Enabling Phosphorus and Peptide based Chemical Biology using Ionic Liquids

这个多学科项目的目标是在离子液体（ILs）中开发前所未有的化学，与QUB目前正在进行的医学研究项目直接相关，因此对科学和临床社区都有重大影响。总的来说，这些多学科项目将把磷和蛋白质化学结合在一起，通过使用生物化学试剂，开发新的化学生物学技术和诊断/治疗方法。虽然科学界在磷和蛋白质化学领域取得了重大进展，但这只是通过工业社区的中介作用转化为最终用户（如生物学家和临床医生）的进展，工业社区使生物学家急需的一些化学物质能够获得，否则无法获得。虽然该行业为生物学和医学科学提供了广泛的化学物质，但由于缺乏化学物质的可用性，许多研究仍然未知。这种限制通常是由于缺乏化学知识，或者仅仅是由于化学本身也是未知的。这项工作旨在解决磷和肽化学领域的这一限制。磷制剂在生物学中发挥着重要作用，经常需要研究诸如细胞增殖或细胞信号传导等生物事件。虽然很多都可以在市场上买到，但由于在制备过程中遇到的困难，很多都非常昂贵。同样，虽然通过非常特殊的修饰可以获得许多类似的化合物，但目前的化学没有提供足够的范围来获得这些急需的生物化学物质。我们建议使用离子液体来操纵含磷试剂，使生物相关化学品的制备变得更直接，对环境的总体影响更小，同时最大限度地减少合成所需的步骤。以类似的方式，蛋白质化学和生物偶联极大地促进了化学生物学，并使非常强大的治疗方法的发展成为可能。迄今为止，有限的焦点已经解决了利用包含生物偶联的化学过程，以试图调节在给定蛋白质上被修饰的肽位点的数量或被修饰位点的性质。这与不断增长的生产用于治疗用途的GMP材料的需求特别相关。我们再次建议使用离子液体来操纵小蛋白质的特定残基进行偶联。使用ILs代替目前开发的标准生物偶联条件将提供一种方法，将许多疏水、水不稳定试剂的化学反应性与亲水肽侧链的化学反应性结合起来，从而更容易获得更广泛的肽连接剂和肽/蛋白质修饰剂。

The objective of this multidisciplinary program is to develop unprecedented chemistry in ionic liquids (ILs) of immediate relevance to medical research programs currently pursued at QUB, and as such have a major impact on both the scientific and the clinical communities. Overall, these multidisciplinary projects will bring together phosphorus and protein chemistry, enabled by the use of ILs, for the development of novel chemical biology technologies, and diagnostic/therapeutic approaches. While the scientific community has made major progress in the field of phosphorus and protein chemistry, this has only been translated into progress for the end users such as biologists and clinicians via the intermediacy of the industrial community which makes available some of the chemicals that the biologists are in great need of and cannot access otherwise. While the industry provides a broad range of chemicals that enables biology and medical sciences, much research remains unchartered due to a lack of chemical availability. Often this limitation comes from a lack of chemical know-how or is simply due to the chemistry itself which also remains unchartered. This work aims at addressing this limitation in the field of phosphorus and peptide chemistry. Phosphorous agents have a major role to play in biology and are often needed to investigate biological events such as cell proliferation or cellular signaling. While many are commercially available, a lot are extremely expensive due to the difficulties encountered in their preparations. Similarly, while much could be gained by accessing similar compounds with very specific modifications, the current chemistry does not provide sufficient scope to allow access to these much needed biochemicals. We propose to use ionic liquids to manipulate phosphorous reagents so that the preparation of biologically relevant chemicals become more straight-forward with a lesser overall impact on the environment while minimising the number of steps required for their syntheses. In a similar manner protein chemistry and bioconjugation has greatly facilitated chemical biology and has enabled the development of very powerful therapeutics. To date, limited focus has been addressed to harnessing the chemical processes that encompass bioconjugation in order to try to modulate either the number of peptidic sites being modified on a given protein or the nature of the sites being modified. This is particularly relevant with the ever-increasing demand for the production of GMP material for therapeutic applications. Once again we propose to use ionic liquids to manipulate specific residues of small proteins for conjugation. Using ILs instead of the standard bioconjugation conditions so far developed will provide means to combine the chemical reactivity of many hydrophobic, water unstable reagents to that of the water-loving peptide side chains to access more readily a broader range of peptide linkers and peptide/protein modifiers.