Novel Antiretroviral Agents

描述（由申请人提供）：研究目的是开发诱导hiv感染细胞凋亡的分子。病毒的细胞复制已被证明是通过DOHH形成氨基酸hypusine而发生的。真核起始因子5A （elFSA）是唯一含有hypusine的蛋白。假设认为，当被激活时，elFSA可以刺激核糖体功能，稳定mRNA并运输hiv -mRNA。一个系统的方法来合成新的hypusine抑制剂将进行了解抑制剂和DOHH之间的SAR。因为去铁酮和环匹罗酮已经证明在高浓度下抑制DOHH，目标是开发更有效的吡啶酮类似物。在六元环的2位和5位上有取代基的一类HPOs将被合成。羟基部分的酰化也将用于制备类似物作为前药，以增加细胞渗透性。此外，将获得与八面体金属酶理想相似的铁（ll）模型化合物，以了解螯合剂与铁（ll）之间的键合性质。最后，hiv感染的H9细胞将用新设计的分子处理，并观察这些细胞的凋亡行为。

DESCRIPTION (provided by applicant): The aim of the research is to develop molecules that induce apoptosis of HIV-infected cells. Viral replication of cells has been shown to occur through the formation of the amino acid hypusine by DOHH. The eukaryotic initiation factor 5A (elFSA) is the only protein to contain hypusine. Hypotheses suggest that when activated, elFSA can then stimulate ribosome function, stabilize mRNA, and transport HIV-mRNAs. A systematic approach toward synthesizing novel hypusine inhibitors will be performed to understand the SAR between the inhibitor and DOHH. Because deferiprone and ciclopirox have demonstrated inhibition of DOHH at high concentrations, the goal is to develop more effective pyridinone analogues. A class of HPOs will be synthesized, bearing substituents in the 2 and 5 position on the six-member ring. Acylation of the hydroxyl moiety will also be performed to prepare analogues as prodrugs to increase cellular permeability. Moreover, iron(lll) model compounds that are ideally similar to the octahedral metalloenzyme will be acquired to understand the bonding nature between the chelator and iron(lll). Finally, HIV-infected H9 cells will be treated with newly designed molecules, and the apoptotic behavior of these cells will be inspected.