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AASLD2017[940]
The HBV capsid assembly modulator JNJ-379 is
a potent inhibitor of viral replication across full
length genotype A-H clinical isolates in vitro
Jan Martin Berke1, Thierry Verbinnen1, Ying Tan2, Pascale
Dehertogh1, Karen Vergauwen1, Koen Vandyck1, Oliver
Lenz1; 1Janssen Research & Development, Beerse, Belgium;
2Janssen China Research & Development Center, Shanghai,
China
BACKGROUND: Hepatitis B Virus (HBV) capsid assembly is
a critical step in virus production. The HBV core protein
represents an attractive target for new antiviral therapies
due to its multiple functions within the viral life-cycle.
Here, we report the antiviral activity of JNJ-56136379 (JNJ-
379), a potent capsid assembly modulator (CAM) in Phase
1 clinical trials, on a broad panel of HBV genotype (GT)
A-H clinical isolates and assessed the impact of core amino
acid (aa) substitutions. METHODS: The anti-HBV activity
of JNJ-379 was tested on a panel of 53 different clinical
isolates, representing HBV GT A-H. The constructs were
synthesized based on sequences obtained from public
databases, cloned as 1.1- and 1.3mer into a pcDNA3.1 backbone,
and activity was compared with a GT D reference
construct (NCBI ID V01460) in a transient HBV replication
assay in HepG2 cells using qPCR as read out. In addition,
site-directed mutants with mutations in the CAM-binding
domain were tested in the pTRE-HBVT backbone. RESULTS:
The isolate panel (N=53) encompasses 50 unique HBV core
sequences which differ by at least 1 aa from each other
and have 1 to 21 aa changes in the core assembly domain
(aa1-149) compared to the reference GT D sequence. The
median EC50 values of JNJ-379 across all genotypes ranged
from 10 nM to 33 nM by genotype compared to 17 nM for
the GT D reference construct. One isolate with a polymorphism at core aa position 33 (T33N) showed an EC50 value
of 5,160 nM for JNJ-379 whereas nucleos(t)ide analogues
retained full activity. Core aa substitutions T33N, Y118F,
and T128I reduced JNJ-379 anti-HBV activity by 78-, 6.9-,
and 19-fold, respectively, whereas D29G, T33S, I105T, and
T114I resulted in fold reductions ranging from 2.1 to 2.9.
These substitutions were very rare among >7,600 HBV core
sequences derived from a public database, with frequencies
ranging from 0.03% for T33N to 0.9% for T114I.
JNJ-379 retained activity against isolates carrying nucleos(t)ide analogue resistance mutations as well as against
isolates with basal core promoter (BCP) and/or precore
(PC) mutations (median EC50 values of 12, 16, and 12 nM,
respectively). CONCLUSION: JNJ-379 is a potent HBV CAM
which generally remained fully active against an extensive
panel of diverse GT-A-H clinical isolates, irrespective of the
presence of nucleos(t)ide analogue resistance or BCP/PC
mutations. HBV core aa substitutions within the putative
HAP-binding pocket at positions 29, 33, 105, 114, 118, and
128 result in reduced activity of JNJ-379. These variants
are rarely observed in HBV sequence databases. JNJ-379 is
currently in phase 1 clinical development.
Disclosures:
Jan Martin Berke - Employment: Janssen Research and Development
Thierry Verbinnen - Employment: Janssen Research and Development
Pascale Dehertogh - Employment: Janssen Research and Development
Karen Vergauwen - Employment: Janssen Research and Development
Koen Vandyck - Employment: Janssen Research and Development
Oliver Lenz - Employment: Janssen; Stock Shareholder: Janssen (J&J)
The following people have nothing to disclose: Ying Tan
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发表于 2017-10-22 20:23
