活性位点聚合酶抑制剂核苷酸 (ASPIN)：慢性 HBV 治愈方案的潜

StephenW

活性位点聚合酶抑制剂核苷酸 (ASPIN)：慢性 HBV 治愈方案的潜在药物
Robert G Gish 1 2 岁，Tarik Asselah 3 岁 4 岁，Katherine Squires 5 岁，Douglas Mayers 5 岁
隶属关系
隶属关系

    1个
    206052 乙型肝炎基金会，美国宾夕法尼亚州多伊尔斯敦。
    2个
    Robert G. Gish Consultants, LLC，美国加利福尼亚州拉霍亚。
    3个
    巴黎大学，Inserm U1149，Centre de Recherche sur l'inflammation，巴黎，法国。
    4个
    肝病学系，AP-HP，55100Hôpital Beaujon，法国克利希。
    5个
    Antios Therapeutics，门德姆，新泽西州，美国。

    PMID：36423233 DOI：10.1177/20402066221138705

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慢性乙型肝炎病毒 (HBV) 感染影响全球 240 至 3 亿人。在受感染的肝细胞的细胞核中，HBV 基因组被转化为共价闭合环状 DNA (cccDNA)，它持续存在并作为病毒后代的转录模板。因此，慢性 HBV 感染的长期治愈需要消除 cccDNA。尽管目前可用的核苷（酸）类似物（例如富马酸替诺福韦地索普西、替诺福韦艾拉酚胺、恩替卡韦）可有效控制 HBV 复制，但它们很少能治愈（功能性治愈率约 10%）并且大多数患者需要终生治疗。因此，需要具有新作用机制的抗病毒剂。活性位点聚合酶抑制剂核苷酸 (ASPIN) 非竞争性地扭曲 HBV 聚合酶活性位点以完全抑制所有聚合酶功能，这与传统的链终止核苷（酸）类似物不同，后者仅针对选定的聚合酶功能并在此过程中被消耗。 Clevudine 是第一代 ASPIN，在 2 期和 3 期临床研究中显示出有效且延长的 HBV 抑制作用，但长期治疗与少数患者的可逆性肌病相关。 ATI-2173 是一种新型的下一代 ASPIN，在结构上与克拉夫定相似，但以肝脏为靶点，在治疗期间和治疗期间均表现出有效的抗 HBV 活性，并可能通过显着降低全身性克拉夫定暴露最终证明药代动力学和安全性得到改善。因此，ATI-2173 目前正处于作为 HBV 治愈剂的临床开发阶段。在这里，我们回顾了克拉夫定和 ATI-2173 的作用机制以及临床前和临床概况，以支持 ASPIN 作为慢性 HBV 感染治疗方案的一部分的作用。

关键词：ATI-2173； ccDNA;慢性乙型肝炎；克拉夫定;核苷（酸）类似物。

StephenW

Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens
Robert G Gish  1   2 , Tarik Asselah  3   4 , Katherine Squires  5 , Douglas Mayers  5
Affiliations
Affiliations

    1
    206052Hepatitis B Foundation, Doylestown, PA, USA.
    2
    Robert G. Gish Consultants, LLC, La Jolla, CA, USA.
    3
    Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France.
    4
    Department of Hepatology, AP-HP, 55100Hôpital Beaujon, Clichy, France.
    5
    Antios Therapeutics, Mendham, NJ, USA.

    PMID: 36423233 DOI: 10.1177/20402066221138705

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Abstract

Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.

Keywords: ATI-2173; cccDNA; chronic hepatitis B; clevudine; nucleos(t)ide analogues.

StephenW

https://doi.org/10.1177/20402066221138705