Skip Navigation



Mol. Hum. Reprod. Advance Access published online on October 27, 2005
Molecular Human Reproduction, doi:10.1093/molehr/gah236
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
11/10/767    most recent
gah236v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by D’Cruz, O. J.
Right arrow Articles by Uckun, F. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by D’Cruz, O. J.
Right arrow Articles by Uckun, F. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 11, 2005
Revised September 21, 2005
Accepted September 26, 2005

Article

Discovery of 2,5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum anti-human immunodeficiency virus microbicide

Osmond J. D’Cruz 1* and Fatih M. Uckun 2

1 Department of Reproductive Biology, Drug Discovery Program; Paradigm Pharmaceuticals, LLC, St. Paul, MN, USA
2 Department of Virology, Parker Hughes Institute; Paradigm Pharmaceuticals, LLC, St. Paul, MN, USA

* To whom correspondence should be addressed.
Osmond J. D’Cruz, E-mail: odcruz{at}ih.org


  Abstract

The increased risk of heterosexual transmission of human immunodeficiency virus-1 (HIV-1) has prompted the search for safe and effective female-controlled vaginal microbicides. Because endogenous reverse transcription is implicated in augmenting the sexual transmission of HIV-1, potential microbicides should have the inherent ability to optimally inhibit both wild-type and drug-resistant mutant strains of HIV-1. N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-236) is a rationally designed non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI) that was deduced from changes in binding pocket size, shape and residue character that result from clinically observed NNRTI resistance mutations. PHI-236 displayed high-binding affinity (Ludi Ki= 0.07 µM) for HIV-1 RT and robust anti-HIV activity against the wild type (IC50 = <0.001 µM) as well as primary clinical isolates (IC50 = 0.009-0.04 µM) carrying multiple RT gene mutations associated with NRTI and NNRTI resistance. PHI-236 displayed high-selectivity index against human vaginal and cervical epithelial cells and did not affect human sperm functions. In the humanized severe combined immunodeficient mouse model for HIV/acquired immune deficiency syndrome (AIDS), pretreatment of HIV-1 (BaL)-infected human monocytes and semen with PHI-236 prevented the systemic infection via the vaginal route. PHI-236 has particular clinical utility as a non-spermicidal microbicide as well as a prophylactic antiviral agent to inactivate cell-free and cell-associated HIV-1 in semen before assisted reproductive technology procedures.

Keywords: AIDS or HIV/drug resistance/intravaginal/m icrobicide/non-nucleoside inhibitor/reverse transcriptase/sperm/thymidine analogue mutations.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.