中國科學(xué)家從玉米中獲得一種能夠選擇性地殺傷HIV感染細(xì)胞的蛋白酶突變體，為研發(fā)新型抗HIV藥物提供了新思路和新策略。
這是今天從此間的中國科學(xué)院昆明動物研究所傳出的消息,。毗鄰東南亞多國的云南省一度是中國毒品和艾滋病的重災(zāi)區(qū)。
消息稱,，中國科學(xué)院昆明動物研究所鄭永唐研究員學(xué)科組與香港中文大學(xué)邵鵬柱教授學(xué)科組合作完成了這一研究課題,。
鄭永唐研究員從事免疫學(xué)、病毒學(xué)和抗HIV藥物等研究20余年,，尤其在抗HIV藥物,、AIDS靈長類動物模型、病毒限制因子等研究方面積累豐富的經(jīng)驗(yàn),。
他稱,，“HIV病毒存在潛藏機(jī)制，可以長期潛伏在細(xì)胞中而逃逸宿主免疫系統(tǒng)的攻擊,，目前已上市的抗HIV藥物均不能選擇性地殺傷感染細(xì)胞而根除病毒,，研究具有選擇性地殺傷HIV感染細(xì)胞而保護(hù)正常細(xì)胞不受傷害的抗HIV藥物極為重要。”
經(jīng)過多年合作,，內(nèi)地與香港科學(xué)家對玉米核糖體失活蛋白的內(nèi)部失活結(jié)構(gòu)域進(jìn)行一系列的結(jié)構(gòu)修飾和改造,，獲得了能識別并激活HIV蛋白酶特異的玉米核糖體失活蛋白突變體。
細(xì)胞水平實(shí)驗(yàn)的研究表明,，此種突變體對未感染細(xì)胞毒性低,，但突變體進(jìn)入HIV感染細(xì)胞后，則可被細(xì)胞內(nèi)的HIV蛋白酶識別并切割去除失活結(jié)構(gòu)域轉(zhuǎn)變成為活性蛋白,，從而選擇性地殺傷HIV感染細(xì)胞,。研究結(jié)果還表明，因?yàn)榇朔N突變體能夠高效率地進(jìn)入感染細(xì)胞,，因此對HIV-1感染細(xì)胞的殺傷力更強(qiáng),；突變體也可以被HIV蛋白酶耐藥株的蛋白酶識別并激活，因此突變體對HIV蛋白酶耐藥株感染細(xì)胞也有很好的選擇殺傷性,。
鄭永唐表示,，該研究成果為研發(fā)特異性靶向HIV感染細(xì)胞的新型抗HIV藥物提供了新思路和新策略。“研究成果已經(jīng)在國際著名學(xué)術(shù)期刊Nucleic Acids Research 發(fā)表并申請國家專利,。”
鄭透露,，此次研究獲得了香港研究資助局、中國國家科技部973項(xiàng)目,、國家重大科技專項(xiàng),、中國科學(xué)院等項(xiàng)目資助。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
