Inna V. Krieger, Subbarao Yalamanchili, Paige Dickson, Curtis A. Engelhart, Matthew D Zimmerman, Jeremy Wood, Ethan Clary, Jasmine Nguyen, Natalie Thornton, Paolo A. Centrella, Betty Chan, John W Cuozzo, Martin Gengenbacher, Marie-Aude Guié, John P Guilinger, Corey Bienstock, Hajnalka Hartl, Christopher D. Hupp, Rachael Jetson, Takashi Satoh, John T. S. Yeoman, Ying Zhang, Veronique Dartois, Dirk Schnappinger, Anthony D. Keefe* and James C. Sacchettini*,
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引用次数: 0
Abstract
DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.
DNA 编码化学文库(DEL)技术提供了一种省时、省钱的方法,可同时筛选数十亿种化合物,以确定它们与感兴趣的蛋白质靶标的亲和性。在此,我们报告了利用该技术鉴定结核分枝杆菌(Mtb)多酮合成酶 13(Pks13)硫酯酶活性抑制剂的新型化学系列。我们介绍了三个化学性质不同的抑制剂系列,以及它们的酶效和 Mtb 全细胞效价、细胞内靶向活性的测量值,以及阐明它们与酶活性位点相互作用的抑制剂-酶复合物晶体结构。其中一种抑制剂显示出良好的药代动力学特征,并在结核病(TB)感染的急性小鼠模型中显示出疗效。这些发现和检测方法的开发将有助于推动结核病药物的发现。
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.