Enabling Phosphorus and Peptide based Chemical Biology using Ionic Liquids

这个多学科计划的目标是开发前所未有的离子液体（IL）化学，与目前在QUB进行的医学研究计划直接相关，因此对科学和临床社区都有重大影响。总体而言，这些多学科项目将通过使用离子液体将磷和蛋白质化学结合在一起，以开发新型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，但这只是通过工业界的中介作用转化为生物学家和临床医生等最终用户的进步，工业界提供了一些生物学家非常需要并且无法获得的化学品。虽然该行业提供了广泛的化学品，使生物学和医学科学，许多研究仍然由于缺乏化学品的可用性未经特许。通常这种限制来自于缺乏化学知识，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。磷试剂在生物学中起着重要作用，并且经常需要研究生物事件，如细胞增殖或细胞信号传导。虽然许多是商业上可获得的，但由于其制备过程中遇到的困难，许多是极其昂贵的。同样，虽然通过获得具有非常特定修饰的类似化合物可以获得很多，但目前的化学没有提供足够的范围来允许获得这些急需的生物化学品。我们建议使用离子液体来操纵磷试剂，使得生物相关化学品的制备变得更加直接，对环境的总体影响较小，同时最大限度地减少合成所需的步骤数量。以类似的方式，蛋白质化学和生物缀合极大地促进了化学生物学，并使非常强大的治疗方法得以发展。到目前为止，有限的焦点已经解决了利用化学过程，包括生物缀合，以试图调节给定蛋白质上被修饰的肽位点的数量或被修饰的位点的性质。这与生产用于治疗应用的GMP材料的不断增长的需求特别相关。我们再次提出使用离子液体来操纵小蛋白质的特定残基进行缀合。使用IL代替迄今为止开发的标准生物缀合条件将提供将许多疏水的、水不稳定的试剂的化学反应性与喜水的肽侧链的化学反应性结合的联合收割机的手段，以更容易地获得更宽范围的肽接头和肽/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.