Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation

作者：Nagraj Mani, Andrew G. Cole, Janet R. Phelps, Andrzej Ardzinski, Kyle D. Cobarrubias, Andrea Cuconati, Bruce D. Dorsey, Ellen Evangelista, Kristi Fan, Fang Guo, Haitao Guo, Ju‐Tao Guo, Troy O. Harasym, Salam Kadhim, Steven G. Kultgen, Amy C. H. Lee, Alice H. L. Li, Quanxin Long, Sara A. Majeski, Richeng Mao, Kevin McClintock, Stephen P. Reid, René Rijnbrand, Nicholas M. Snead, Holly M. Micolochick Steuer, Kim Stever, Sunny Tang, Xiaohe Wang, Qiong Zhao, Michael J. Sofia · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2018 · DOI：10.1128/aac.00082-18 · 被引用次数：59 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Hepatitis Viruses Studies and Epidemiology

ABSTRACT AB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC 50 ] = 0.08 to 0.27 μM; EC 90 = 0.33 to 1.32 μM) with no significant cytotoxicity (50% cytotoxic concentration > 10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC 50 s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro . Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a de novo infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydr...