Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379

被引:59
作者
Berke, Jan Martin [1 ]
Dehertogh, Pascale [1 ]
Vergauwen, Karen [1 ]
Mostmans, Wendy [1 ]
Vandyck, Koen [1 ,2 ]
Raboisson, Pierre [1 ,2 ]
Pauwels, Frederik [1 ]
机构
[1] Janssen Res & Dev, Beerse, Belgium
[2] Aligos Belgium BVBA, Heverlee, Belgium
关键词
capsid; capsid assembly modulator; cccDNA; hepatitis; hepatitis B virus; primary human hepatocytes; DOSE SAFETY; C-TERMINUS; PROTEIN; REPLICATION; HBC; PHARMACOKINETICS; TOLERABILITY; ORGANIZATION; DERIVATIVES; INHIBITION;
D O I
10.1128/AAC.02439-19
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the core protein. Core is a potential target for new antiviral therapies, the capsid assembly modulators (CAMs). JNJ-56136379 (JNJ-6379) is a novel and potent CAM currently in phase II trials. We evaluated the mechanisms of action (MOAs) and antiviral properties of JNJ-6379 in vitro. Size exclusion chromatography and electron microscopy studies demonstrated that JNJ-6379 induced the formation of morphologically intact viral capsids devoid of genomic material (primary MOA). JNJ-6379 accelerated the rate and extent of HBV capsid assembly in vitro. JNJ-6379 specifically and potently inhibited HBV replication; its median 50% effective concentration (EC50) was 54 nM (HepG2.117 cells). In HBV-infected primary human hepatocytes (PHHs), JNJ-6379, when added with the viral inoculum, dose-dependently reduced extracellular HBV DNA levels (median EC50 of 93 nM) and prevented covalently closed circular DNA (cccDNA) formation, leading to a dose-dependent reduction of intracellular HBV RNA levels (median EC50 of 876 nM) and reduced antigen levels (secondary MOA). Adding JNJ-6379 to PHHs 4 or 5 days postinfection reduced extracellular HBV DNA and did not prevent cccDNA formation. Time-of-addition PHH studies revealed that JNJ-6379 most likely interfered with postentry processes. Collectively, these data demonstrate that JNJ-6379 has dual MOAs in the early and late steps of the HBV life cycle, which is different from the MOA of nucleos(t)ide analogues. JNJ-6379 is in development for chronic hepatitis B treatment and may translate into higher HBV functional cure rates.
引用
收藏
页数:15
相关论文
共 48 条
[11]  
Eley T, 2017, HEPATOLOGY, V66, p490A
[12]   EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection [J].
Lampertico P. ;
Agarwal K. ;
Berg T. ;
Buti M. ;
Janssen H.L.A. ;
Papatheodoridis G. ;
Zoulim F. ;
Tacke F. .
JOURNAL OF HEPATOLOGY, 2017, 67 (02) :370-398
[13]   RO7049389, a core protein allosteric modulator, demonstrates robust anti-HBVactivity in chronic hepatitis B patients and is safe and well tolerated [J].
Gane, E. ;
Liu, A. ;
Yuen, M-F. ;
Schwabe, C. ;
Bo, Q. ;
Das, S. ;
Gao, L. ;
Zhou, X. ;
Wang, Y. ;
Coakley, E. ;
Jin, Y. .
JOURNAL OF HEPATOLOGY, 2018, 68 :S101-S101
[14]   HEPATITIS B CORE (HBC) PROTEIN IS A KEY AND VERY EARLY NEGATIVE REGULATOR OF THE INTERFERON RESPONSE [J].
Gruffaz, M. ;
Testoni, B. ;
Luangsay, S. ;
Ait-Goughoulte, M. ;
Petit, M-A ;
Ma, H. ;
Klumpp, K. ;
Javanbakht, H. ;
Durantel, D. ;
Zoulim, F. .
JOURNAL OF HEPATOLOGY, 2013, 58 :S155-S156
[15]   Hepatitis B viral core protein disrupts human host gene expression by binding to promoter regions [J].
Guo, Yanhai ;
Kang, Wei ;
Lei, Xiaoying ;
Li, Yongnian ;
Xiang, An ;
Liu, Yonglan ;
Zhao, Jinrong ;
Zhang, Ju ;
Yan, Zhen .
BMC GENOMICS, 2012, 13
[17]   Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application [J].
Hu, Jianming ;
Liu, Kuancheng .
VIRUSES-BASEL, 2017, 9 (03)
[18]   JNJ-64530440, a novel capsid assembly modulator: single- and multiple-ascending dose safety, tolerability and pharmacokinetics in healthy volunteers [J].
Kakuda, Thomas ;
Yogaratnam, Jeysen ;
Westland, Christopher ;
Gane, Edward ;
Schwabe, Christian ;
Patel, Megha ;
Talloen, Willem ;
Lenz, Oliver ;
van Remoortere, Pieter .
JOURNAL OF HEPATOLOGY, 2019, 70 (01) :E469-E469
[19]   Trapping of Hepatitis B Virus Capsid Assembly Intermediates by Phenylpropenamide Assembly Accelerators [J].
Katen, Sarah P. ;
Chirapu, Srinivas Reddy ;
Finn, M. G. ;
Zlotnick, Adam .
ACS CHEMICAL BIOLOGY, 2010, 5 (12) :1125-1136
[20]   Generation of Covalently Closed Circular DNA of Hepatitis B Viruses via Intracellular Recycling Is Regulated in a Virus Specific Manner [J].
Koeck, Josef ;
Roesler, Christine ;
Zhang, Jing-Jing ;
Blum, Hubert E. ;
Nassal, Michael ;
Thoma, Christian .
PLOS PATHOGENS, 2010, 6 (09)