中国科学家从玉米中获得一种能够选择性地杀伤HIV感染细胞的蛋白酶突变体,为研发新型抗HIV药物提供了新思路和新策略。
这是今天从此间的中国科学院昆明动物研究所传出的消息。毗邻东南亚多国的云南省一度是中国毒品和艾滋病的重灾区。
消息称,中国科学院昆明动物研究所郑永唐研究员学科组与香港中文大学邵鹏柱教授学科组合作完成了这一研究课题。
郑永唐研究员从事免疫学、病毒学和抗HIV药物等研究20余年,尤其在抗HIV药物、AIDS灵长类动物模型、病毒限制因子等研究方面积累丰富的经验。
他称,“HIV病毒存在潜藏机制,可以长期潜伏在细胞中而逃逸宿主免疫系统的攻击,目前已上市的抗HIV药物均不能选择性地杀伤感染细胞而根除病毒,研究具有选择性地杀伤HIV感染细胞而保护正常细胞不受伤害的抗HIV药物极为重要。”
经过多年合作,内地与香港科学家对玉米核糖体失活蛋白的内部失活结构域进行一系列的结构修饰和改造,获得了能识别并激活HIV蛋白酶特异的玉米核糖体失活蛋白突变体。
细胞水平实验的研究表明,此种突变体对未感染细胞毒性低,但突变体进入HIV感染细胞后,则可被细胞内的HIV蛋白酶识别并切割去除失活结构域转变成为活性蛋白,从而选择性地杀伤HIV感染细胞。研究结果还表明,因为此种突变体能够高效率地进入感染细胞,因此对HIV-1感染细胞的杀伤力更强;突变体也可以被HIV蛋白酶耐药株的蛋白酶识别并激活,因此突变体对HIV蛋白酶耐药株感染细胞也有很好的选择杀伤性。
郑永唐表示,该研究成果为研发特异性靶向HIV感染细胞的新型抗HIV药物提供了新思路和新策略。“研究成果已经在国际著名学术期刊Nucleic Acids Research 发表并申请国家专利。”
郑透露,此次研究获得了香港研究资助局、中国国家科技部973项目、国家重大科技专项、中国科学院等项目资助。(生物谷Bioon.com)
生物谷推荐英文摘要:
Nucl. Acids Res. (2010) doi: 10.1093/nar/gkq1133
Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids
Erik B. Pedersen1, Jakob T. Nielsen1, Claus Nielsen2 and Vyacheslav V. Filichev3,*
1Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, 5230 Odense, 2Department of Virology, Retrovirus Laboratory, State Serum Institute, 2300 Copenhagen, Denmark and 3Institute of Fundamental Sciences, Massey University, Palmerston North, Private Bag 11-222, New Zealand
Two G-quadruplex forming sequences, 5′-TGGGAG and the 17-mer sequence T30177, which exhibit anti-HIV-1 activity on cell lines, were modified using either locked nucleic acids (LNA) or via insertions of (R)-1-O-(pyren-1-ylmethyl)glycerol (intercalating nucleic acid, INA) or (R)-1-O-[4-(1-pyrenylethynyl)phenylmethyl]glycerol (twisted intercalating nucleic acid, TINA). Incorporation of LNA or INA/TINA monomers provide as much as 8-fold improvement of anti-HIV-1 activity. We demonstrate for the first time a detailed analysis of the effect the incorporation of INA/TINA monomers in quadruplex forming oligonucleotides (QFOs) and the effect of LNA monomers in the context of biologically active QFOs. In addition, recent literature reports and our own studies on the gel retardation of the phosphodiester analogue of T30177 led to the conclusion that this sequence forms a parallel, dimeric G-quadruplex. Introduction of the 5′-phosphate inhibits dimerisation of this G-quadruplex as a result of negative charge–charge repulsion. Contrary to that, we found that attachment of the 5′-O-DMT-group produced a more active 17-mer sequence that showed signs of aggregation—forming multimeric G-quadruplex species in solution. Many of the antiviral QFOs in the present study formed more thermally stable G-quadruplexes and also high-order G-quadruplex structures which might be responsible for the increased antiviral activity observed.