SULFATED CHITOSAN DERIVATIVES AS ANTI HIV 1 AGENTS

THE OBJECTIVE OF THIS PROJECT IS TO VARY THE METHOD OF SYNTHESIS AND ISOLATION OF N-CARBOXYMETHYLCHITOSAN-N,O-SULFATE (NCMCS) SO AS TO OPTIMIZE ITS BIOLOGICAL ACTIVITY, WHILE MAINTAINING LOW CYTOTOXICITY. THE DEGREE OF SUBSTITUTION OF THE INDIVIDUAL SUBSTITUENTS OF CHITOSAN WILL BE VARIED, AND THE PRODUCTS WILL BE FRACTIONATED INTO DIFFERENT MOLECULAR WEIGHT RANGES USING MEMBRANE TECHNOLOGY. THE NCMCS PRODUCTS WILL UNDERGO PRECLINICAL EVALUATION AS AGENTS FOR THE TREATMENT OF INFECTIONS WITH THE HUMAN ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS). OUR PREVIOUS WORK HAS SHOWN THAT NCMCS DEMONSTRATES ANTIVIRAL ACTIVITY AGAINST HIV-1 AND RAUSCHER MURINE LEUKEMIA VIRUS (RLV) WITH LOW TOXICITY IN CULTURED CELLS. THE COMPOUNDS WILL BE TESTED IN TISSUE CULTURE SYSTEMS FOR ANTI-RETROVIRAL ACTIVITY. THE EFFICACY AND TOXICITY OF NCMCS WILL BE DETERMINED IN MICE INOCULATED WITH RLV. AN HPLC ASSAY WILL BE DEVELOPED TO MEASURE DRUG LEVELS IN TISSUES AND BODY FLUIDS, AND PHARMACOKINETICS PARAMETERS OF NCMCS WILL BE MEASURED IN NORMAL MICE. FURTHER WORK WILL INCLUDE VARYING THE SUBSTITUENTS ON THE SULFATED CHITOSAN TO ENHANCE BIOLOGICAL ACTIVITY. IN PHASE II, THE ANTI-HIV-1 EFFICACY AND TOXICITY WILL BE DETERMINED IN HU-PBL-SCID MICE.