Verbinnen Thierry, Tan Ying, Wang Gengyan, Dehertogh Pascale, Vergauwen Karen, Neefs Jean-Marc, Jacoby Edgar, Lenz Oliver, Berke Jan Martin
Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
Janssen China Research & Development Center, 5F North Building #1 Jinchuang Mansion, 4560 Jinke Road, Shanghai 201210, China.
J Antimicrob Chemother. 2020 Sep 1;75(9):2526-2534. doi: 10.1093/jac/dkaa179.
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.
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.
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.
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.
表征衣壳组装调节剂（CAM-N）JNJ-56136379对乙型肝炎病毒（HBV）基因型以及核心蛋白中携带氨基酸替换的变体的抗病毒活性。
研究了JNJ-56136379对53株不同的HBV临床分离株（A-H基因型）的抗HBV活性。在瞬时复制试验中评估了使用定点突变体（SDM）进行核心氨基酸替换的影响。
JNJ-56136379在所有基因型中的半数有效浓度（EC50）中位数为10-33 nM，而基因型D参考株为17 nM。JNJ-56136379对携带核苷（酸）类似物耐药突变（EC50中位数为2-25 nM）或基础核心启动子（BCP）±前核心（PC）突变（EC50中位数为13-20 nM）或PC突变（EC50中位数为11 nM）的分离株仍具有活性，这代表了其对HBeAg阳性和阴性乙型肝炎患者分离株的活性。当在第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替换降低了JNJ-56136379的抗HBV活性；EC50倍数增加范围为3.0（S106T）至85（T33N）。在一个超过7600个HBV核心序列的公共数据库中，所有替换都很罕见（频率为0.01%-0.3%）。核苷（酸）类似物对这些核心SDM仍保持完全活性。
JNJ-56136379是一种有效的HBV CAM-N，目前正处于2期临床开发阶段，通常对A-H基因型的广泛临床分离株具有完全活性，无论是否存在核苷（酸）类似物耐药性或BCP/PC突变。CAM结合口袋中的一些核心氨基酸替换降低了JNJ-56136379的活性。
