The overall goal of this proposal is the synthesis of prodrug derivatives of known anti-retroviral agents with improved ability to cross the blood-brain barrier and the evaluation of these compounds for the ability to halt retroviral infection in a murine model designed to screen candidate anti-AIDS agents targeted against virally induced CNS disease. The antiviral agent to be used in phosphonoformic acid (PFA).
Specific aims are: 1. To convert the very hydrophilic, negatively charged PFA molecule to lipophilic, less negative derivatives with favorable membrane diffusion properties and the ability to cross the blood- brain barrier. Depending on the latentiation group used, chemical and/or enzymatic release of PFA will occur at varying rates after entry into the CNS sanctuary. The proposed drugs will thus have the potential to act as sustained release formulations of PFA in the CNS. PFA will be modified at both the phosphonic and carboxylic acid moieties by ester and/or amide linkages. Pivaloyloxymethyl, dihydropyridyl, and diacylglyceride groups will be used to block PFA. 2. To perform biological evaluation of the PFA prodrugs in murine models that have been found useful in studies of the action of 3'-azido-3'-deoxythymidine (AZT) in the CNS. The test virus Cas-Br-E produces hind-limb paralysis in 3-5 months when injected inot newborn SWJ/R mice, and in 2-3 weeks when injected into midgestation embryos. Initially, virus replicates in the spleen and subsequently spreads to the CNS. Histopathology shows spongiform changes in gray matter of the spinal cord, cerebellum, and brain stem without inflammatory reaction. These pathological changes are similar to those seen in human AIDS patients with certain neurological syndromes. Work by the Co- Principal Investigator has recently shown that AZT, which is known to penetrate the blood-brain barrier, suppresses hind-limb paralysis and significantly prolongs life of Cas-Br-E infected mice in a dose-dependent manner. A rapid and cost-effective in vivo assay is thus already in place to perform side by side comparison of PFA and its lipophilic prodrug derivatives in a neurotropic virus model. The significance of this work lies in its potential to identify novel sustained release produrgs of PFA that will deliver the active agent to the CNS sanctuary for treatment of HIV infections of the CNS.
| Fazely, F; Dezube, B J; Allen-Ryan, J et al. (1991) Pentoxifylline (Trental) decreases the replication of the human immunodeficiency virus type 1 in human peripheral blood mononuclear cells and in cultured T cells. Blood 77:1653-6 |
| Rosowsky, A; Saha, J; Fazely, F et al. (1990) Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate esters of 3'-azido-3'-deoxythymidine. Biochem Biophys Res Commun 172:288-94 |
