The causative agent of the fatal disease known as acquired immune deficiency syndrome (AIDS) is a lymphotropic retrovirus referred to as human immunodeficiency virus (HIV-1). Other retroviruses related to HIV-1 are also being identified. The replicative cycle of HIV-1 offers a number of targets for possible intervention by judiciously designed therapeutic agents. The long-term goals of this research program are to contribute to the chemistry and biochemistry of novel nucleosides, carbohydrates, and related molecules with useful therapeutic potential against AIDS.
The specific aims of this research investigation are concerned with potential synergistic inhibitors of HIV infectivity that are directed at two important post-translational glycosylation. The novel compounds targeted for synthesis as HIV reverse transcriptase inhibitors include strategically functionalized congeners, pro-drugs, and positional isomers of 2',3'- dideoxyinosine (ddl). Potential glycosylation inhibitors (of HIV glycoprotein gp120) proposed are novel aminosugars of the deoxynojirimycin family. Justification for the choice of the target compounds is presented. Chemical and biochemical studies on these compounds have been designed to provide information on hydrolytic stabilities, lipophilicities, substrate activities and inhibition of inosine monophosphate dehydrogenase (IMPDH), and phosphorylation by deoxycytidine kinase. The dideoxyhypoxanthine nucleosides and 1-deoxynojirimycin analogues synthesized in this project will be evaluate in highly purified form for their ability to inhibit the infectivity and cytopathic effect of HIV-1 and HIV-2 in human T4-lymphocyte cell lines. New information on inhibition of HIV reverse transcriptase, on inhibition of viral antigen expression, on inhibition of gp120 glycosylation, on cytotoxicity, and on therapeutic indexes are expected from the biological evaluation data. Combination chemotherapeutic studies involving synergistic inhibition of HIV infectivity are planned. The novel compounds proposed have high probability of being antivirally useful and the investigation is also expected to contribute to filling some of the gaps of knowledge in this area.
| Nair, V; Sells, T B (1992) Interpretation of the roles of adenylosuccinate lyase and of AMP deaminase in the anti-HIV activity of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine. Biochim Biophys Acta 1119:201-4 |
| Nair, V; Buenger, G S; Sells, T B (1991) Inhibition of mammalian adenosine deaminase by novel functionalized 2',3'-dideoxyadenosines. Biochim Biophys Acta 1078:121-3 |
