NOVEL CONTRACEPTIVES WITH ANTI-HIV ACTIVITY

Information

  • Research Project
  • 2799089
  • ApplicationId
    2799089
  • Core Project Number
    R01HD037357
  • Full Project Number
    1R01HD037357-01
  • Serial Number
    37357
  • FOA Number
    PA-98-38
  • Sub Project Id
  • Project Start Date
    12/15/1998 - 25 years ago
  • Project End Date
    11/30/2001 - 22 years ago
  • Program Officer Name
    KAUFMAN, STEVEN
  • Budget Start Date
    12/15/1998 - 25 years ago
  • Budget End Date
    11/30/1999 - 24 years ago
  • Fiscal Year
    1999
  • Support Year
    1
  • Suffix
  • Award Notice Date
    12/14/1998 - 25 years ago
Organizations

NOVEL CONTRACEPTIVES WITH ANTI-HIV ACTIVITY

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.

IC Name
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT
  • Activity
    R01
  • Administering IC
    HD
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
  • Sub Project Total Cost
  • ARRA Funded
  • CFDA Code
    865
  • Ed Inst. Type
  • Funding ICs
  • Funding Mechanism
  • Study Section
    ZRG5
  • Study Section Name
  • Organization Name
    PARKER HUGHES INSTITUTE
  • Organization Department
  • Organization DUNS
  • Organization City
    ST. PAUL
  • Organization State
    MN
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    55113
  • Organization District
    UNITED STATES