Hit Generation in TB Drug Discovery: From Genome to Granuloma.,Chemical Reviews

当前位置： X-MOL 学术 › Chem. Rev. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Hit Generation in TB Drug Discovery: From Genome to Granuloma.
Chemical Reviews ( IF 51.4 ) Pub Date : 2018-01-31 , DOI: 10.1021/acs.chemrev.7b00602
Tianao Yuan ₁ , Nicole S Sampson _{1,

2}

Affiliation

Current tuberculosis (TB) drug development efforts are not sufficient to end the global TB epidemic. Recent efforts have focused on the development of whole-cell screening assays because biochemical, target-based inhibitor screens during the last two decades have not delivered new TB drugs. Mycobacterium tuberculosis (Mtb), the causative agent of TB, encounters diverse microenvironments and can be found in a variety of metabolic states in the human host. Due to the complexity and heterogeneity of Mtb infection, no single model can fully recapitulate the in vivo conditions in which Mtb is found in TB patients, and there is no single "standard" screening condition to generate hit compounds for TB drug development. However, current screening assays have become more sophisticated as researchers attempt to mirror the complexity of TB disease in the laboratory. In this review, we describe efforts using surrogates and engineered strains of Mtb to focus screens on specific targets. We explain model culture systems ranging from carbon starvation to hypoxia, and combinations thereof, designed to represent the microenvironment which Mtb encounters in the human body. We outline ongoing efforts to model Mtb infection in the lung granuloma. We assess these different models, their ability to generate hit compounds, and needs for further TB drug development, to provide direction for future TB drug discovery.

中文翻译：

结核病药物发现的成功一代：从基因组到肉芽肿。

当前结核病（TB）药物开发的努力不足以结束全球结核病流行。最近的努力集中在全细胞筛选测定法的开发上，因为在过去的二十年中，基于靶标的生化抑制剂筛选尚未交付新的结核病药物。结核分枝杆菌（Mtb）是结核病的病原体，它会遇到多种微环境，并且可以在人类宿主的各种代谢状态中发现。由于Mtb感染的复杂性和异质性，没有单一的模型可以完全概括在TB患者中发现Mtb的体内状况，也没有单一的“标准”筛选条件可以产生用于结核病药物开发的有效化合物。然而，随着研究人员试图在实验室反映结核病的复杂性，当前的筛选测定法变得越来越复杂。在这篇综述中，我们描述了使用替代物和Mtb工程菌株将屏幕聚焦在特定目标上的努力。我们解释了从碳饥饿到缺氧的模型培养系统，及其组合，旨在代表Mtb在人体中遇到的微环境。我们概述了正在进行的为肺肉芽肿中Mtb感染建模的努力。我们评估了这些不同的模型，它们产生命中化合物的能力以及对进一步的结核病药物开发的需求，从而为未来的结核病药物发现提供了指导。我们解释了从碳饥饿到缺氧的模型培养系统，及其组合，旨在代表Mtb在人体中遇到的微环境。我们概述了正在进行的为肺肉芽肿中Mtb感染建模的努力。我们评估了这些不同的模型，它们产生命中化合物的能力以及对进一步的结核病药物开发的需求，从而为未来的结核病药物发现提供了指导。我们解释了从碳饥饿到缺氧的模型培养系统，及其组合，旨在代表Mtb在人体中遇到的微环境。我们概述了正在进行的为肺肉芽肿中Mtb感染建模的努力。我们评估了这些不同的模型，它们产生命中化合物的能力以及对进一步的结核病药物开发的需求，从而为未来的结核病药物发现提供了指导。

更新日期：2018-01-31

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11