title: WHI-05, a novel bromo-methoxy substituted phenyl phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity.
abstract: Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a potent anti-HIV agent that has spermicidal activity and is devoid of mucosal toxicity, WHI-05 shows a unique clinical potential to become the active ingredient for a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
authors.affiliation: Department of Reproductive Biology, Hughes Institute, St. Paul, Minnesota 55113, USA. odcruz@ih.org
authors.forename: O J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: Z
authors.initials: Z
authors.lastname: Zhu
authors.forename: S H
authors.initials: SH
authors.lastname: Yiv
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Waurzyniak
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects; D054306:Dideoxynucleotides; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007202:Indicators and Reagents; D007249:Inflammation; D008297:Male; D015394:Molecular Structure; D011817:Rabbits; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013089:Spermatocidal Agents / Q000494:pharmacology*; D013094:Spermatozoa / Q000187:drug effects*; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014621:Vagina / Q000187:drug effects* / Q000502:physiology; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C114569:5-Bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl)methoxyalaninyl phosphate; D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D016655:HIV Core Protein p24; D007202:Indicators and Reagents; D013089:Spermatocidal Agents; D013938:Thymidine Monophosphate; D015215:Zidovudine