非线性组合肽库及人工核酸酶的研制

AIDS (acquired immunodeficiency syndrome) is one of the most dangerous diseases in the world. Now people are making great efforts to probe into the origin of AIDS, control the infection of AIDS and seek the valid methods to treat AIDS. Treating AIDS is the great challenge to human beings. People have already developed some methods to control AIDS. One of the best methods is restraining the reverse transcriptase (RT) to terminate the viral DNA chain. So scientists are working hard to develop the RT inhibitors now. In this project the following results were obtained: (1)Two simple and efficient methods were developed for synthesis of nucleoside 5￠-phosphoramidates.(2)Nucleoside 5￠-thiophosphoramidates were developed as new efficient anti-HIV inhibitors，and have higher activity of anti-HIV and lower toxicity as compared to their parent nucleosides. (3)Enzymatic degradation studies of nucleoside 5￠-thiophosphoramidates in mouse liver esterase showed that these thiophosphoramidate derivatives could be transferred into active monophosphates of nucleosides. This project demonstrated that nucleoside 5￠-thiophosphoramidates had higher activities of anti-HIV and had the potential to be developed as anti-HIV RT inhibitors prodrugs. (4)The bioorganic model confirmed that anti-HIV prodrugs of nucleoside 5￠-phosphoramidates could undergo pentacoordinated phosphorane intermediates in the amino acid decomposition. The pentacoordinated phosphorane was synthesized, their hydrlysis pathway was tudied.(5)Nucleoside 5￠-phosphoramidates were determined by electrospray ionization mass spectrometry, and their fragmentation pathway was studied, so the results provided useful information for analysis of other hosphoramidates.

利用有机磷化合物活化氨基酸成肽特性建立组合肽库，该方法的优点在于：只需将氨基酸衍生物与有机磷活化试剂按一定比例混合均匀，肽库自动形成，打破传统的建立肽库方法，即保护、偶合、去保护等多次重复烦琐过程，而区种方法得到的是非线性组合肽库，这有利于寻找最小有效片段的活性肽；从肽库中寻找能高效催化切割核酸的人工核酸酶。