GENE-BASED AND BACTERIA HIGH THROUGHOUT TB DRUG SCREEN

对新结核病药物的研究终于赶上了本世纪后半叶的制药革命：基于固体基质的化学合成方法现在创建了包含数百万种独特化合物的药物组合化学库。 使用机器人技术和复杂的分析仪器，这些文库可以高通量筛选，以鉴定对特定生物体致命的化合物，或影响已知对细菌存活至关重要的特定途径的化合物。 NIAID和Sequella公司之间的一年之久的CRADA。开发了组合化学和高通量筛选分析，成功地在很短的时间内合成和筛选了结核药物乙胺丁醇的大约100，000种类似物。 这些研究中使用的基于基因的筛选鉴定了影响M.结核病基因组中的一种，其响应乙胺丁醇治疗而被激活，并且参与对细胞壁损伤的细胞反应。The Sequella，Inc. NIH的合作势头令人印象深刻（筛选了10万种化合物，200次点击，9个月内有4种先导化合物）。 该基金会打算向感兴趣的制药公司提供几种基于基因和全细胞的高通量筛选试验，以在类似的时间范围内筛选他们的化学文库。 例如，有一家公司有50万种特征明确的化学品从未进行过结核病测试。 他们有兴趣为基金会提供这些化学品，以在特定的全细胞筛选试验中进行测试，作为命中的初始筛选。 在内部设置高通量筛选，虽然不是那么昂贵，但对该公司来说是一种机会成本，需要BL 3设施。此外，一个有效的全菌高通量筛选试验将有利于目前的NIAID/DAIDS药物筛选计划。 基金会将有兴趣在这个挑战赠款的过程中将屏幕转移到NIH计划。基金会的目标是减少大型制药公司在考虑结核病新药市场时面临的进入壁垒。 因此，提供量身定制的筛选计划，支持制药合作伙伴的特定需求是一个相对便宜的奋进，可以提高药物出现的可能性，以改善这种被忽视的疾病的治疗。

The search for new TB drugs has finally caught up with the pharmaceutical revolution of the last half of this century: solid-matrix-based methods of chemical synthesis now create combinatorial chemistry libraries of pharmaceuticals that contain millions of unique compounds. Using robotics and sophisticated assay instrumentation, these libraries can be screened with high throughput to identify compounds which are lethal to specific organisms, or which affect specific pathways known to be critical for bacterial survival. A year-old CRADA between the NIAID and Sequella, Inc. to develop combinatorial chemistry and a high throughput screening assay succeeded in synthesizing and screening approximately 100,000 analogues of the TB drug ethambutol in a very short period of time. The gene-based screen used in these studies identified compounds that affect specific regions of the M. tuberculosis genome that are activated in response to ethambutol therapy, and are involved in the cellular response to cell wall damage. The Sequella, Inc./NIH collaboration had impressive momentum (100,000 compounds screened, 200 hits, 4 lead compounds in 9 months). The Foundation intends to provide several gene-based and whole-cell high throughput screening assays to interested pharmaceutical companies to screen their chemical libraries in a similar timeframe. One company, for example, has 500,000 well- characterized chemicals that have never been tested for TB. They are interested in providing the Foundation with these chemicals to test in a specific whole cell-screening assay as an initial screen for hits. Setting up the high throughput screen in-house, while not that expensive, represents an opportunity cost for that company and would require a BL3 facility. In addition, a validated whole-bacteria high throughput screening assay would be of benefit to the current NIAID/DAIDS drug screening program. The foundation would be interested in transferring the screen to the NIH program over the course of this challenge grant. The Foundation goal is to reduce the barriers to entry that the major pharmaceutical companies face when considering the market for new TB drugs. Thus, providing tailored screening programs that support the specific needs of pharmaceutical partners is a relatively inexpensive endeavor that may improve the likelihood that medicines will emerge to improve the treatment of this neglected disease.