二甲苯酮类非核苷类逆转录酶抑制剂的体外抗HIV-1活性  

The anti-HIV-1 activities of benzophenones non-nucleoside reverse transcriptase inhibitors in vitro

作　　者：王萍[1,2] 张高红[1] 向思颖 杨柳萌[1] 唐成润[1,2] 马晓东[3] 郑永唐[2] 

机构地区：[1]中国科学院昆明动物研究所,中国科学院和云南省动物模型与人类疾病机理重点实验室,云南昆明650223 [2]昆明医科大学药学院暨云南省天然药物药理重点实验室,云南昆明650500 [3]大连医科大学药学院,辽宁大连116044

出　　处：《药学学报》2016年第11期1704-1710,共7页Acta Pharmaceutica Sinica

基　　金：国家科技重大专项资助项目(2009ZX09501-029,2014ZX10005-002);国家自然科学基金资助项目(81471620,81102483);云南省应用基础研究计划资助项目(2015FB182)

摘　　要：本文评价了5个二甲苯酮类非核苷类逆转录酶抑制剂(DY1203、DY1204、DY1119、DY1208和DY1209)的体外抗HIV-1药效学。采用MTT法检测了5个化合物对人T淋巴细胞系(C8166、MT-4、H9)和PBMC的毒性作用;p24抗原ELISA方法测定了化合物对1株HIV-1实验株、4株耐药株和3株临床株的抗病毒活性;HIV逆转录酶试剂盒检测了化合物体外对HIV-1重组逆转录酶的抑制活性。结果表明,5个化合物中,DY1203和DY1204对不同细胞的毒性均很小(CC50>200μg·m L-1)。DY1119、DY1208和DY1209具有显著的抗病毒活性,对实验株HIV-1IIIB、NRTI耐药株HIV-174V、PI耐药株HIV-1RF/V82F/184V、FI耐药株HIV-1NL4-3 gp41(36G)N42S和临床分离株(HIV-1KM018、HIV-1TC-1、HIV-1Wan)均有很强的抑制作用,而NNRTI耐药株HIV-1A17对其有不同程度耐药。5个化合物对HIV-1重组逆转录酶有不同程度的抑制效应,其中DY1208有显著的抗HIV-1活性和较高的治疗指数,安全性高,有望成为新的抗HIV-1先导化合物。o evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors （NNRTIs） such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC50 greater than 200 μg·mL^-1. DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1IIIB, HIV-174V, HIV-1RF/V82F/184V, HIV-1NL4-3 gp41（36G） N42S, HIV-1KM018, HIV-1TC-1 and HIV-1Wan. However, NNRTIs drug-resistant strain HIV-1A17 showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.

关 键 词：非核苷类逆转录酶抑制剂 HIV-1 实验株 耐药株 临床株 抗病毒活性 

分 类 号：R965[医药卫生—药理学]