Deveropment of the Anti-AIDS Drug Based on the Aspartyl Protease Inhbitor

艾滋病病毒的RNA编码了各种蛋白质的序列，并在其靶细胞中实现，然后产生帮助病毒分化和生长的构建蛋白和酶。其中指出了一种酶的存在，这种酶处理一种在病毒分化和增殖中起重要作用的蛋白质。这种酶是天冬氨酸蛋白酶，其活性中心有天冬氨酸。指出用Asn取代所提出的活性位点Asp-25，消除了病毒的传染性。本研究的目的是化学合成该酶，研究其特性，并规划其抑制剂，从而开发出治疗AJDS的药物。至于抑制剂的研制，一般合成反式烯烃型二肽异构体。1)将作者开发的有机ococp - lewis酸配合物应用于同手性CL， P -enoate, 1,3手性转移反应，证明了目标基本结构(E)-alken等构二肽可以高选择性、高收率地得到。合成了几种反式烯烃型同分异构体。2)采用基于fmoc的固相法合成天冬氨酸蛋白酶时，研究人员开发的化学选择性纯化技术对固相法合成的由99个氨基酸残基组成的蛋白质具有很好的纯化效果。本研究合成了因官能团较多而被认为难以合成的反式烯烃二肽异构体，并建立了其高效立体选择性合成方法。该方法可用于用Isester合成抗HIV蛋白酶抑制肽。

Sequences of various proteins are encoded in the RNA of AIDS virus and they are realized in their target cells and then constructive proteins and enzymes which help viruses be differentiated and grow are produced.Among them the existence of an enzyme was pointed out, which processes a protein playing an essential role in the viruses differentiation and multiplication.This enzyme is aspartic protease having aspartic acid at its active center. It is pointed out that the replacement of the proposed active site Asp-25 with Asn, eliminate the infectivity of the virus.Our study aimes to synthesize this enzyme chemically to investigate its characteristics and to plan its inhibitor so that the medicine to cure the AJDS will be able to be developed. As for the development of the inhibitor, the general synthesis of trans-olefine type dipeptide-isostere.1)Organocupper-Lewis acid complex developed by the reporters was applied to homochiral CL, P -enoate, 1, 3chirality transfer reaction was performed, and it was proved that the aimed basic structure, (E)-alken isosteric dipeptide, can be obtained highly selectively at high yield. Some sorts of trans-olefine type isosteres were synthesized.2)When the aspartyl protease was synthesized by Fmoc-based solid phase synthesis, the chemoselectively purification technique developed by the reporters was proved to be very effective for the purification of protein consisted of 99 amino acid residues synthesized by solid phase technique.By this study, trans-alkene dipeptide-isostere, which has been considered to be hardly synthesized because of many functional groups, was synthesized and its highly efficient and stereoselective synthesis was established.This method can be applied to the synthesis of inhibiting peptides against HIV protease produced with the Isester.