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他汀类药物幕后的无名英雄Alfred Alberts逝世

2018-07-08 BioArt BioArt

据《纽约时报》的一则新闻报道,美国批准的第一种降胆固醇的他汀类药物背后鲜为人知的英雄人物Alfred W. Alberts于6月16日在科罗拉多州去世,享年87岁。

据《纽约时报》的一则新闻报道,美国批准的第一种降胆固醇的他汀类药物背后鲜为人知的英雄人物Alfred W. Alberts于6月16日在科罗拉多州去世,享年87岁。

血管疾病是目前世界范围内的头号健康杀手,而血浆中胆固醇浓度升高,则是导致心脑血管疾病的主要风险之一。

在胆固醇研究的历史上,有几位关键的人物不得不提。

1964年,犹太生化学家Konrad Emil Bloch与德国科学家Feodor Lynen共同分享了诺贝尔生理学或医学奖。Bloch用同位素示踪的方法揭示了胆固醇的合成机制,而Lynen则是因为发现了乙酰辅酶A(胆固醇合成的前体)。

Bloch与Lynen之后,胆固醇代谢调控研究历史上另外两位重量级人物,德克萨斯西南医学中心的Joseph Goldstein和Michael Brown因共同揭示了胆固醇代谢调节机理而获得了1985年的诺贝尔生理学或医学奖。

Goldstein和Brown上世纪70年代的工作发现胆固醇合成的限速酶HMG辅酶A还原酶(HMG-CoA reductase)的活性受细胞培养中的血清强烈抑制,最后发现是低密度脂蛋白影响了HMG辅酶A还原酶的活性。后续他们通过对家族性高胆固醇血症(Familial hypercholeslerolemia,FH)患者的相关研究发现,低密度脂蛋白LDL是通过与细胞膜上相应的受体结合然后将胆固醇转运到细胞体内,最后抑制体内胆固醇的合成。

Michael S. Brown在Alfred Alberts去世后接受《纽约时报》记者采访时说,“他(Alfred Alberts)在Merck之外绝少由公众所知,他从未寻求过关注,他本质上是一个害羞的人”。

前文已经讲到,HMG辅酶A还原酶是胆固醇合成的限速酶,如果有一种靶向HMG辅酶A还原酶的安全化合物,那么这种化合物极有可能成为降低血液中胆固醇水平的药物。

事实上,第一个提纯到有效抑制胆固醇合成的他汀类分子的是日本制药公司Daiichi Sankyo的Akira Endo博士。 Endo早上世纪70年代早期就开始在大量的真菌中筛选抑制胆固醇合成的活性成分,后来Endo到德克萨斯西南医学中心与Goldstein和Brown合作,于1978年合作在JBC杂志发表论文证明了Endo找到的他汀类分子ML-236B能够有效抑制胆固醇的合成。

与此同时,来自Merck公司的Alberts在另一种真菌中找到了第二种他汀类分子lovastatin(洛伐他汀)能够有效抑制胆固醇的合成,该分子迅速被用于临床前研究并进入一期临床试验。

“每个药物后面都有英雄, Alberts就是洛伐他汀背后的无名英雄”,Michael S.Brown在《纽约时报》的采访中说道。

1995年Alberts在Merck。然而,接下来日本的Daiichi Sankyo停止了对他汀类分子ML-236B的所有测试,有传闻说是在狗身上进行测试时发现它导致了狗的肿瘤。因为Endo和Alberts找到的他汀类分子都是HMG辅酶A还原酶抑制剂,如果上述传闻是真的,那么对于Merck来说不啻也是一种打击。随后,默克公司相关研究负责人的P. Roy Vagelos博士(Merck制药公司前总裁,美国科学院、美国人文与科学学院、美国国家医学院三院院士,他还对中国乃至世界有着很多慈善之举)一下子停止了所有的研究。后来发现,lovastatin在高剂量下的毒性是因为HMG辅酶A还原酶被过度抑制,从而导致了一些药理反应,而lovastatin本身没有致癌性。此外,由于当时很多家族性高血脂患者急需要一些降低LDL的药物,因此,1982年Merck之外的一些研究人员对这群特殊的小人群进行了临床试验,发现lovastatin的效果很好,于是乎lovastatin就要复活了。终于,1987年,美国FDA最终批准了lovastatin用于治疗胆固醇疾病,商业名称被命名为Mevacor。这款药物,后来为Merck公司带来了巨大的收益。后来各大制药公司纷纷开发了他汀类药物,lovastatin的地位也逐渐被辉瑞、诺华、阿斯利康的药物取代了。

Alfred William Alberts于1931年5月16日出生在曼哈顿,他在陆军工作过一段时间后接受了堪萨斯大学的博士项目,两年后转到马里兰大学继续完成细胞生物学博士学位。由于给Alberts财政资助的G.I. Bill项目(Servicemen's Readjustment Act of 1944,军人安置法案)结束,因为需要更多钱维持家庭的原因,Alberts最终放弃了攻读博士学位的机会到NIH找了一份工作,尽管此时他已经完成了博士期间的实验就差撰写学位论文了。

所以,Alberts没有一个博士学位,但是最后跟随传奇人物P. Roy Vagelos博士最终找到了第一个被美国FDA批准上市的降胆固醇药物lovastatin,Alberts当之无愧可以称为他汀类药物研发领域的英雄。

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    2018-11-20 xiongliangxl
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    2018-07-23 cooco
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    2018-07-09 童小孩

    学习

    0

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    2018-07-08 惠映实验室

    学习了.谢谢分享.

    0

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    2018-07-08 zwjnj2

    好好学习天天向上认真学习

    0

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