Molecular Umbrellas: a Novel Class of Candidate Topical Microbicides To Prevent Human Immunodeficiency Virus and Herpes Simplex Virus Infections
- 15 July 2007
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 81 (14), 7636-7646
- https://doi.org/10.1128/jvi.02851-06
Abstract
Molecular umbrella compounds may function as novel topical microbicides to prevent human immunodeficiency virus (HIV) and herpes simplex virus (HSV) infections. In a preliminary structure-activity investigation, one umbrella compound, designated Spm8CHAS, was identified which inhibited both HIV and HSV infections with no cellular toxicity. The objectives of the current studies were to define its spectrum of antiviral activity, characterize its mechanism of action, and explore the possibility of combining Spm8CHAS with HIV-specific reverse transcriptase inhibitors. Spm8CHAS inhibited infections by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical tissue explants exposed to HIV-1 BaL in the presence of Spm8CHAS were completely protected (50% inhibitory concentration [IC 50 ], 13.6 μg/ml), and transfer of virus to target T cells via migratory cells was abolished (IC 50 , 3.8 μg/ml). Spm8CHAS inhibited HSV-2 infection of epithelial cells 10,000-fold if present throughout the infection. Notably, adding Spm8CHAS to cultures following HSV entry significantly reduced viral infection, indicating that the drug also acts postentry. Subsequent studies indicated that Spm8CHAS blocks cell-to-cell spread of HSV. Confocal microscopy using a fluorescently labeled analog of Spm8CHAS demonstrated that this conjugate crosses the plasma cell membrane and is transported to the nucleus. Combinations of Spm8CHAS with UC-781 or 9-[ R -2-(phosphonylmethoxy)propyl] adenine monohydrate in vitro exhibited additive anti-HIV activity with preserved anti-HSV activity. The abilities of Spm8CHAS to inhibit primary isolates of HIV, block HSV infection postentry, and cross cell membranes support the development of a combination microbicide containing Spm8CHAS with an HIV-specific reverse transcriptase inhibitor to prevent both HIV and HSV infections by multiple mechanisms.Keywords
This publication has 36 references indexed in Scilit:
- Access to Nectin Favors Herpes Simplex Virus Infection at the Apical Surface of Polarized Human Epithelial CellsJournal of Virology, 2006
- In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1Journal of Virology, 2006
- Cellulose Acetate 1,2-Benzenedicarboxylate Inhibits Infection by Cell-Free and Cell-Associated Primary HIV-1 IsolatesAIDS Research and Human Retroviruses, 2006
- Direct measurement of in-vivo vaginal microbicide levels of PRO 2000 achieved in a human safety studyAIDS, 2006
- Risk Factors Influencing HIV Infection Incidence in a Rural African Population: A Nested Case‐Control StudyThe Journal of Infectious Diseases, 2006
- Persulfated Molecular Umbrellas as Anti-HIV and Anti-HSV AgentsJournal of the American Chemical Society, 2004
- Optimisation of the Degree of Sulfation of a Polymer Based Construct to Block the Entry of HIV-1 into CellsJournal of Drug Targeting, 2003
- Recent Herpes Simplex Virus Type 2 Infection and the Risk of Human Immunodeficiency Virus Type 1 Acquisition in IndiaThe Journal of Infectious Diseases, 2003
- Poly(Sodium 4‐Styrene Sulfonate): An Effective Candidate Topical Antimicrobial for the Prevention of Sexually Transmitted DiseasesThe Journal of Infectious Diseases, 2000
- In vitro HIV1 infection of human cervical tissueResearch in Virology, 1994