发现金刚烷甲酰胺作为埃博拉病毒细胞进入和糖蛋白抑制剂
Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors.
作者信息
Plewe Michael B, Sokolova Nadezda V, Gantla Vidyasagar Reddy, Brown Eric R, Naik Shibani, Fetsko Alexandra, Lorimer Donald D, Dranow David M, Smutney Hayden, Bullen Jameson, Sidhu Rana, Master Arshil, Wang Junru, Kallel E Adam, Zhang Lihong, Kalveram Birte, Freiberg Alexander N, Henkel Greg, McCormack Ken
机构信息
Arisan Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego, California 92121, United States.
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, Washington 98105, United States.
出版信息
ACS Med Chem Lett. 2020 May 1;11(6):1160-1167. doi: 10.1021/acsmedchemlett.0c00025. eCollection 2020 Jun 11.
We identified and explored the structure-activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC values) of ∼10-15 nM in (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates.
我们确定并探索了埃博拉病毒（EBOV）抑制剂金刚烷甲酰胺化学系列的构效关系（SAR）。在水疱性口炎病毒（VSV）假型化埃博拉病毒（pEBOV）感染性试验中，选定的类似物表现出约10-15 nM的半数最大抑制浓度（EC值），对野生型埃博拉病毒的EC活性为低数百纳摩尔，水溶性>20 mg/mL，并且在人和非人类肝微粒体中具有良好的代谢稳定性。一种先导化合物与埃博拉病毒糖蛋白（GP）的X射线共结晶表征确定埃博拉病毒GP是直接化合物抑制活性的靶点，并进一步提供了相关结构模型，这可能有助于识别优化的治疗候选物。
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