发现具有耐药性等位基因的新生物学。
Discovering new biology with drug-resistance alleles.
机构信息
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
出版信息
Nat Chem Biol. 2021 Dec;17(12):1219-1229. doi: 10.1038/s41589-021-00865-9. Epub 2021 Nov 19.
Small molecule drugs form the backbone of modern medicine's therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic biology. In this Review, we highlight how resistance mutations have unlocked the potential of small molecule chemical probes to discover new biology. We describe key instances in which resistance mutations and related genetic variants yielded foundational biological insight and categorize these examples on the basis of their role in the discovery of novel molecular mechanisms, protein allostery, physiology and cell signaling. Next, we suggest ways in which emerging technologies can be leveraged to systematically introduce and characterize resistance mutations to catalyze basic biology research and drug discovery. By recognizing how resistance mutations have propelled biological discovery, we can better harness new technologies and maximize the potential of small molecules to advance our understanding of biology and improve human health.
小分子药物构成了现代医学治疗武器库的支柱。然而，人们往往较少关注到小分子在推进基础生物学方面所发挥的作用。在这篇综述中，我们强调了耐药突变如何使小分子化学探针能够发现新的生物学，从而释放出其潜力。我们描述了耐药突变和相关遗传变异在发现新的分子机制、蛋白质变构、生理学和细胞信号传导方面产生基础生物学见解的关键实例，并根据它们在发现新分子机制、蛋白质变构、生理学和细胞信号传导方面的作用对这些实例进行了分类。接下来，我们提出了利用新兴技术系统引入和表征耐药突变以促进基础生物学研究和药物发现的方法。通过认识到耐药突变如何推动生物学发现，我们可以更好地利用新技术，并最大限度地发挥小分子的潜力，以加深我们对生物学的理解并改善人类健康。
Zotero 插件