The long-term objective of the proposed research is to develop new therapeutic drug regimens which could be effectively employed either alone or in combination for the treatment of acquired immunodeficiency syndrome (AIDS). To achieve this goal, a multidisciplinary effort has been initiated to synthesize a series of novel prodrugs of selected inhibitors of the enzyme reverse transcriptase of human immunodeficiency virus (HIV). The new analogs would be designed to achieve higher intracellular drug concentrations, to decrease bone marrow toxicity and to overcome the blood brain barrier. Based upon our encouraging results with isoleucine and retinoic acid esters of zidovudine (AZT), these prodrug moieties will also be linked to other 2', 3'-dideoxynucleosides (ddNs). Rational design of new analogs would include: (a) ddN esters of alpha-difluoremethylornithine (DFMO) or other inhibitors of ornithine decarboxylase in an attempt to deplete polyamine levels to overcome bone marrow toxicity and increase anti-HIV activity; (b) AZT ester of probenecid to increase intracellular uptake and to inhibit glucuronidation of AZT at the site of hepatic metabolism; and (c) dimers of ddNs with uridine (e.g. AZT-P-U) or ddN esters of orotic acid in an attempt to decrease bone marrow toxicity. A second major effort will be directed toward our finding that alpha-D- tocopherol succinate (ATS) increased the therapeutic efficacy of AZT significantly, and therefore, this combination will be explored with other ddNs (ddC, ddI, and d4T). The mechanism(s) involved in the synergistic increase in anti-HIV activity and decrease in bone marrow toxicity will be investigated. The physicochemical parameters such as partition coefficients and protein binding capacities of newly synthesized agents will be determined. Evaluation of intracellular uptake and antiviral activity of prodrugs will be carried out in vitro by employing HIV-infected cells such as peripheral blood lymphocytes (PBL), or lymphocytic (H9, MT4) and monocytic (U937) cell lines. Active agents resulting from this program will be studied in mice and rabbits for pharmacokinetic parameters to determine the extent and rate of entry of various prodrugs in the cerebrospinal fluid and brain tissue. The multidisciplinary approach of this application will allow maximum efficiency in the development of the most effective therapeutic regimens which can be used for the treatment of AIDS.
Showing the most recent 10 out of 21 publications
