Show simple item record Jay, JI Lai, BE Myszka, DG Mahalingam, A Langheinrich, K Katz, DF Kiser, PF
dc.coverage.spatial United States 2011-06-21T17:27:00Z 2010-02-01
dc.identifier.citation Mol Pharm, 2010, 7 (1), pp. 116 - 129
dc.description.abstract Microbicides are women-controlled prophylactics for sexually transmitted infections. The most important class of microbicides target HIV-1 and contain antiviral agents formulated for topical vaginal delivery. Identification of new viral entry inhibitors that target the HIV-1 envelope is important because they can inactivate HIV-1 in the vaginal lumen before virions can come in contact with CD4+ cells in the vaginal mucosa. Carbohydrate binding agents (CBAs) demonstrate the ability to act as entry inhibitors due to their ability to bind to glycans and prevent gp120 binding to CD4+ cells. However, as proteins they present significant challenges in regard to economical production and formulation for resource-poor environments. We have synthesized water-soluble polymer CBAs that contain multiple benzoboroxole moieties. A benzoboroxole-functionalized monomer was synthesized and incorporated into linear oligomers with 2-hydroxypropylmethacrylamide (HPMAm) at different feed ratios using free radical polymerization. The benzoboroxole small molecule analogue demonstrated weak affinity for HIV-1BaL gp120 by SPR; however, the 25 mol % functionalized benzoboroxole oligomer demonstrated a 10-fold decrease in the K(D) for gp120, suggesting an increased avidity for the multivalent polymer construct. High molecular weight polymers functionalized with 25, 50, and 75 mol % benzoboroxole were synthesized and tested for their ability to neutralize HIV-1 entry for two HIV-1 clades and both R5 and X4 coreceptor tropism. All three polymers demonstrated activity against all viral strains tested with EC(50)s that decrease from 15000 nM (1500 microg mL(-1)) for the 25 mol % functionalized polymers to 11 nM (1 microg mL(-1)) for the 75 mol % benzoboroxole-functionalized polymers. These polymers exhibited minimal cytotoxicity after 24 h exposure to a human vaginal cell line.
dc.format.extent 116 - 129
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof Mol Pharm
dc.relation.isversionof 10.1021/mp900159n
dc.subject Administration, Intravaginal
dc.subject Anti-HIV Agents
dc.subject Anti-Infective Agents
dc.subject Binding Sites
dc.subject Boronic Acids
dc.subject CD4-Positive T-Lymphocytes
dc.subject Female
dc.subject HIV Envelope Protein gp120
dc.subject HIV Infections
dc.subject HIV-1
dc.subject Humans
dc.subject In Vitro Techniques
dc.subject Models, Molecular
dc.subject Molecular Structure
dc.subject Polymers
dc.subject Surface Plasmon Resonance
dc.subject Vagina
dc.subject Virus Internalization
dc.title Multivalent benzoboroxole functionalized polymers as gp120 glycan targeted microbicide entry inhibitors.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-2-jan en_US
duke.description.endpage 129 en_US
duke.description.issue 1 en_US
duke.description.startpage 116 en_US
duke.description.volume 7 en_US
dc.relation.journal Molecular Pharmaceutics en_US
pubs.issue 1
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Pratt School of Engineering
pubs.organisational-group /Duke/Pratt School of Engineering/Biomedical Engineering
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Obstetrics and Gynecology
pubs.publication-status Published
pubs.volume 7
dc.identifier.eissn 1543-8392

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