Targeting MDR-TB

描述（由申请人提供）：高度耐药的结核病（称为耐多药（MDR）和广泛耐药（XDR）结核病）在世界范围内呈上升趋势，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选计划（MLSCN 和 TAACF），大量初步高通量筛选（HTS）数据将很快提供给研究公众，这些数据与可能针对高度耐药结核病的化合物的发现有关。不幸的是，这些数据只是早期阶段的初步结果，这些筛选中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，通常情况下，个别研究人员无法轻易获得所需的资金或工具，以将大量 HTS 数据正确排序到特定的支架中，以进行进一步的药物化学和药物开发。我们打算开展适当的早期阶段工作，将这一庞大的初步数据转化为可管理的信息，这将帮助社区和小型生物技术公司在努力开发抗结核新药的过程中专注于最佳化合物类别。具体来说，我们将可用的 HTS 信息的总数据集聚类为具有良好药物化学性质和最小反应功能的活性化合物集；将根据与已知抗结核药物的不同性和已知文献引用来选择组。有了这些信息，我们将通过商业开展化学工作，购买大约 10 个顶级簇中的初始后续化合物组，总共 1,000 种化合物。这些样本将通过各种测定进行筛选，用于优先考虑潜在的新抗结核药物。根据这些结果，将在 3-5 个最活跃的簇中鉴定和购买 300 种化合物的子集，以便充实更彻底的结构-活性关系。建议进一步筛选以增加所选特定化合物的价值。这种方法在时间和金钱方面更加有效，并且该计划应该有助于轻松地将大量筛选数据转移到社区的重点药物发现计划中。拟议的研究预计将产生十个高活性化合物簇，在一系列已接受的新药发现候选筛选组中显示出有趣的抗结核活性。此外，我们期望鉴定出大约三类在整个优先小组中表现出显着活性的化合物，包括针对 MDR 和 XDR 结核菌株的活性；这些候选药物应该成为未来药物发现计划的高度优先事项。总的来说，该申请解决了开发治疗耐药结核病新药的挑战，特别是耐多药和广泛耐药菌株。具体来说，该计划将继续推进 TAACF 计划中的初步活性化合物的开发进程。就影响而言，该申请的目标是将一组选定的化合物的数据引入公共和商业领域，这些化合物有望用于新药发现，以进一步开发新的抗结核药物来治疗耐药性疾病。 公共卫生相关性：高度耐药的结核病，即耐多药 (MDR) 和广泛耐药 (XDR) 结核病在全球范围内呈上升趋势，引发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选计划（MLSCN 和 TAACF），大量初步高通量筛选（HTS）数据将很快提供给研究公众，这些数据与可能针对高度耐药结核病的化合物的发现有关。不幸的是，这些数据只是早期阶段的初步结果，这些筛选中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，通常情况下，个别研究人员无法轻易获得所需的资金或工具，以将大量 HTS 数据正确排序到特定的支架中，以进行进一步的药物化学和药物开发。我们打算开展适当的早期阶段工作，将这一庞大的初步数据转化为可管理的信息，这将帮助社区和小型生物技术公司在努力开发抗结核新药的过程中专注于最佳化合物类别。这种方法在时间和金钱方面更加有效，并且该计划应该有助于轻松地将大量筛选数据转移到社区的重点药物发现计划中。拟议的研究预计将产生十个高活性化合物簇，在一系列已接受的新药发现候选筛选组中显示出有趣的抗结核活性。此外，我们期望鉴定出大约三类在整个优先小组中表现出显着活性的化合物，包括针对 MDR 和 XDR 结核菌株的活性；这些候选药物应该成为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.