High throughput TB drug screens

描述(摘自申请者的摘要)：新药的寻找终于赶上了后半个世纪的药物革命 本世纪：基于固体基质的化学合成方法现在创造了 包含数百万种药物的组合化学库 独特的化合物。使用机器人技术和复杂的化验仪器， 这些文库可以通过高通量筛选来鉴定化合物 哪些对特定的生物体是致命的，或者哪些影响特定的途径已知 对细菌的生存至关重要。一只一岁的CRADA介于NIAID和 Sequella，Inc.开发组合化学和高通量 筛选试验成功合成并筛选了约100,000个 结核病药物乙胺丁醇的类似物在非常短的时间内。这个基因- 这些研究中使用的基于筛选的方法确定了影响特定基因的化合物 结核分枝杆菌基因组中被激活的区域 乙胺丁醇治疗，并参与细胞对细胞壁的反应 损坏。 Sequella，Inc./NIH的合作势头令人印象深刻(100,000 化合物筛选，200次命中，9个月内4个先导化合物)。基金会 打算提供几种基于基因和全细胞的高通量筛选 对感兴趣的制药公司进行化验，以筛选其化学物质 库在类似的时间范围内。例如，一家公司拥有50万口油井- 从未进行过结核病检测的特色化化学物质。他们是 有兴趣向基金会提供这些化学品，以便在 特异性全细胞筛选试验作为HITS的初始筛选。设置 内部的高吞吐量屏幕虽然不是那么昂贵，但代表着一种 该公司的机会成本，并将需要BL3设施。 此外，一种经过验证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。这个 基金会将有兴趣将屏幕转移到NIH计划 在这项挑战拨款的过程中。 基金会的目标是降低进入门槛， 制药公司在考虑结核病新药的市场时面临着。 因此，提供量身定制的筛查计划，支持特定的需求 制药合作伙伴是一项相对廉价的努力，可能会有所改善 出现药物来改善这种疾病治疗的可能性 被忽视的疾病。

DESCRIPTION (adapted from applicant's abstract): 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 know 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 taht 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.