Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA.
Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA.
Molecules. 2022 Oct 17;27(20):6948. doi: 10.3390/molecules27206948.
Unlike Tuberculosis (TB), lung disease is a highly drug-resistant bacterial infection with no reliable treatment options. De novo drug discovery is urgently needed but is hampered by the bacterium's extreme drug resistance profile, leaving the current drug pipeline underpopulated. One proposed strategy to accelerate de novo drug discovery is to prioritize screening of advanced TB-active compounds for anti- activity. This approach would take advantage of the greater chance of homologous drug targets between mycobacterial species, increasing hit rates. Furthermore, the screening of compound series with established structure-activity-relationship, pharmacokinetic, and tolerability properties should fast-track the development of in vitro anti- hits into lead compounds with in vivo efficacy. In this review, we evaluated the effectiveness of this strategy by examining the literature. We found several examples where the screening of advanced TB chemical matter resulted in the identification of anti- compounds with in vivo proof-of-concept, effectively populating the drug pipeline with promising new candidates. These reports validate the screening of advanced TB chemical matter as an effective means of fast-tracking drug discovery.
与结核病（TB）不同，肺部疾病是一种对药物高度耐药的细菌感染，目前尚无可靠的治疗方法。急需进行全新的药物发现，但由于细菌具有极强的耐药性，这一过程受到阻碍，导致目前的药物研发管道缺乏候选药物。加速全新药物发现的一种提议策略是优先筛选对结核病有活性的先进化合物。这种方法将利用分枝杆菌属之间同源药物靶点的更大机会，提高命中率。此外，对具有既定结构-活性关系、药代动力学和耐受性特性的化合物系列进行筛选，应能加速体外抗结核活性化合物向具有体内疗效的先导化合物的开发。在这篇综述中，我们通过查阅文献评估了这一策略的有效性。我们发现了一些例子，其中筛选先进的结核病化学物质导致了具有体内概念验证的抗结核化合物的鉴定，有效地为有前途的新候选药物填充了药物研发管道。这些报告验证了筛选先进的结核病化学物质作为加速药物发现的有效手段。
