Targeting MDR-TB

描述(由申请人提供)：被称为多药耐药(MDR)和广泛耐药(XDR)的高度耐药结核病在全球范围内呈上升趋势，这引发了人们对这种疾病可能再次变得几乎无法治愈的担忧。通过两个政府资助的筛查计划(MLSCN和TAACF)，大量的高通量筛查(HTS)初步数据将很快提供给研究公众，这些数据与发现可能针对高度耐药结核病的化合物有关。不幸的是，这些数据是早期的初步结果，来自这些筛查的活性化合物需要通过结核病药物发现管道进一步转化。然而，个别研究人员往往不容易获得所需的资金或工具，以适当地将海量HTS数据优先放入特定的支架，用于进一步的药物化学和药物开发。我们打算进行必要的适当早期工作，将这些庞大的初步数据转化为可管理的信息，帮助社区和小型生物技术公司专注于最好的化合物类别，以努力开发治疗结核病的新药。具体地说，我们将把可用的HTS信息的总数据集聚集到具有良好药用化学性质和最小反应功能的化合物的活性集合中；将根据与已知抗结核药物的不同和已知的文献引用来选择集合。有了这些信息，我们将通过商业进行化学操作，购买大约10个顶级簇中的化合物的初始后续集合，总共1000个化合物。这些样本将在各种分析中进行筛选，用于优先选择潜在的新抗结核药物。根据这些结果，将在3-5个最活跃的簇中识别和购买300个化合物的子集，以便充实更全面的结构-活性关系。建议进一步筛选，以增加所选特定化合物的价值。这样的方法在时间和金钱方面更有效率，这个项目应该有助于将大型筛查数据随时转移到社区的有针对性的药物发现计划中。拟议的研究预计将在一系列接受的新药发现候选筛选中产生10个高活性化合物簇，显示出有趣的抗结核活性。此外，我们预计将在整个优先排序小组中确定大约三类显示出显著活性的化合物，包括对MDR和XDR结核菌株的活性；这些候选化合物应该是未来药物发现计划的高度优先事项。广泛地说，这项申请解决了为治疗耐药形式的结核病，特别是MDR和XDR菌株而开发新药的挑战。具体地说，该计划将继续推进TAACF计划中的初步活性化合物的开发工作。就影响而言，这项应用的目标将是将一组有望发现新药的精选化合物的数据带入公共和商业领域，以进一步推动治疗耐药疾病的新抗结核药物的发展。 与公共卫生相关：被称为多药耐药(MDR)和广泛耐药(XDR)的高度耐药结核病在世界范围内正在上升，这引发了人们对这种疾病可能再次变得几乎无法治愈的担忧。通过两个政府资助的筛查计划(MLSCN和TAACF)，大量的高通量筛查(HTS)初步数据将很快提供给研究公众，这些数据与发现可能针对高度耐药结核病的化合物有关。不幸的是，这些数据是早期的初步结果，来自这些筛查的活性化合物需要通过结核病药物发现管道进一步转化。然而，个别研究人员往往不容易获得所需的资金或工具，以适当地将海量HTS数据优先放入特定的支架，用于进一步的药物化学和药物开发。我们打算进行必要的适当早期工作，将这些庞大的初步数据转化为可管理的信息，以帮助社区和小型生物技术公司专注于最好的化合物类别，以努力开发治疗结核病的新药。这样的方法在时间和金钱方面更有效率，这个项目应该有助于将大型筛查数据随时转移到社区的有针对性的药物发现计划中。拟议的研究预计将在一系列接受的新药发现候选筛选中产生10个高活性化合物簇，显示出有趣的抗结核活性。此外，我们预计将在整个优先排序小组中确定大约三类显示出显著活性的化合物，包括对MDR和XDR结核菌株的活性；这些候选化合物应该是未来药物发现计划的高度优先事项。

DESCRIPTION (provided by applicant): Highly drug resistant forms of tuberculosis termed multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis are on the rise worldwide raising the specter that this disease may once again become virtually incurable. Through two government sponsored screening programs (the MLSCN and TAACF), a large amount of preliminary high throughput screening (HTS) data will soon become available to the research public relating to the discovery of compounds that might target highly drug resistant forms of tuberculosis. Unfortunately, these data are early stage preliminary results, and active compounds from these screens need further translation through the tuberculosis drug discovery pipeline. Oftentimes, however, individual researchers do not readily have access to the funds or tools required to properly prioritize the vast amounts of HTS data into specific scaffolds for further medicinal chemistry and drug development. It is our intention to carry out the appropriate early stage exercises necessary to translate this vast set of preliminary data into manageable information that will help the community and small biotech companies to focus on the best compound classes in their efforts to pursue new drugs against tuberculosis. Specifically, we will cluster the total data set of available HTS information into active sets of compounds that have good medicinal chemistry properties and minimal reactive functions; sets will be selected based on dissimilarity to known antitubercular drugs and known literature citations. With this information we will carry out chemistry through commerce, buying an initial follow up set of compounds in approximately ten of the top clusters for a total of 1,000 compounds. These samples will be screened in a variety of assays used for prioritizing potential new antitubercular drugs. From these results, a subset of 300 compounds will be identified and purchased in 3-5 of the most active clusters in order to flesh out a more thorough structure-activity relationship. Further screens are proposed to add value to the specific compounds chosen. Such an approach is more efficient in terms of time and money, and this program should help readily move the large screening data into focused drug discovery programs in the community. The proposed studies are anticipated to result in ten highly active clusters of compounds showing interesting antitubercular activity in a series of accepted panels of screens for new drug discovery candidates. Furthermore, we expect to identify approximately three classes of compounds showing significant activity throughout the prioritization panel including activity against MDR and XDR tuberculosis strains; these candidates should be a high priority for future drug discovery programs. Broadly, this application addresses the challenge of pursuing the development of new drugs for the treatment of drug resistant forms of tuberculosis, particularly MDR and XDR strains. Specifically, this program will continue the advancement of preliminary active compounds from the TAACF program further along the development pipeline. In terms of an impact, the goal of this application will be to bring data for a select set of compounds that have promise for new drug discovery into the public and commercial domain for further advancement towards new antitubercular agents to treat drug resistant disease. PUBLIC HEALTH RELEVANCE: Highly drug resistant forms of tuberculosis termed multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis are on the rise worldwide raising the specter that this disease may once again become virtually incurable. Through two government sponsored screening programs (the MLSCN and TAACF), a large amount of preliminary high throughput screening (HTS) data will soon become available to the research public relating to the discovery of compounds that might target highly drug resistant forms of tuberculosis. Unfortunately, these data are early stage preliminary results, and active compounds from these screens need further translation through the tuberculosis drug discovery pipeline. Oftentimes, however, individual researchers do not readily have access to the funds or tools required to properly prioritize the vast amounts of HTS data into specific scaffolds for further medicinal chemistry and drug development. It is our intention to carry out the appropriate early stage exercises necessary to translate this vast set of preliminary data into manageable information that will help the community and small biotech companies to focus on the best compound classes in their efforts to pursue new drugs against tuberculosis. Such an approach is more efficient in terms of time and money, and this program should help readily move the large screening data into focused drug discovery programs in the community. The proposed studies are anticipated to result in ten highly active clusters of compounds showing interesting antitubercular activity in a series of accepted panels of screens for new drug discovery candidates. Furthermore, we expect to identify approximately three classes of compounds showing significant activity throughout the prioritization panel including activity against MDR and XDR tuberculosis strains; these candidates should be a high priority for future drug discovery programs.