The long-term objective of the proposed research is to develop new therapeutic regimens which may be employed effectively either alone or in combination with other drugs for treatment of the acquired immunodeficiency syndrome (AIDS). To achieve this goal, the Principal Investigator has established a multi- disciplinary effort to synthesize novel prodrugs of 2',3'- dideoxynucleosides (DDN's). In the proposed research, he and his associates will design new analogs to attain higher intracellular drug concentrations, to decrease bone marrow toxicity, and to overcome limited permeability through the blood brain barrier. They will synthesize, specifically, sterically-hindered esters of DDN's in an attempt to increase the plasma half-life and permeability into the central nervous system (CNS) and hexadecyl esters linked at the phosphate function of the glycerol phosphate esters of DDN's and of dimers such as AZT-P-U in order to enhance transmembrane transport properties. In a second major effort, the researchers will examine the effects of vitamin E and of growth factors (i.e., IL-3, GMSCF, and SCF) with respect to protection of bone marrow cells from AZT-induced inhibition of erythropoietin-receptor expression as well as of protein kinase C activity, determining such physicochemical parameters as partition coefficients and protein binding capacities of the newly synthesized agents. They will evaluate the intracellular uptake and antiviral action of prodrugs in vitro, employing cells infected with the human immunodeficiency virus (HIV), such as human peripheral blood lymphocytes (PBL's) and monocytes/ macrophages of lymphocytic and monocytic cell lines (H9 and MT4, and U937, respectively). Finally, in order to determine the extent and rate of entry of the various prodrugs into the cerebrospinal fluid (CSF) and brain tissue, the researchers will study the active agents developed by this program in mice and rabbits to evaluate pharmacokinetic parameters.
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