抗乙肝病毒治疗新策略:阻断P-ε相互作用

New Strategy for Anti-HBV Therapy:Blocking P-ε interaction

目前,临床上治疗乙型肝炎病毒(Hepatitis B virus,HBV)导致的慢性乙肝药物存在应答率低、副作用大和耐药性等缺点,急需寻找抗病毒治疗的新靶点。HBV反转录过程中,反转录酶(P蛋白)和位于病毒前基因组RNA(Pregenome RNA,pgRNA)5′邻近的RNA包装信号(ε)的相互作用(又称P-ε相互作用)非常关键,该相互作用有宿主蛋白如热激蛋白的参与。P-ε复合物形成后,一方面引发反转录的启动,另一方面启动核衣壳的包装。目前封闭P-ε相互作用的策略主要有热激蛋白抑制剂、ε适配子和阻断P蛋白的化合物三个方面,其机制为针对性靶向P蛋白或者宿主蛋白,从而直接或间接地阻断P-ε相互作用。前期,我们首次体外筛选到干扰P-ε相互作用的适配子,体外实验及动物实验均证实,该类适配子强烈抑制HBV复制。总之,P-ε相互作用为抗乙肝研究的临床治疗提供了一个极具吸引力和应用前景的药物靶点,上述三种策略绕过或克服了目前临床上HBV对化疗药的耐药问题,具有较高的应用前景。

Clinically being applied treatment against chronic hepatitis has three limitations：low response rates,severe adverse effects and a high rate of drug resistance.Hence,novel targets for antiviral therapy need to be developed so as to provide an armory of different strategies.During the replication of hepatitis B virus,the interaction of viral polymerase（P protein,also called P）andεRNA is indispensable for the initiation of reverse transcription via protein priming and the pregenome RNA（pgRNA）packaging.Three strategies are currently developed for blocking P-εinteraction：heat shock protein inhibitors,εaptamers and chemical compounds for blocking formation of P-εcomplex.Previously,our group has for the first time worldwide in vitro screened several aptamers,which are able to interfere with the P-εinteraction.A strong inhibition against HBV was observed in vitro and in vivo experiments,respectively.In conclusion,the so far developed chemicals suppressing the P-εinteraction may bypass or overcome the viral resistance problems during clinic treatment and represent a highly attractive option for therapeutic intervention.