Liang Yanke, de Wispelaere Melissanne, Carocci Margot, Liu Qingsong, Wang Jinhua, Yang Priscilla L, Gray Nathanael S
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States; Departments of Biological Chemistry & Molecular Pharmacology and Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States.
Departments of Biological Chemistry & Molecular Pharmacology and Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
ACS Med Chem Lett. 2017 Feb 3;8(3):344-349. doi: 10.1021/acsmedchemlett.7b00008. eCollection 2017 Mar 9.
Here we report the structure-activity relationship (SAR) investigations of QL-XII-47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35-fold lower concentrations relative to inhibition of host-cell proliferation.
在此，我们报告了QL-XII-47（QL47）的构效关系（SAR）研究，QL47是一种对登革病毒和其他RNA病毒具有广谱抗病毒活性的化合物。从先前报道的共价BTK抑制剂QL47开始的药物化学研究，衍生出了YKL-04-085，在针对468种激酶进行筛选时，YKL-04-085没有任何激酶活性，并且具有改善的药代动力学性质。QL47和YKL-04-085都是病毒翻译的有效抑制剂，相对于抑制宿主细胞增殖，它们在低35倍的浓度下就表现出细胞抗病毒活性。
