HTS to Find Inhibitors of p47phox, a Regulatory Protein of Noxes

描述（由申请人提供）：许多疾病与炎症和氧化应激有关。氮氧化物酶提供了与氧化应激相关的大部分活性氧，最近已被证实为预防和治疗这些疾病的药物靶点。迄今为止，技术问题阻碍了对高通量筛选（HTS）的Nox活性测定的适应。我们与Emory的MLSCN中心主任Dr. Haian Fu合作，开发并优化了一种新的HTS方法，通过该方法我们成功地选择了新的候选Noxes抑制剂。我们开发和测试的二级活性筛选使我们能够确定真正的氮氧化物抑制剂，这些抑制剂是先导药物化合物的候选物。我们将继续与傅博士合作，使用HTS方法筛选Emory MLSCN中心的MLSCN文库。利用该筛选结果，我们将进行二次活性和反筛选，以确定最高效力和最具选择性的Nox1和Nox2抑制剂。这些抑制剂应该为研究提供有价值的工具，并可能作为预防和/或治疗疾病的药物的线索。后续研究将侧重于hit-to-lead开发，目标是确定候选药物。

DESCRIPTION (provided by applicant): Numerous diseases are linked to inflammation and oxidative stress. Nox enzymes provide the majority of reactive oxygen species associated with oxidative stress and have recently been validated as targets for drugs that would prevent and treat these conditions. Technical problems have to date prevented the adaptation of Nox activity assays for high throughput screening (HTS). In collaboration with Dr. Haian Fu, Director of Emory's MLSCN center, we have developed and optimized a novel HTS method with which we have successfully selected new candidate inhibitors of Noxes. Secondary activity screens that we developed and tested allowed us to identify bona fide Nox inhibitors that are candidates for lead drug compounds. Continuing our collaboration with Dr. Fu, we will use the HTS method to screen the MLSCN library at the Emory MLSCN center. Using hits from this screen, we will carry out secondary activity and counterscreens to determine the highest potency and most selective Nox1 and Nox2 inhibitors. Such inhibitors should provide valuable tools for research, and may serve as leads for drugs that can prevent and/or cure disease. Follow-on studies will focus on hit-to-lead development with the goal of identifying candidate drugs.