DICATIONIC DRUGS--METABOLISM AND TOXICITY

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The goal of this program is to understand the mechanism(s) of action, structure/activity relationships, and mechanism(s) of toxicity of the dicationic class of antimicrobial agents (pentamidine analogs). Dicationic molecules are important therapeutic (or potential therapeutic) agents in the treatment of opportunistic agents associated with AIDS. This class of agents has previously demonstrated potency against Pneumocystis carinii, the most serious infection in AIDS patients, and has recently demonstrated activity against two other AIDS-related opportunistic pathogens; Toxoplasma gondii, and Cryptosporidium parvum. Although dicationic agents are accepted as important in the clinical management of the AIDS patient, this status has been achieved with no understanding of their mode of action, metabolism, or toxicity. In this proposal, our expertise in the synthesis and chemotherapeutic applications of pentamidine analogs will be used to obtain an understanding of the molecular interactions and metabolic fate of these compounds in the infected patient. This basic understanding of the mode(s) of action of dicationic agents in treating opportunistic agents will allow the rational design of new drugs with improved therapeutic indices and spectra of use. The above questions will be addressed in three separate projects. The following project titles clearly indicate the focus of the program as a whole and the areas of responsibility for each project: Project I. Dicationic Drugs: Metabolism and Toxicity; Project II. Dicationic Drugs: Mechanism(s) of Action; Project III. Dicationic Molecules Against C. parvum and T. gondii. Project I will determine the in vitro and in vivo structure/toxicity profiles for pentamidine and selected pentamidine analogs. In addition, this project will continue our preliminary pharmacokinetic/metabolism studies for pentamidine, and initiate similar studies on selected analogs that have demonstrated patterns of toxicity and/or activity different from those of the parent drug. Project II will focus on two previously described activities of dicationic agents, DNA binding and inhibition of DNA topoisomerases using a variety of biochemical techniques. Such studies will attempt to determine if the above drug- target interactions are of therapeutic significance. In addition, Project II will use radiolabeled ligand binding assays and antiidiotype antibodies directed toward anti-drug antibodies to characterize additional drug binding sites in both pathogens and human cells. Project III will rely on the expertise of the two senior investigators to establish models for drug testing against T. gondii and C. parvum and to provide organisms for Project II studies. Projects III will use radiolabeled drug and electron microscopy to identify binding sites of the pentamidine analogs and determine their physiological significance. Close interaction between the three Projects will be assured and the progress of the Program monitored through an active Administrative Core. Fujisawa Pharmaceutical Company (FPC) will serve as the corporate sponsor. As such, FPC will patent and develop key discoveries by the group, commit $135,000/yr to the total budget and provide comprehensive animal toxicity studies on selected compounds.