NOVEL CONTRACEPTIVES WITH ANTI-HIV ACTIVITY

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DESCRIPTION: (Adapted from Applicant's Abstract) Human immunodeficiency virus (HIV), the causative agent of AIDS is the fastest growing cause of death in women of reproductive age. Heterosexual transmission accounts for >80% of all HIV infections world- wide, and constitutes a growing proportion of new HIV infections in the United States. The currently used topical vaginal microbicide, nonoxynol-9 (N-9)-a detergent-based virucidal spermicide in addition to its high contraceptive failure rates also causes mucosal erosion and local inflammation which might increase the risk of HIV transmission. Therefore, new, effective, safe, and female-controlled vaginal microbicides are urgently needed to curb vaginal transmission of HIV infection. With an attempt to identify a microbicide contraceptive potentially capable of preventing sexual transmission of HIV as well as providing fertility control, a series of bromo-methoxy substituted novel derivatives of the anti-HIV drug, azidothymidine (AZT; zidovudine), were synthesized and examined for dual anti-HIV activity and spermicidal activity. Two lead compounds, WHI-05 and WHI-07, exhibited potent anti- HIV as well as spermicidal activity. Results of in vivo spermicidal efficacy and lack of local toxicity in the mouse model indicated that SHI-05 and WHI-07 would be attractive candidates as dual function vaginal microbicides. The applicants are now proposing preclinical studies to further evaluate the clinical potential of these dual- function AZT derivatives. The specific aims are: (i) to evaluate the in vivo contraceptive activity of WHI-05 and WHI-07 in rabbits; (ii) to evaluate the ability of WHI-05 and WHI-07 to prevent transmucosal and perinatal transmission of feline immunodeficiency virus in cats as the natural host model; (iii) to evaluate the ability of WHI-05 and WHI-07 to prevent transmucosal transmission of HIV-1 in chimpanzees as a surrogate host model; and (iv) to perform in vivo developmental, reproductive toxicology, and carcinogenesis studies of WHI-05 and WHI-07 in rodent models. The development of dual function vaginal microbicides to curb HIV transmission and prevent fertility will be a significant step forward to protect sexually active women from vaginal HIV transmission. The preclinical data on in vivo efficacies of WHI-05 and WHI-07 will be essential to further explore the utility of these novel drugs for clinical studies in human patients.