Nluc-ADGRG2-ECL1/2/3-Flash的细胞中,用底物Flash-EDT2 37℃恒温孵育40分钟,之后PBS清洗两次,再给予不同浓度的DHEA刺激,利用多功能酶标仪实时记录荧光值,对结果进行统计分析作图,结果见图1。
将DHEA用PBS配制成工作浓度为10-8M、10-7M、10-6M、10-5.5M、10-5M、10-4.5M、10-4M,在过表达人或鼠ADGRG2和Glosensor的HEK293细胞中,给予不同浓度的配体刺激,阴性对照为表达空载体pcDNA和Glosensor的HEK293细胞,利用多功能酶标仪实时记录荧光值,对结果进行统计分析作图,结果见图2。
将野生鼠和ADGRG2全身敲除小鼠脱颈处死,分离输出小管,胶原酶消化半小时并打散成单细胞,用腺病毒ADGRG2-promoter-RFP-labeled病毒感染,48h后消化原代细胞至24mm×24mm的玻片上,12h原代细胞贴壁后,取细胞玻片至荧光显微镜的载物台上,给予不同浓度的DHEA刺激,挑选发红色荧光的原代细胞用HEKA EPC10双探头放大器记录全细胞电流,结果见图3和图4。
体外用HEK293细胞检测DHEA诱导的CFTR电流的变化,将DHEA用PBS配制成工作浓度为10-8M、10-7M、10-6M、10-5.5M、10-5M、10-4.5M、10-4M,在共表达人或鼠ADGRG2与CFTR或单独过表达CFTR的HEK293细胞中,给予不同浓度的配体刺激,用HEKA EPC10双探头放大器记录全细胞电流,结果见图5。
实验结果表明,DHEA能够特异性地结合黏附类受体ADGRG2,并且诱导胞外环ECL2的变化的半数有效浓度是25uM;DHEA刺激黏附类受体ADGRG2能够产生Gs通路,其中人源和鼠源半数有效浓度各是11uM和2uM;DHEA可以诱导野生鼠和共表达人或鼠ADGRG2和CFTR的HEK293细胞中的CFTR电流增加,对全敲ADGRG2鼠原代细胞和单独过表达CFTR的HEK293细胞没有作用,原代细胞中DHEA诱导ADGRG2介导的CFTR电流增加的半数有效浓度是14.2uM,体外过表达体系DHEA诱导的人或鼠ADGRG2介导的CFTR电流增加的半数有效浓度分别是19.6uM和2.1uM。
上述实验结果表明本实施例中提供的类固醇化合物DHEA能够靶向ADGRG2成为其特异性配体,并能够有效激活ADGRG2,产生Gs信号通路。从而,本本发明提供了有前景的化合物,可构成干预男性生殖疾病诊断和治疗药物的基础。
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.ADGRG2调节化合物在制备诊断和/或治疗男性生殖***相关疾病药物中的用途;
所述ADGRG2调节化合物是受体ADGRG2激动剂或受体ADGRG2诱导表达剂。
2.如权利要求1所述应用,其特征在于,所述男性生殖***相关疾病包括弱精症、死精症、附睾淤积症、伴***和男性不育。
3.如权利要求1所述应用,其特征在于,所述ADGRG2激动剂包括激活ADGRG2的配体、多肽、抗体或小分子化合物;
优选的,所述配体包括类固醇激素DHEA。
4.脱氢表雄酮在作为受体ADGRG2激动剂配体中的应用。
5.一种药物组合物,其特征在于,其包含脱氢表雄酮或其溶剂化物或其药学上可接受的盐。
6.一种药物制剂,其特征在于,其包含脱氢表雄酮或其溶剂化物或其药学上可接受的盐,和至少一种药学上可接受的辅料和/或载体。
7.如权利要求6所述的药物制剂,其特征在于,所述辅料包括缓冲剂、稳定剂、防腐剂或赋型剂。
8.DHEA或其溶剂化物或其药学上可接受的盐或者权利要求5所述药物组合物或权利要求7或8所述药物制剂在制备ADGRG2激活剂药物或试剂中的应用。
9.DHEA或其溶剂化物或其药学上可接受的盐或者权利要求5所述药物组合物或权利要求7或8所述药物制剂在制备与ADGRG2异常表达相关疾病的药物或试剂中的应用;
优选的,所述ADGRG2异常表达相关疾病包括男性生殖***相关疾病,进一步包括弱精症、死精症、附睾淤积症、伴***和男性不育。
10.一种治疗ADGRG2异常表达相关疾病的方法,其特征在于,所述方法包括向受试者施用治疗有效量的DHEA或权利要求5所述药物组合物或权利要求7或8所述药物制剂。
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