Novel Antiretroviral Agents

Duke University, Durham NC

Investigators

Abstract

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.