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: O J D'Cruz, Z Zhu, S H Yiv, C L Chen, B Waurzyniak, F M Uckun
• Journal: Contraception (Contraception) Vol. 59 Issue 5 Pg. 319-31 (May 1999) ISSN: 0010-7824 [Print] United States
• PMID: 10494486 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 5-Bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl)methoxyalaninyl phosphate
• Anti-HIV Agents
• Dideoxynucleotides
• HIV Core Protein p24
• Indicators and Reagents
• Spermatocidal Agents
• Thymidine Monophosphate
• Zidovudine

Topics

• Animals
• Anti-HIV Agents (pharmacology)
• Cell Survival (drug effects)
• Cells, Cultured
• Cervix Uteri (cytology, drug effects)
• Dideoxynucleotides
• Epithelial Cells (cytology, drug effects)
• Female
• HIV Core Protein p24 (metabolism)
• HIV-1 (drug effects, physiology)
• Humans
• Indicators and Reagents
• Inflammation
• Male
• Molecular Structure
• Rabbits
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Spermatocidal Agents (pharmacology)
• Spermatozoa (drug effects)
• Thymidine Monophosphate (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Tumor Cells, Cultured
• Vagina (drug effects, physiology)
• Zidovudine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)