评估和利用酯酶特异性在抗菌前药开发中的应用。
Assessing and utilizing esterase specificity in antimicrobial prodrug development.
机构信息
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States; Broad Institute of MIT and Harvard, Cambridge, MA, United States.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States; Broad Institute of MIT and Harvard, Cambridge, MA, United States.
出版信息
Methods Enzymol. 2022;664:199-220. doi: 10.1016/bs.mie.2021.11.008. Epub 2021 Dec 23.
As a class of enzymes, esterases have been investigated for decades and have found use in industrial processes, synthetic organic chemistry, and elsewhere. Esters are functional groups composed of an alcohol moiety and a carboxylic acid moiety. Although much work has explored the influence of the carboxyl moiety of an ester on its susceptibility to esterases, little work has explored the influence of the alcohol moiety. Here, we describe an in vitro methodology to explore the influence of changing the alcohol moiety of an ester on its enzymatic hydrolysis, including strategies for analyzing such data. We then describe leveraging data from these assays to develop targeted antimicrobial prodrugs that activate in certain species due to the discriminatory activity of species-specific esterases. We envisage the potential of genomics and machine learning to further these efforts. Finally, we anticipate the potential future uses of these ideas, including developing targeted anti-cancer compounds.
作为一类酶，酯酶已经被研究了几十年，并在工业过程、合成有机化学等领域得到了应用。酯是由醇部分和羧酸部分组成的官能团。虽然已经有很多工作探讨了酯的羧酸部分对其对酯酶的敏感性的影响，但很少有工作探讨醇部分的影响。在这里，我们描述了一种体外方法来探索改变酯的醇部分对其酶水解的影响，包括分析此类数据的策略。然后，我们描述了利用这些测定中的数据来开发靶向抗菌前药，这些前药由于特定物种特异性酯酶的有区别的活性而在某些物种中激活。我们设想了基因组学和机器学习在这些工作中的进一步发展潜力。最后，我们预计这些想法的未来应用，包括开发靶向抗癌化合物。
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