title: Macromolecular Prodrugs of Ribavirin: Structure-Function Correlation as Inhibitors of Influenza Infectivity.
abstract: The requirement for new antiviral therapeutics is an ever present need. Particularly lacking are broad spectrum antivirals that have low toxicity. We develop such agents based on macromolecular prodrugs whereby both the polymer chain and the drug released from the polymer upon cell entry have antiviral effects. Specifically, macromolecular prodrugs were designed herein based on poly(methacrylic acid) and ribavirin. Structure-function parameter space was analyzed via the synthesis of 10 polymer compositions varied by molar mass and drug content. Antiviral activity was tested in cell culture against both low and high pathogenic strains of influenza. Lead compounds were successfully used to counter infectivity of influenza in chicken embryos. The lead composition with the highest activity against influenza was also active against another respiratory pathogen, respiratory syncytial virus, providing opportunity to potentially treat infection by the two pathogens with one antiviral agent. In contrast, structure-function activity against the herpes simplex virus was drastically different, revealing limitations of the broad spectrum antiviral agents based on macromolecular prodrugs.
authors.affiliation: Department of Chemistry, Aarhus University , 8000 Aarhus, Denmark.
authors.forename: Camilla Frich
authors.initials: CF
authors.lastname: Riber
authors.affiliation: CSIRO-Health and Biosecurity Business Unit, Australian Animal Health Laboratory , Geelong, Vic 3220 Australia.
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Hinton
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital , 8000 Aarhus, Denmark.
authors.forename: Paulina
authors.initials: P
authors.lastname: Gajda
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital , 8000 Aarhus, Denmark.
authors.forename: Kaja
authors.initials: K
authors.lastname: Zuwala
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital , 8000 Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.affiliation: CSIRO-Health and Biosecurity Business Unit, Australian Animal Health Laboratory , Geelong, Vic 3220 Australia.
authors.forename: Cameron
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Department of Chemistry, Aarhus University , 8000 Aarhus, Denmark.|iNano Interdisciplinary Nanoscience Centre, Aarhus University , 8000 Aarhus, Denmark.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Zelikin
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects; D007251:Influenza, Human / Q000188:drug therapy*; D046911:Macromolecular Substances / Q000737:chemistry* / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D012254:Ribavirin / Q000737:chemistry* / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D046911:Macromolecular Substances; D011108:Polymers; D011355:Prodrugs; D012254:Ribavirin
keywords: antiviral agents; drug delivery; herpes simplex virus; influenza; macromolecular prodrugs; respiratory syncytial virus