GENE-BASED AND BACTERIA HIGH THROUGHOUT TB DRUG SCREEN

对结核病新药的探索终于赶上了本世纪最后半个世纪的制药革命：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的组合化学库。使用机器人和复杂的分析仪器，这些文库可以高通量筛选，以识别对特定生物体致命的化合物，或影响已知对细菌生存至关重要的特定途径的化合物。NIAID和Sequella，Inc.合作了一年的CRADA开发组合化学和高通量筛选试验，在非常短的时间内成功地合成和筛选了大约10万个结核病药物乙胺丁醇的类似物。这些研究中使用的基于基因的筛选确定了影响结核分枝杆菌基因组特定区域的化合物，这些化合物在乙胺丁醇治疗后被激活，并参与细胞对细胞壁破坏的反应。Sequella，Inc./NIH的合作势头令人印象深刻(在9个月内筛选了100,000个化合物，200个匹配，4个先导化合物)。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分析，以在类似的时间框架内筛选他们的化学库。例如，一家公司拥有50万种特性良好的化学物质，这些化学物质从未进行过结核病检测。他们有兴趣向基金会提供这些化学物质，以便在特定的全细胞筛选试验中进行测试，作为HITS的初始筛查。在内部安装高通量屏幕虽然不是那么昂贵，但对该公司来说是一种机会成本，需要BL3设施。此外，一种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项挑战拨款的过程中将屏幕转移到NIH计划。基金会的目标是减少主要制药公司在考虑新的结核病药物市场时面临的进入门槛。因此，提供支持制药合作伙伴特定需求的量身定制的筛查计划是一项相对廉价的努力，可能会增加出现药物来改善这种被忽视疾病的治疗的可能性。

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.