Journal article
Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1
Biomedicine & pharmacotherapy, v 64(10), pp 723-732
2010
PMID: 21106331
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Previous investigations showing that polydisperse biguanide (PDBG) molecules have activity against human immunodeficiency virus type 1 (HIV-1) also suggested a relationship between PDBG biologic activity and the lengths of hydrocarbon linkers surrounding the positively charged biguanide unit. To better define structure-activity relationships, PDBG molecules with select linker lengths were evaluated for cytotoxicity, anti-HIV-1 activity, and
in vivo toxicity. Results of the
in vitro experiments demonstrated that increases in linker length (and, therefore, increases in compound lipophilicity) were generally associated with increases in cytotoxicity and antiviral activity against HIV-1. However, a relationship between linker length asymmetry and
in vitro therapeutic index (TI) suggested structural specificity in the mechanism of action against HIV-1. Polyethylene hexamethylene biguanide (PEHMB; biguanide units spaced between alternating ethylene and hexamethylene linkers) was found to have the highest
in vitro TI (CC
50/IC
50) among the compounds examined. Recent improvements in PEHMB synthesis and purification have yielded preparations of PEHMB with
in vitro TI values of 266 and 7000 against HIV-1 strains BaL and IIIB, respectively. The minimal toxicity of PEHMB relative to polyhexamethylene biguanide (PHMB; biguanide units alternating with hexamethylene linkers) in a murine model of cervicovaginal microbicide toxicity was consistent with considerable differences in cytotoxicity between PEHMB and PHMB observed during
in vitro experiments. These structure-activity investigations increase our understanding of PDBG molecules as agents with activity against HIV-1 and provide the foundation for further preclinical studies of PEHMB and other biguanide-based compounds as antiviral and microbicidal agents.
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Details
- Title
- Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1
- Creators
- Shendra R Passic - Department of Microbiology and Immunology, and Center for Sexually Transmitted Disease, Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USAMary Lee Ferguson - Department of Microbiology and Immunology, and Center for Sexually Transmitted Disease, Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USABradley J Catalone - Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USATina Kish-Catalone - Department of Microbiology and Immunology, and Center for Sexually Transmitted Disease, Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USAVladyslav Kholodovych - Department of Pharmacology, University of Medicine and Dentistry, New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USAWei Zhu - Department of Pharmacology, University of Medicine and Dentistry, New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USAWilliam Welsh - Department of Pharmacology, University of Medicine and Dentistry, New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USARobert Rando - Novaflux Biosciences, Inc., Princeton, New Jersey 08540, USAMary K Howett - Department of Bioscience and Biotechnology, Drexel University, Philadelphia, Pennsylvania 19104, USABrian Wigdahl - Department of Microbiology and Immunology, and Center for Sexually Transmitted Disease, Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USAMohamed Labib - Novaflux Biosciences, Inc., Princeton, New Jersey 08540, USAFred C Krebs - Department of Microbiology and Immunology, and Center for Sexually Transmitted Disease, Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA
- Publication Details
- Biomedicine & pharmacotherapy, v 64(10), pp 723-732
- Publisher
- Elsevier SAS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000286087600013
- Scopus ID
- 2-s2.0-78649825673
- Other Identifier
- 991014878034704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental
- Pharmacology & Pharmacy