Volume 2 Supplement 1

2005 International Meeting of The Institute of Human Virology

Open Access

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
Retrovirology20052(Suppl 1):P30


Published: 8 December 2005

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.


Authors’ Affiliations

Department of Microbiology and Immunology, and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine
Novaflux Biosciences, Inc.
University of Medicine and Dentistry of New Jersey


© The Author(s) 2005