跳动城乡网如今，人们对引人注目的新医疗疗法议论纷纷，例如利用改良免疫细胞或抗体进行个性化癌症治疗。然而，此类治疗非常复杂且昂贵，因此应用范围有限。大多数医疗疗法仍然基于可以大量生产且成本低廉的小分子化合物。
开发新分子疗法的瓶颈在于，使用现有技术可以找到的新活性物质数量有限。哈佛大学和苏黎世联邦理工学院在 21 世纪开发出了一种有望提供补救措施的方法：DNA 编码化学库 (DEL)。
到目前为止，DEL 技术可用于一次性生产数百万种化合物并测试其有效性。然而，这种方法的缺点是研究人员只能从少数化学构件中构建小分子。苏黎世联邦理工学院的化学家们现在已经改进并显著改善了这一工艺。
借助发表在《科学》杂志上的新方法，研究人员现在可以在几周内自动合成和测试数十亿种不同的物质，而不仅仅是几百万种。该方法还可用于生产更大的药物分子，例如环状肽，可用于对其他药理学目标。
创建并测试所有组合
“借助早期 DEL 技术开发的首批活性物质目前正处于高级临床试验阶段。这种新的 DEL 方法再次极大地扩展了可能性，”Jörg Scheuermann 解释道。
他和他在药物科学研究所的研究小组是 DEL 技术的先驱之一，该技术被认为是在实践中利用分子化学生产中的组合可能性的关键。
The aim of combinatorial chemistry is to produce as many molecular variants as possible from individual building blocks. From all these combinations, the researchers fish out those that demonstrate the desired activity. The number of different molecules grows exponentially with the number of synthesis cycles and with the number of different building blocks that are combined in each synthesis cycle.
Using DNA code to identify the active molecules
For researchers to be able to identify the individual active compounds in the rapidly growing "molecular soup" in efficacy tests, the DEL method attaches a defined short fragment of DNA to the molecule in parallel with each active-ingredient building block. This creates a unique DNA sequence as a readable barcode for each combination of building blocks.
For example, the entire soup of molecules can be tested for its ability to bind to a specific protein, and individual DNA segments can be amplified and clearly identified using the PCR (polymerase chain reaction) technique familiar from COVID tests.
Preventing exponential growth of contamination
Chemical reality, however, has thus far severely limited the possibilities of DEL technology. The process of linking the DNA fragments with the chemical building blocks is invariably reliable, but the effectiveness with which those building blocks link together chemically varies depending on the combination. As a result, the DNA code loses its uniqueness.
The same code can refer not just to the complete molecule with all building blocks, but also to truncated variants containing only some of the building blocks. These impurities also increase exponentially with each round of synthesis. In practice, this has limited the manageable size of DEL libraries to combinations of three to four connected blocks and thus to several million different compounds.
Self-purification built in
Scheuermann's research team have now found a way to prevent the increasing contamination of the molecular library: to purify the DEL that has been synthesized down to the very last building block. The ETH researchers' method is based on two main parts.
First, synthesis of the molecules is coupled to magnetic particles that can be handled easily and automatically. This enables washing cycles, among other things. Second, the team introduced a second chemical coupling component on the particles that can bind only to the last of the planned building blocks.
All truncated molecules that are missing, say, the last building block, can be removed in a single washing step. In the end, the library has only those molecules that contain all the building blocks specified in the DNA code.
Conflict with combinatorial chemistry
虽然这种方法在纸面上看起来很优雅，但实施起来却很困难，正如 Scheuermann 所说，“找到不干扰 DNA 片段酶促偶联的磁性粒子尤其具有挑战性。在博士项目过程中，我团队的 Michelle Keller 和 Dimitar Petrov 投入了大量的时间和精力来确保该方法可靠地发挥作用。”
在粒子上进行这种组合化学的想法早在 20 世纪 90 年代就出现了，但直到现在，ETH 的研究人员才能够将其付诸实践，用于库合成。
更加多样化和更大的分子
自净化 DEL 技术不仅能够处理包含数十亿个分子的大型分子库，还允许研究人员合成由五个或更多个构建块组成的更大分子。
“以前，我们可以寻找像钥匙一样能插入治疗相关蛋白质活性位点锁的小活性物质，但现在我们也可以寻找更大的活性物质。这些较大的活性物质不仅可以停靠在蛋白质的活性中心，还可以停靠在蛋白质表面的其他特定区域，例如，以防止其与受体结合，”Scheuermann 说。
基础生物学研究也受益于找到与某些蛋白质表面结合的分子的可能性，因为这使得在细胞环境中标记和检查蛋白质成为可能。此外，ETH 方法可能对诸如 2035 目标之类的重大国际研究计划大有裨益。
该计划对约 20,000 种人类蛋白质，旨在到 2035 年为每一种蛋白质找到一种能够特异性结合该蛋白质并进而影响其功能的分子。
面向工业和科学的衍生服务
为了尽可能高效地将这项技术提供给制药行业和基础研究，Scheuermann 和他的团队将成立一家衍生公司。该公司将提供整个流程：从开发 DEL 集合和自动合成到自动功效测试和基于 DNA 的分子识别。
“我们看到工业界和研究界的极大兴趣，尤其是对环状分子，因为迄今为止这种分子还无法大量获得，”Scheuermann 说道。
