Novel Neplanocin A Derivatives as Selective Inhibitors of Hepatitis B Virus with a Unique Mechanism of Action
Novel Neplanocin A Derivatives as Selective Inhibitors of Hepatitis B Virus with a Unique Mechanism of Action
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新型 Neplanocin A 衍生物作为乙型肝炎病毒的选择性抑制剂，具有独特的作用机制
DOI：
10.1128/aac.02073-21
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发表时间：
2022
影响因子：
4.9
通讯作者：
Masanori Baba
中科院分区：
文献类型：
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作者：
Masaaki Toyama;Koichi Watashi; Masanori Ikeda; Atsuya Yamashita;Mika Okamoto;Kohji Moriishi;Masamichi Muramatsu; Takaji Wakita;Ashoke Sharon;Masanori Baba
新的奈普拉霉素A衍生物在体外被鉴定为有效的和选择性的B肝炎病毒（HBV）复制抑制剂。这些包括（1 S，2 R，5 R）-5-（5-溴-4-甲基-7H-吡咯并[2，3-d]-嘧啶-7-基）-3-（羟甲基）环戊二烯-3-烯-1，2-二醇（AR-II-04-26）和（1 S，2 R，5 R）-5-（4-氨基-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基）-3-（羟甲基）环戊二烯-3-烯-1，2-二醇（MK-III-02-03）。在HepG2.2.15.7细胞中，AR-II-04-26和MK-III-02-03的50%有效浓度分别为0.77 ± 0.23和0.83 ± 0.36 μM。这些化合物降低了HepG2.2.15.7细胞和感染的原代人肝细胞中的细胞内HBV RNA水平。因此，它们可以减少培养上清液中的HBs和HBe抗原产生，这在临床批准的抗HBV核苷和核苷酸（逆转录酶抑制剂）中没有观察到。neplanocin A衍生物还抑制源自cccDNA的HBV RNA。此外，与奈普拉霉素A本身不同，该化合物不具有S-腺苷-L-高半胱氨酸水解酶活性。因此，AR-II-04-26和MK-III-02-03的作用机制似乎与临床批准的抗HBV药物不同。尽管它们的确切机制（靶分子）仍有待阐明，但新型新霉素A衍生物被认为是抑制HBV复制的有前途的候选药物。
Novel neplanocin A derivatives have been identified as potent and selective inhibitors of hepatitis B virus (HBV) replicationin vitro. These include (1S,2R,5R)-5-(5-bromo-4-methyl-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol (AR-II-04-26) and (1S,2R,5R)-5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(hydroxylmethyl)cyclopent-3-ene-1,2-diol (MK-III-02-03). The 50% effective concentrations of AR-II-04-26 and MK-III-02-03 were 0.77 ± 0.23 and 0.83 ± 0.36 μM in HepG2.2.15.7 cells, respectively. These compounds reduced intracellular HBV RNA levels in HepG2.2.15.7 cells and infected primary human hepatocytes. Accordingly, they could reduce HBs and HBe antigen production in the culture supernatants, which was not observed with clinically approved anti-HBV nucleosides and nucleotides (reverse transcriptase inhibitors). The neplanocin A derivatives also inhibited HBV RNA derived from cccDNA. In addition, unlike neplanocin A itself, the compounds did not inhibitS-adenosyl-l-homocysteine hydrolase activity. Thus, it appears that the mechanism of action of AR-II-04-26 and MK-III-02-03 differs from that of the clinically approved anti-HBV agents. Although their exact mechanism (target molecule) remains to be elucidated, the novel neplanocin A derivatives are considered promising candidate drugs for inhibition of HBV replication.