Nitsche Christoph, Zhang Linlin, Weigel Lena F, Schilz Jonas, Graf Dominik, Bartenschlager Ralf, Hilgenfeld Rolf, Klein Christian D
Medicinal Chemistry, IPMB, Heidelberg University , INF-364, 69120 Heidelberg, Germany.
Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck , Ratzeburger Allee 160, 23562 Lübeck, Germany.
J Med Chem. 2017 Jan 12;60(1):511-516. doi: 10.1021/acs.jmedchem.6b01021. Epub 2016 Dec 14.
A thousand-fold affinity gain is achieved by introduction of a C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika, West Nile, and dengue virus proteases. The resulting compounds have K values in the two-digit nanomolar range, are not cytotoxic, and inhibit virus replication. Structure-activity relationships and a high resolution X-ray cocrystal structure with West Nile virus protease provide a basis for the design of optimized covalent-reversible inhibitors aimed at emerging flaviviral pathogens.
通过将C末端硼酸部分引入寨卡病毒、西尼罗河病毒和登革热病毒蛋白酶的二肽抑制剂中，实现了亲和力提高一千倍。所得化合物的K值在两位数纳摩尔范围内，无细胞毒性，并能抑制病毒复制。结构-活性关系以及与西尼罗河病毒蛋白酶的高分辨率X射线共晶体结构为设计针对新兴黄病毒病原体的优化共价-可逆抑制剂提供了基础。
