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Journal of Virology, July 2007, p. 7636-7646, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02851-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Molecular Umbrellas: a Novel Class of Candidate Topical Microbicides To Prevent Human Immunodeficiency Virus and Herpes Simplex Virus Infections{triangledown}

Rebecca Pellett Madan,1,{dagger} Pedro M. M. Mesquita,1,3,{dagger} Natalia Cheshenko,1 Bingwen Jing,4 Vikas Shende,1 Esmeralda Guzman,1 Taylor Heald,1 Marla J. Keller,2 Steven L. Regen,4 Robin J. Shattock,3 and Betsy C. Herold1*

Departments of Pediatrics,1 Medicine, Mount Sinai School of Medicine, New York, New York,2 Department of Cellular and Molecular Medicine, St. George's University of London, London, England,3 Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania4

Received 22 December 2006/ Accepted 30 April 2007

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-1BaL in the presence of Spm8CHAS were completely protected (50% inhibitory concentration [IC50], 13.6 µg/ml), and transfer of virus to target T cells via migratory cells was abolished (IC50, 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.

* Corresponding author. Mailing address: Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: (212) 241-5272. Fax: (212) 426-4813. E-mail: betsy.herold{at}mssm.edu

{triangledown} Published ahead of print on 9 May 2007.

{dagger} R.P.M. and P.M.M.M. contributed equally to this work.

Journal of Virology, July 2007, p. 7636-7646, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02851-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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