治疗艾滋病又有新希望
赞助媒体：医药招商网 时间：2011-03-08 12:57:16
美国斯克里普斯研究所科学家最近发现了两种化合物，可作用于人类免疫缺陷病毒(HIV)蛋白酶的新的结合点位，从而为开发出疗效更好、更抗耐药性的新型艾滋病药物奠定了基础。
蛋白酶抑制剂是艾滋病治疗中广泛使用的药物之一。通常情况下，HIV蛋白酶的形状会表明它的功能。在自我复制过程中，病毒会制成一种长的蛋白链，而蛋白酶会将其碎裂为更短的片段，以使新的HIV病毒粒子最终装配成功。
蛋白酶分子两侧生有两个剪刀样的襟翼，通过襟翼的开闭来完成从长蛋白链上分离出片段的任务。目前的HIV蛋白酶药物，即是模仿HIV蛋白酶链的某些区域(如裂解位点)的形状，与蛋白酶中空部位的活性位点绑定，从而使蛋白酶失去效能，阻止HIV产生新的传染粒子。
斯克里普斯研究所亚瑟奥尔森实验室的研究助理亚历克斯佩里曼，用计算机对一种具有多重抗药性的变异HIV毒株(V82F/I84V)的运动状况进行了模拟。结果表明，抗药性蛋白酶分子的襟翼比普通蛋白酶分子的襟翼会开放更多，且更灵活。当药物进入活性位点绑定凹槽时，要关闭襟翼就需要更多的能量，而目前的药物却无法提供这些能量。其结果是药物不会停留在绑定位点，凹槽还是会被HIV蛋白链所用，从而产生新的传染粒子。
通过模拟实验，佩里曼及同事确定了解决该问题的方法。如同控制剪刀开闭需要在剪刀柄上施力一样，佩里曼设想，新药物应该能与蛋白酶两侧的可选位点绑定，从末端抑制襟翼，给抗HIV药物以足够的帮助来关闭襟翼，使蛋白酶失效。这些化合物应该是一种“变构片段”，具有小分子结构，可转变分子的力学特性。
为找到这种化合物，在过去几年里，佩里曼研究小组对数百个化合物片段进行了筛选。他们首先对分子的不同构象进行晶化处理，然后从这些晶体中筛选出一组片段，通过斯坦福同步辐射光源(SSRL)来判定它们中哪一个具有所需的结构特点。最终，研究人员发现了两个采样——片段2-甲基环乙醇和吲哚-6-羧酸。通过附加x射线结晶实验证实，这些片段的确会与蛋白酶的新位点绑定，从而会改变蛋白酶的结构偏好。
斯克里普斯研究所的助理教授C?戴维?斯托特指出，该研究能使科学家窥探到一个对抗HIV蛋白酶的全新药物设计方法。研究表明，蛋白酶分子具有两个非活性位点绑定凹槽(变构部位)，可用来开发对抗HIV的耐药性的新战略。
佩里曼则称，实验证实了计算模型假设，即HIV蛋白酶具有除活性位点外的表面凹槽，可将药物绑定。以这些位点为靶点的药物可使现在的活性位点抑制药物更有效。而将非活性位点作为药物标靶的战略对其他疾病也有效果，尤其是当存在基因突变导致抗药性出现时更是如此。这两个新化合物十分微小，仅是“片段”，因此目前还不能指望它们成为强力抑制剂。但这是一个开始，佩里曼表示，这一研究结果为开发新型的抗艾滋病药物奠定了结构基础。
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| 图示∶2010年12月即将出版的《中国特色医疗金鉴》登载的刘君主任及其机构 |
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New hope for treatment of AIDS have
Media Sponsor: Pharmaceutical Investment Network Time :2011-03-08 12:57:16
Scripps Institute of American Scientists recently discovered that two compounds can act on the human immunodeficiency virus (HIV) protease combination of the new points, so as to effect the development of better, more resistant to new anti-AIDS drugs to lay the foundation.
Protease inhibitors are widely used in AIDS treatment drugs. Under normal circumstances, HIV protease shape that its function. In the process of self-replication, the virus made a long protein chain, and protease for the shorter will be the broken fragments, so that the new final assembly of the HIV virus particles successfully.
Protease molecules had two scissors-like on both sides of the flap, through the flaps of the opening and closing to complete the protein chain from the long task of isolated fragments. The current HIV protease drugs, that is, imitation of certain areas of HIV protease chain (such as the cleavage site) shape, and hollow parts of the protease active site binding, so that the protease ineffective to prevent the spread of HIV to generate new particles.
Arthur Olson, Scripps Research Institute research assistant Alex 克斯佩里曼 laboratory, using a computer with multiple drug-resistant variant HIV strains (V82F/I84V), the movement of simulated. The results showed that resistance to protease molecules flap flap than the average protein molecule may open up more, and more flexible. When the drug into the active site binding groove, we should close the flap on the need for more energy, and the current drugs can not provide the energy. The result is that drugs will not remain in the binding sites, the groove will still be HIV protein chains used to generate new infectious particles.
Through simulation experiments, Perryman and colleagues determined to solve the problem. Control the opening and closing like scissors on the force needs to handle, like scissors, Perryman ideas, new drugs should be optional on both sides with the protease binding site from the end of the inhibition of the flap, to the anti-HIV drugs for enough help to close the flap, so that protease failure. These compounds should be an "allosteric fragments", with a small molecular structure, can change the mechanical properties of molecules.
To find the compound, in the past few years, Perryman Study Group on the hundreds of compounds were screened fragments. They first molecules of different conformation crystallization treatment, and these crystals were selected from a group of fragments, through the Stanford Synchrotron Radiation Light Source (SSRL) to determine which of them has the required structural characteristics. Eventually, the researchers found that two samples - segments 2 - methyl alcohol and indole ring -6-- acid. By additional x-ray crystallography experiments confirmed that these fragments do with the new protease binding sites, which will change the structure of protease preference.
Scripps Research Institute Assistant Professor C? David? Stout pointed out that the research enable scientists a glimpse into a new fight against HIV protease drug design methods. Studies have shown that protease molecule with two non-active site binding groove (allosteric site), can be used to develop drug resistance against HIV, the new strategy.
Perryman called experimental model confirmed the hypothesis that the HIV protease active site with the addition to the surface outside the groove, you can bind the drug. To target these sites for the drug could inhibit the active site of the current drugs more effective. The non-active site as a drug target strategy is also effective against other diseases, especially when there is mutation causes resistance to emerge even more so. The two new compounds is very small, only a "fragment", so currently can not expect them to become potent inhibitors. But this is a start, Perryman said the results of this study for the development of new anti-AIDS drugs laid the structural foundation.
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