Novel Antiretroviral Agents

新型抗逆转录病毒药物

• 批准号: 6937859
• 负责人: Bradford J Pistorio
• 金额: $ 3.46万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937859
• 关键词: HIV infections; acylation; aminoacid analog; aminoacid inhibitor; antiAIDS agent; apoptosis; chelating agents; chemical structure function; drug design /synthesis /production; iron; lysine; membrane permeability; postdoctoral investigator; virus replication

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.

描述（由申请人提供）：研究的目的是开发诱导感染HIV感染细胞凋亡的分子。已经证明，通过DOHH形成氨基酸降量，已经证明了细胞的病毒复制。真核引发因子5a（ELFSA）是唯一含有非胰蛋白酶的蛋白质。假设表明，当激活时，ELFSA可以刺激核糖体功能，稳定mRNA和运输HIV-MRNA。将采用一种系统的合成新型抑制剂的系统方法，以了解抑制剂和DOHH之间的SAR。由于脱氟酮和ciclopirox在高浓度下表现出对DOHH的抑制作用，因此目标是开发更有效的吡啶酮类似物。将合成一类HPO，在六成员环上的2和5位置轴承取代基。还将进行羟基部分的酰化，以制备类似物作为前药，以增加细胞的渗透性。此外，将获得与八面体金属酶相似的铁（LLL）模型化合物，以了解螯合剂和铁（LLL）之间的键合性。最后，将使用新设计的分子处理HIV感染的H9细胞，并将检查这些细胞的凋亡行为。