EAGER: High throughput inhibitor discovery for dissecting serine hydrolase function

酶直接参与人类健康的各个方面，从消化和神经系统信号到细菌感染。理解每种酶的作用需要有能力特异性地改变每种酶？S的活性而不影响具有相似结构特征的酶。该项目将评估一种新的策略，如果成功，将使研究人员能够快速识别具有这种极端选择性功能的分子。这种能力将彻底改变我们对疾病的理解以及制定有效治疗方案的能力。该项目还将通过女性和代表性不足的少数民族研究生和本科生的参与，促进发展多样化的生物技术工作队伍。该项目将评估一个潜在的强大平台，通过非规范氨基酸（ncAA）酵母展示，将小分子与抗体融合，设计出特异性的、有效的酶抑制剂。该项目将采用非规范氨基酸（ncAAs）的遗传结合方法来制造一种杂交抗体，而不是繁琐的化学偶联，这种方法可能会产生大量的小分子杂交抗体。该项目将首先开发平台，以有效地将这些ncAAs整合到抗体中，然后使用所得系统识别有效的抑制剂。

Enzymes are directly involved in every aspect of human health, from digestion and nervous system signaling to bacterial infection. Understanding the role that each enzyme plays requires the ability to specifically alter each enzyme?s activity without affecting enzymes with similar structural features. This project will evaluate a new strategy that, if successful, would enable researchers to quickly identify molecules capable of this extremely selective function. Such a capability could revolutionize our understanding of diseases and our ability to formulate effective treatments. This project will also contribute to the development of a diverse biotechnology workforce through the involvement of female and underrepresented minority graduate and undergraduate students. This project will evaluate a potentially robust platform for the design of specific, potent enzyme inhibitors through fusion of small molecules with antibodies through noncanonical amino acid (ncAA) yeast display. Rather than chemical conjugation, which can be tedious and results in bulky moieties, the project will use genetic incorporation of noncanonical amino acids (ncAAs) into a hybrid antibody as a potentially transformative approach to produce these antibody-small molecule hybrids. This project will first develop the platform to efficiently incorporate these ncAAs into the antibodies and then use the resulting system to identify potent inhibitors.