Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States.
Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60612, United States.
J Med Chem. 2024 Aug 22;67(16):13737-13764. doi: 10.1021/acs.jmedchem.4c00527. Epub 2024 Aug 6.
Since the largest and most fatal Ebola virus epidemic during 2014-2016, there have been several consecutive filoviral outbreaks in recent years, including those in 2021, 2022, and 2023. Ongoing outbreak prevalence and limited FDA-approved filoviral therapeutics emphasize the need for novel small molecule treatments. Here, we showcase the structure-activity relationship development of N-substituted pyrrole-based heterocycles and their potent, submicromolar entry inhibition against diverse filoviruses in a target-based pseudovirus assay. Inhibitor antiviral activity was validated using replication-competent Ebola, Sudan, and Marburg viruses. Mutational analysis was used to map the targeted region within the Ebola virus glycoprotein. Antiviral counter-screen and phospholipidosis assays were performed to demonstrate the reduced off-target activity of these filoviral entry inhibitors. Favorable antiviral potency, selectivity, and drug-like properties of the N-substituted pyrrole-based heterocycles support their potential as broad-spectrum antifiloviral treatments.
自 2014-2016 年期间发生最大且最致命的埃博拉病毒疫情以来，近年来已连续发生了几次丝状病毒疫情，包括 2021 年、2022 年和 2023 年。持续的暴发流行率和有限的 FDA 批准的丝状病毒治疗药物强调了需要新型小分子治疗方法。在这里，我们展示了基于 N-取代吡咯的杂环的结构-活性关系的发展，以及它们在基于靶标的假病毒测定中针对各种丝状病毒的有效、亚微摩尔的进入抑制作用。使用复制型埃博拉、苏丹和马尔堡病毒验证了抑制剂的抗病毒活性。突变分析用于定位埃博拉病毒糖蛋白中的靶向区域。进行抗病毒反筛选和磷脂酶病测定以证明这些丝状病毒进入抑制剂的脱靶活性降低。基于 N-取代吡咯的杂环具有良好的抗病毒效力、选择性和类药性，支持它们作为广谱抗丝状病毒治疗药物的潜力。
