HIV-1前体蛋白早成熟化小分子激活剂的筛选与评价

Screening and evaluation of small molecule activators for premature activation of HIV-1 precursors

人免疫缺陷病毒1(human immunodeficiency virus type 1,HIV-1)蛋白酶活性的严格调控对于病毒的生存至关重要。在病毒蛋白表达及病毒颗粒装配过程中,处于病毒前体蛋白Gag-Pol中的蛋白酶必须以无活性状态存在,避免前体蛋白Gag-Pol和Gag被提前酶切加工(前体蛋白早成熟化)。干扰HIV-1蛋白酶活性的调控机制,特异性激活前体蛋白中的蛋白酶,诱导前体蛋白早成熟化,就可直接抑制病毒复制。根据这一设想,利用前期已建立的细胞水平HIV-1前体蛋白早成熟化激活剂筛选模型,对3500个化合物进行筛选与评价,得到6个活性化合物具有激活作用,并具有一定的抗病毒活性,同时在一定程度上诱导了HIV-1感染细胞的凋亡。本研究为抗病毒药物的研发提供了思路。

Strict regulation of human immunodeficiency virus type 1(HIV-1)protease function is critical for efficient production of mature viral particles.During viral protein expression and viral assembly,HIV-1 protease(PR)located within Gag-Pol precursor must be inactive to prevent premature cytoplasmic processing of the viral Gag and Gag-Pol precursors.Premature activation of HIV-1 precursors leads to major defects in viral assembly and production of viral particles.Specifically activating the protease in the precursor protein can directly inhibit the replication of the virus.In addition,HIV-1 PR is able to induce cell apoptosis.In this study,we identified 6 small molecule compounds using a cell-based assay for screening compounds that activate HIV-1 PR and induce premature of HIV-1 precursors.Results showed the active compounds are able to activate HIV-1 PR,inhibit HIV-1 replication,and induce cell apoptosis.This study provides ideas for the research and development of antiviral drugs.