Department of Medicinal Chemistry , Virginia Commonwealth University , Richmond , Virginia 23298 , United States.
Institute for Structural Biology, Drug Discovery and Development , Virginia Commonwealth University , Richmond , Virginia 23219 , United States.
J Med Chem. 2019 Jun 13;62(11):5501-5511. doi: 10.1021/acs.jmedchem.9b00379. Epub 2019 May 28.
Cystic fibrosis (CF) is a disease of dysregulated salt and fluid homeostasis that results in the massive accumulation of neutrophil elastase, resulting in lung degradation and death. The current CF therapy relies on inhaled deoxyribonuclease and hypertonic saline but does not address the elastolytic degradation of the lung. We reasoned that allosteric agents targeting the heparin-binding site of neutrophil elastase would offer a therapeutic paradigm. Screening a library of 60 nonsaccharide glycosaminoglycan mimetics (NSGMs) led to the discovery of 23 hits against neutrophil elastase. To identify a lead NSGM that works in sync with the current CF-relieving agents, we developed a rigorous protocol based on fundamental computational, biochemical, mechanistic, and adverse effect studies. The lead NSGM so identified neutralized neutrophil elastase present in the sputum of CF patients in the presence of deoxyribonuclease and high-salt conditions. Our work presents the process for discovering potent, small, synthetic, allosteric, anti-CF agents, while also identifying a novel lead for further studies in animal models of CF.
囊性纤维化 (CF) 是一种盐和液体稳态失调的疾病，导致中性粒细胞弹性蛋白酶的大量积累，导致肺损伤和死亡。目前的 CF 治疗依赖于吸入脱氧核糖核酸酶和高渗盐水，但不能解决肺的弹性酶降解问题。我们认为，针对中性粒细胞弹性蛋白酶肝素结合位点的变构剂将提供一种治疗范例。对 60 种非糖基化糖胺聚糖类似物 (NSGM) 的文库进行筛选，发现了 23 种针对中性粒细胞弹性酶的有效物质。为了确定与当前 CF 缓解剂协同作用的 NSGM 先导化合物，我们根据基本的计算、生化、机制和不良作用研究，制定了严格的方案。在脱氧核糖核酸酶和高盐条件下，所确定的 NSGM 先导化合物中和了 CF 患者痰液中的中性粒细胞弹性酶。我们的工作展示了发现有效、小、合成、变构、抗 CF 药物的过程，同时也为 CF 动物模型的进一步研究确定了一种新的先导化合物。
