title: Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1.
abstract: Polyhexamethylene biguanide (PHMB) is a polybiguanide (PBG) oligomer with antimicrobial activity that is used extensively and safely as a disinfectant. The reported mechanism of PHMB antimicrobial activity, which involves interactions with cell membrane components, suggested that PHMB or other PBG-based compounds might also have antiviral or virucidal activity against the human immunodeficiency virus type 1 (HIV-1). PHMB had modest in vitro activity against both cell-free and cell-associated HIV-1, as well as the ability to interfere with viral binding and entry. However, PHMB was comparable in cytotoxicity to the spermicidal agent nonoxynol-9 (N-9), a compound that has been characterized in previous studies as generally cytotoxic and detrimental to cervicovaginal epithelial integrity. To identify structural variants of PHMB with greater anti-HIV-1 activity and/or less cytotoxicity, modified versions of PHMB incorporating length changes in the hydrocarbon linker units were synthesized and evaluated for in vitro cytotoxicity and inhibition of HIV-1 infectivity. These experiments demonstrated that the PHMB variant polyethylene hexamethylene biguanide (PEHMB) was just as active against HIV-1 as PHMB, yet was much less cytotoxic than either N-9 or PHMB, resulting in an in vitro therapeutic index (TI) approximately 114-fold greater than the TI of N-9. PEHMB, which has been identified in these studies as a promising microbicidal candidate in this family of compounds, will be the focus of further in vitro and in vivo evaluations of anti-HIV-1 activity, toxicity, and mechanisms of action.
authors.affiliation: Department of Microbiology and Immunology, and Center for Sexually Transmitted Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129 USA.
authors.forename: Fred C
authors.initials: FC
authors.lastname: Krebs
authors.forename: Shendra R
authors.initials: SR
authors.lastname: Miller
authors.forename: Mary Lee
authors.initials: ML
authors.lastname: Ferguson
authors.forename: Mohamed
authors.initials: M
authors.lastname: Labib
authors.forename: Robert F
authors.initials: RF
authors.lastname: Rando
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001645:Biguanides / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016264:Dextran Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D017137:Nonoxynol / Q000494:pharmacology; D013089:Spermatocidal Agents; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D001645:Biguanides; D013089:Spermatocidal Agents; D017137:Nonoxynol; C031233:polihexanide; D016264:Dextran Sulfate