Nat Struc Mole Bio:蜗牛的“致命毒液”成“救命良药”,迄今最小胰岛素有望彻底治疗糖尿病

2020-06-04 竹子 转化医学网

导言:海洋生物锥形蜗牛(鸡心螺,cone snail),迅速射出的毒液可让受伤者一命呼呜。来自美国和澳大利亚的研究人员利用其“迅雷不及掩耳之势”,作为新药“缪斯&r

导言:海洋生物锥形蜗牛(鸡心螺,cone snail),迅速射出的毒液可让受伤者一命呼呜。来自美国和澳大利亚的研究人员利用其“迅雷不及掩耳之势”,作为新药“缪斯”,希望利用从毒液中提取的胰岛素开发一种新的速效胰岛素,来彻底治疗糖尿病。


锥形蜗牛用毒液麻痹鱼,然后吞食它的全过程。科学家发现,那些受害的小鱼儿在死亡之前并没有什么痛苦,于是灵机一动,提取毒素的麻醉剂制成了止痛药,一开始就在治疗癌症上小有建树。

发现胰岛素将近一个世纪之后,由美国犹他大学健康研究所(U of U Health)的科学家领导的国际研究小组开发出了结构最小但功能齐全的胰岛素。它基于捕鱼的锥形蜗牛产生的速效毒液胰岛素,同时也显示出人类胰岛素的全部功能,并与人胰岛素受体(hIR)结合。在啮齿动物中进行的测试表明,微型胰岛素(Mini-Ins)具有与人胰岛素相似的生物活性。研究人员声称,微型胰岛素是个不错的跳板,能开发速效胰岛素,改善糖尿病患者生活。研究结果发表在《自然-结构与分子生物学》期刊上。

 

锥形蜗牛,主要是生活在印度洋、太平洋以及大西洋西部。对于锥形蜗牛毒液的研究在2011年就有媒体报道,它的毒性是非常明显的,仅一滴毒液便足以杀死20人。当在珊瑚礁上狩猎时,锥形蜗牛会向周围水体释放一种含有独特形式胰岛素的致命毒液。速效胰岛素能让鱼的血糖水平迅速下降,导致暂时性麻痹,使蜗牛有时间从其外壳中出来,并吞下猎物。


对南太平洋所罗门群岛附近的水肺潜水员收集的锥形蜗牛进行分类。

早期研究中,研究人员发现,这种毒液胰岛素具有许多跟人胰岛素相同的生化特征。它似乎比目前可用的起效最快的人胰岛素还要快。这提供了一个独特的机会,来研究可影响猎物葡萄糖稳态的速效天然蛋白质的药理潜力。

哥本哈根大学生物医学科学助理教授海伦娜·萨法维(Helena Safavi)博士表示,一种用于治疗糖尿病患者的速效胰岛素,可以降低高血糖和其他严重并发症的风险。它还可以改善胰岛素泵或人工胰腺装置的性能,后者可以根据需要自动将胰岛素释放到体内。他们希望能帮助糖尿病患者更快速地控制血糖。

研究人员发现,源自锥形蜗牛毒液胰岛素缺乏“铰链”成分,该成分会导致人类胰岛素聚集在一起,因此可以储存在胰腺中。这些聚集体必须分解成单个分子,然后才能开始作用于血糖,这个过程可能需要一个小时。由于锥形蜗牛胰岛素是单体性且不会聚集,因此它可以有效地准备好,并可以立即使用。

这引起了研究人员的兴趣,于是开始研究锥形蜗牛毒胰岛素的天然蛋白,Con-Ins-G1,将其转变为可以用来快速恢复1型糖尿病患者体内葡萄糖水平。由于患者皮下注射胰岛素的单体制剂时可以更快吸收,因此一个关键问题是,如何使Con-Ins–G1抗hIR活性的结构特征转移到人胰岛素主链上,从而产生速效治疗性胰岛素类似物。

因此,他们试图从蜗牛中获取一些有利的特性,并将其嫁接到人类化合物上。这在概念上是可行的,因为锥形蜗牛胰岛素本质上具有人类胰岛素那样的基本结构骨架。然而,一个缺点是天然蜗牛胰岛素的效力远低于人胰岛素。研究人员怀疑,人类需要比锥形蜗牛胰岛素多20至30倍才能降低血糖水平。

最近的研究努力克服了这一问题。首先,他们利用结构生物学和药物化学技术,来分离四种有助于蜗牛胰岛素与胰岛素受体结合的氨基酸。然后,他们创建了没有结块的人类胰岛素分子的截短形式。该团队将这些氨基酸的修饰形式整合到人类分子中,希望创建一种不会结块并高效结合人胰岛素受体的杂交体。

在实验室小鼠的测试中,所得的混合型微型胰岛素分子,用锥形蜗牛胰岛素不具备的方式,跟胰岛素受体相互作用。结果表明,通过微型胰岛素可以实现与胰岛素受体的另一种结合模式(其特征在于较弱的一级结合位点相互作用和较强的二级结合位点相互作用)。这些新的相互作用结合了微型胰岛素与跟正常人的胰岛素一样强的小鼠体内的胰岛素受体,因此这种微型胰岛素的功效与人胰岛素相同,但作用更快,也没有证据表明这种分子会触发免疫系统反应。微型胰岛素也未产生抗体应答,表明这四种突变并未改变小鼠中人胰岛素的免疫原性。鉴于其单体特性,微型胰岛素代表了餐前胰岛素治疗开发的新平台。

总而言之,微型胰岛素具有巨大的潜力。这是迄今为止最小的完全活性的胰岛素。由于它很小,因此易于合成,成为新一代胰岛素治疗剂开发的主要候选者。

原始出处:

Xiaochun Xiong, John G. Menting, Maria M. Disotuar, et.al. A structurally minimized yet fully active insulin based on cone-snail venom insulin principles. Nature Structural & Molecular Biology 01 June 2020

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    2021-02-02 sunylz
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    2020-08-12 日月
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    2020-08-12 liye789132251
  4. [GetPortalCommentsPageByObjectIdResponse(id=1919082, encodeId=da991919082c5, content=<a href='/topic/show?id=4f26341994' target=_blank style='color:#2F92EE;'>#Bio#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3419, encryptionId=4f26341994, topicName=Bio)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=12de429, createdName=sunylz, createdTime=Tue Feb 02 10:36:11 CST 2021, time=2021-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1795148, encodeId=54dc1e9514895, content=<a href='/topic/show?id=1c9f16846fe' target=_blank style='color:#2F92EE;'>#Struc#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16846, encryptionId=1c9f16846fe, topicName=Struc)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4a4d285, createdName=日月, createdTime=Wed Aug 12 07:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1884363, encodeId=6dbe18843631b, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Wed Aug 12 11:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1750153, encodeId=29231e50153ed, content=<a href='/topic/show?id=be7c8385345' target=_blank style='color:#2F92EE;'>#胰岛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83853, encryptionId=be7c8385345, topicName=胰岛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a7a536274692, createdName=baoya, createdTime=Thu Feb 25 14:36:11 CST 2021, time=2021-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1573190, encodeId=570715e3190f3, content=<a href='/topic/show?id=8f1788812b4' target=_blank style='color:#2F92EE;'>#蜗牛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88812, encryptionId=8f1788812b4, topicName=蜗牛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7d4c15829007, createdName=xfpan17, createdTime=Sat Jun 06 01:36:11 CST 2020, time=2020-06-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=601450, encodeId=ba05601450ad, content=厉害, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=lifefamily@163, createdTime=Thu Jun 04 23:35:31 CST 2020, time=2020-06-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1043146, encodeId=531b104314620, content=谢谢MedSci提供最新的资讯, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=misszhang, createdTime=Thu Jun 04 13:36:11 CST 2020, time=2020-06-04, status=1, ipAttribution=)]
    2021-02-25 baoya
  5. [GetPortalCommentsPageByObjectIdResponse(id=1919082, encodeId=da991919082c5, content=<a href='/topic/show?id=4f26341994' target=_blank style='color:#2F92EE;'>#Bio#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3419, encryptionId=4f26341994, topicName=Bio)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=12de429, createdName=sunylz, createdTime=Tue Feb 02 10:36:11 CST 2021, time=2021-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1795148, encodeId=54dc1e9514895, content=<a href='/topic/show?id=1c9f16846fe' target=_blank style='color:#2F92EE;'>#Struc#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16846, encryptionId=1c9f16846fe, topicName=Struc)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4a4d285, createdName=日月, createdTime=Wed Aug 12 07:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1884363, encodeId=6dbe18843631b, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Wed Aug 12 11:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1750153, encodeId=29231e50153ed, content=<a href='/topic/show?id=be7c8385345' target=_blank style='color:#2F92EE;'>#胰岛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83853, encryptionId=be7c8385345, topicName=胰岛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a7a536274692, createdName=baoya, createdTime=Thu Feb 25 14:36:11 CST 2021, time=2021-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1573190, encodeId=570715e3190f3, content=<a href='/topic/show?id=8f1788812b4' target=_blank style='color:#2F92EE;'>#蜗牛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88812, encryptionId=8f1788812b4, topicName=蜗牛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7d4c15829007, createdName=xfpan17, createdTime=Sat Jun 06 01:36:11 CST 2020, time=2020-06-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=601450, encodeId=ba05601450ad, content=厉害, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=lifefamily@163, createdTime=Thu Jun 04 23:35:31 CST 2020, time=2020-06-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1043146, encodeId=531b104314620, content=谢谢MedSci提供最新的资讯, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=misszhang, createdTime=Thu Jun 04 13:36:11 CST 2020, time=2020-06-04, status=1, ipAttribution=)]
    2020-06-06 xfpan17
  6. [GetPortalCommentsPageByObjectIdResponse(id=1919082, encodeId=da991919082c5, content=<a href='/topic/show?id=4f26341994' target=_blank style='color:#2F92EE;'>#Bio#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3419, encryptionId=4f26341994, topicName=Bio)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=12de429, createdName=sunylz, createdTime=Tue Feb 02 10:36:11 CST 2021, time=2021-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1795148, encodeId=54dc1e9514895, content=<a href='/topic/show?id=1c9f16846fe' target=_blank style='color:#2F92EE;'>#Struc#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16846, encryptionId=1c9f16846fe, topicName=Struc)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4a4d285, createdName=日月, createdTime=Wed Aug 12 07:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1884363, encodeId=6dbe18843631b, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Wed Aug 12 11:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1750153, encodeId=29231e50153ed, content=<a href='/topic/show?id=be7c8385345' target=_blank style='color:#2F92EE;'>#胰岛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83853, encryptionId=be7c8385345, topicName=胰岛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a7a536274692, createdName=baoya, createdTime=Thu Feb 25 14:36:11 CST 2021, time=2021-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1573190, encodeId=570715e3190f3, content=<a href='/topic/show?id=8f1788812b4' target=_blank style='color:#2F92EE;'>#蜗牛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88812, encryptionId=8f1788812b4, topicName=蜗牛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7d4c15829007, createdName=xfpan17, createdTime=Sat Jun 06 01:36:11 CST 2020, time=2020-06-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=601450, encodeId=ba05601450ad, content=厉害, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=lifefamily@163, createdTime=Thu Jun 04 23:35:31 CST 2020, time=2020-06-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1043146, encodeId=531b104314620, content=谢谢MedSci提供最新的资讯, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=misszhang, createdTime=Thu Jun 04 13:36:11 CST 2020, time=2020-06-04, status=1, ipAttribution=)]
    2020-06-04 lifefamily@163

    厉害

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=1919082, encodeId=da991919082c5, content=<a href='/topic/show?id=4f26341994' target=_blank style='color:#2F92EE;'>#Bio#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3419, encryptionId=4f26341994, topicName=Bio)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=12de429, createdName=sunylz, createdTime=Tue Feb 02 10:36:11 CST 2021, time=2021-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1795148, encodeId=54dc1e9514895, content=<a href='/topic/show?id=1c9f16846fe' target=_blank style='color:#2F92EE;'>#Struc#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16846, encryptionId=1c9f16846fe, topicName=Struc)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4a4d285, createdName=日月, createdTime=Wed Aug 12 07:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1884363, encodeId=6dbe18843631b, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Wed Aug 12 11:36:11 CST 2020, time=2020-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1750153, encodeId=29231e50153ed, content=<a href='/topic/show?id=be7c8385345' target=_blank style='color:#2F92EE;'>#胰岛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83853, encryptionId=be7c8385345, topicName=胰岛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a7a536274692, createdName=baoya, createdTime=Thu Feb 25 14:36:11 CST 2021, time=2021-02-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1573190, encodeId=570715e3190f3, content=<a href='/topic/show?id=8f1788812b4' target=_blank style='color:#2F92EE;'>#蜗牛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88812, encryptionId=8f1788812b4, topicName=蜗牛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7d4c15829007, createdName=xfpan17, createdTime=Sat Jun 06 01:36:11 CST 2020, time=2020-06-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=601450, encodeId=ba05601450ad, content=厉害, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=lifefamily@163, createdTime=Thu Jun 04 23:35:31 CST 2020, time=2020-06-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1043146, encodeId=531b104314620, content=谢谢MedSci提供最新的资讯, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=misszhang, createdTime=Thu Jun 04 13:36:11 CST 2020, time=2020-06-04, status=1, ipAttribution=)]
    2020-06-04 misszhang

    谢谢MedSci提供最新的资讯

    0

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