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This article is part of the supplement: 2005 International Meeting of The Institute of Human Virology

Open Access Poster presentation

Improvement of Polybiguanide-based Microbicides Using Computational Design Methodologies

Mary L Ferguson1*, Shendra Miller1, Mohamed E Labib2, Robert Rando2, Vladyslav Kholodovych3, William Welsh3, Brian Wigdahl1 and Fred C Krebs1

  • * Corresponding author: Mary L Ferguson

Author Affiliations

1 Department of Microbiology and Immunology, and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA

2 Novaflux Biosciences, Inc., Princeton, NJ, USA

3 University of Medicine and Dentistry of New Jersey, Piscataway, NJ

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Retrovirology 2005, 2(Suppl 1):P30  doi:10.1186/1742-4690-2-S1-P30


The electronic version of this article is the complete one and can be found online at:


Published:8 December 2005

©

Poster presentation

Polyethylene hexamethylene biguanide (PEHMB), a polybiguanide compound under development as a topical microbicide effective against HIV-1, was used as a starting point for rational design strategies and novel computational methods focused on identifying similar compounds with greater safety and activity. To investigate the hypothesis that PEHMB may represent a specific 3-D conformation and a degree of chain flexibility that confers the ability to inhibit HIV-1 infection through interactions with HIV-1 co-receptors, patented molecular calculation software (Shape Signatures) was used to predict bioisosteres of PEHMB. These analyses suggested that substitution of a bithiazole group for the ethylene spacers of PEHMB would provide backbone rigidity, nitrogen atom spacing, and electrostatic potentials similar to PEHMB. The resulting molecule, poly(hexamethylene-c-2, 2'-diamino-5, 5'-bithiazole (PHDB), was found to have similar cytotoxicity yet greater activity than PEHMB. These studies strongly support our strategy of design and synthesis of second-generation compounds based on the PEHMB motif.