HBV衣壳装配调节剂JNJ-56136379的全长体外基因型A-H临床分离株

StephenW

J Antimicrob Chemother. 2020 May 17. pii: dkaa179. doi: 10.1093/jac/dkaa179. [Epub ahead of print]
Anti-HBV activity of the HBV capsid assembly modulator JNJ-56136379 across full-length genotype A-H clinical isolates and core site-directed mutants in vitro.
Verbinnen T1, Tan Y2, Wang G2, Dehertogh P1, Vergauwen K1, Neefs JM1, Jacoby E1, Lenz O1, Berke JM1.
Author information

1
    Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
2
    Janssen China Research & Development Center, 5F North Building #1 Jinchuang Mansion, 4560 Jinke Road, Shanghai 201210, China.

Abstract
OBJECTIVES:

To characterize antiviral activity of the capsid assembly modulator (CAM-N) JNJ-56136379 against HBV genotypes and variants carrying amino acid substitutions in the core protein.
METHODS:

Anti-HBV activity of JNJ-56136379 was investigated against a diverse panel of 53 HBV clinical isolates (genotypes A-H). The impact of core amino acid substitutions using site-directed mutants (SDMs) was assessed in a transient replication assay.
RESULTS:

JNJ-56136379 median 50% effective concentration (EC50) values across all genotypes were 10-33 nM versus 17 nM (genotype D reference). JNJ-56136379 remained active against isolates carrying nucleos(t)ide analogue resistance mutations (median EC50 2-25 nM) or basal core promoter (BCP) ± precore (PC) mutations (median EC50 13-20 nM) or PC mutations (median EC50 11 nM), representing activity against isolates from HBeAg-positive and -negative hepatitis B patients. Core amino acid substitutions in the CAM-binding pocket, when tested as SDMs at positions 23, 25, 30, 33, 37, 106, 110, 118, 124, 127 and 128, reduced JNJ-56136379 anti-HBV activity; EC50 fold increases ranged from 3.0 (S106T) to 85 (T33N). All substitutions were rare in a public database of >7600 HBV core sequences (frequencies 0.01%-0.3%). Nucleos(t)ide analogues retained full activity against these core SDMs.
CONCLUSIONS:

JNJ-56136379, a potent HBV CAM-N, currently in Phase 2 clinical development, was generally fully active against an extensive panel of genotype A-H clinical isolates, regardless of the presence of nucleos(t)ide analogue resistance or BCP/PC mutations. JNJ-56136379 activity was reduced by some core amino acid substitutions in the CAM-binding pocket.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].

PMID:
    32417895
DOI:
    10.1093/jac/dkaa179

StephenW

抗微生物化学杂志。 2020年5月17日。pii：dkaa179。土井：10.1093 /江淮/ dkaa179。 [Epub提前发布]
HBV衣壳装配调节剂JNJ-56136379的全长体外基因型A-H临床分离株和核心定点突变株的抗HBV活性。
Verbinnen T1，Tan Y2，Wang G2，Dehertogh P1，Vergauwen K1，Neefs JM1，Jacoby E1，Lenz O1，Berke JM1。
作者信息

1个
Janssen Research and Development，Turnhoutseweg 30，比利时比尔塞2340。
2
中国上海市金科路4560号金创大厦1号楼北楼5楼，詹森中国研究开发中心，上海201210。

抽象
目标：

为了表征衣壳装配调节剂（CAM-N）的抗病毒活性，JNJ-56136379对HBV基因型和在核心蛋白中带有氨基酸取代的变体具有抗病毒活性。
方法：

研究了JNJ-56136379的抗HBV活性，以对抗53种HBV临床分离株（基因型A-H）的多样性。在瞬时复制测定中评估了使用定点突变体（SDM）进行核心氨基酸取代的影响。
结果：

JNJ-56136379所有基因型的50％有效浓度中位数（EC50）值分别为10-33 nM与17 nM（基因型D参考）。 JNJ-56136379对带有核苷（t）ide类似物抗性突变（EC50中位数为25-25 nM）或基础核心启动子（BCP）±前核（PC）突变（EC50中位数13-20 nM）或PC突变（中位数）的分离株仍然具有活性EC50 11 nM），代表针对HBeAg阳性和阴性B型肝炎患者分离株的活性。当在23、25、30、33、37、106、110、118、124、127和128位作为SDM进行测试时，CAM结合口袋中的核心氨基酸取代会降低JNJ-56136379的抗HBV活性； EC50倍数增加范围为3.0（S106T）至85（T33N）。在大于7600 HBV核心序列（频率0.01％-0.3％）的公共数据库中，所有替代都很少见。核（t）ide类似物保留了针对这些核心SDM的全部活性。
结论：

JNJ-56136379是一种有效的HBV CAM-N，目前处于2期临床开发中，无论是否存在类似核苷酸抗性类似物或BCP / PC突变，其一般都对多种基因型AH临床分离株具有充分的活性。 JNJ-56136379活性因CAM结合口袋中的一些核心氨基酸取代而降低。

©作者2020。由牛津大学出版社代表英国抗菌化学协会出版。版权所有。有关权限，请发送电子邮件至：[email protected]。

PMID：
32417895
DOI：
10.1093 /江淮/ dkaa179