乙型肝炎病毒活性位点聚合酶抑制剂核苷酸——ATI-2173

Active site polymerase inhibitor nucleotides for hepatitis B virus:ATI-2173

ATI-2173是Antios Therapeutics公司研发的第二代活性位点聚合酶抑制剂核苷酸(ASPINs),是第一代ASPINs克拉夫定经5’-磷酰胺修饰的前药,旨在改善克拉夫定的药动学特征,降低克拉夫定全身暴露水平以及引起骨骼肌病的风险,目前该药物正在进行治疗慢性乙型肝炎(CHB)的临床试验。在体外模型研究中,ATI-2173能有效抑制乙型肝炎病毒(HBV)的复制,与拉米夫定和恩替卡韦等链终止核苷类药物具有交叉耐药性,对细胞无毒害性,具有良好的口服利用度和肝脏靶向性。Ⅰ期临床试验结果显示,ATI-2173单独给药时表现出良好的安全性、耐药性及抗病毒活性。Ⅱ期临床试验结果表示,ATI-2173与富马酸替诺福韦酯联合治疗HBC感染患者,具有良好的安全性和抗病毒活性,并且能有效延长治疗后的病毒抑制时间,这对HBV感染患者的长期治疗具有重要意义。本文就ATI-2173的基本信息、作用机制、临床前研究及临床研究等进行概述。

ATI-2173 is a second generation active site polymerase inhibitor nucleotidses(ASPINs)developed by Antios Therapeutics.It is the prodrug of the first-generation ASPINs,clevudine,modified by 5'-phosphoramide,aiming to improve the pharmacokinetic characteristics of clevudine and reduce the systemic exposure levels and the risk of skeletal muscle disease.Currently,this drug is undergoing clinical trials for the treatment of chronic hepatitis B(CHB).In vitro studies have shown that ATI-2173 can effectively inhibit the replication of hepatitis B virus(HBV).It exhibits cross-resistance with chain-terminating nucleosides such as lamivudine and entecavir,and demonstrates non-toxicity to cells,good oral bioavailability and liver targeting.Phase I clinical trial results have showed that ATI-2173,when administered alone,exhibites good safety,tolerability,and antiviral activity.The results of phase II clinical trials have indicated that the combination of ATI-2173 and tenofovir disoproxil fumarate shows good safety and antiviral activity in the treatment of patients with HBV infection,and can effectively prolong the viral inhibition time after treatment,which is of great significance for long-term treatment of patients with HBV infection.This article provides an overview of the basic information,mechanism,preclinical research and clinical studies of ATI-2173.