逆转录酶RNase H活性改变对NRTIs和NNRTIs体外药效学的影响：以RNase H为靶点研发HIV逆转录抑制剂的新思路

项目名称： 逆转录酶RNase H活性改变对NRTIs和NNRTIs体外药效学的影响：以RNase H为靶点研发HIV逆转录抑制剂的新思路

项目编号： No.81473256

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 郭颖

作者单位： 中国医学科学院药物研究所

项目金额： 67万元

中文摘要： 艾滋病已成为慢性病，虽有六类二十余个药物供选择，但患者因长期服用多种药物，仍会出现耐药及不良反应。HIV逆转录酶为病毒特有，有DNA聚合酶和RNase H酶活性。现有核苷及非核苷类逆转录酶抑制剂（NRTIs和NNRTIs）是重要抗艾滋病药物，是逆转录酶DNA聚合酶活性抑制剂，是高效抗逆转录病毒治疗方案所必需。本项目以逆转录酶RNaseH活性为研究对象，以NRTIs和NNRTIs为基础，研究改变RNase H活性（升高或降低）对NRTIs和NNRTIs单独/组合抗HIV体外药效学的影响。本项目将明确RNase H激动剂/抑制剂与NRTIs和NNRTIs联合作用方式（协同、加和或拮抗），明确以何种方式改变RNase H活性可实现与现有NRTIs和NNRTIs联合使用的抗病毒最佳药效，提供以RNase H为靶点的抗逆转录药物研发的新思路，为以RNase H为靶点的新型逆转录酶抑制剂研发提供依据。

中文关键词： 人类免疫缺陷病毒；逆转录；核糖核酸酶H；协同作用

英文摘要： Acquired immunodeficiency syndrome (AIDS), which was caused by infection with human immunodeficiency virus (HIV), became a chronic disease. There are more than twenty antiretroviral drugs belong to six classes acting on different stages of viral life cycle. Highly active antiretroviral therapy (HAART) is used for AIDS patients. However, adverse effects and drug resistance would appear after a certain time of therapy. Reverse transcriptase is a crucial enzyme of HIV with RNA dependent DNA polymerase, DNA dependent DNA polymerase and ribonuclease H activities. NRTIs and NNRTIs are important antiretroviral drugs for AIDS treatments by targeting to HIV reverse transcriptase DNA polymerase activity. This study focuses on RNase H activity. We will test NRTIs and/or NNRTIs antiviral effects with RNase H activity increased or decreased. This study will demonstrate the function modes (synergism, additive effect or antagonism) of RNase H inhibitor/activator combined with NRTIs and/or NNRTIs. It will provide a new clue to develop a novel type of reverse transcriptase inhibitors targeting to RNase H.

英文关键词： HIV;Reverse transcription;Ribonuclease H;Synergism