Multivalent benzoboroxole functionalized polymers as gp120 glycan targeted microbicide entry inhibitors.
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.
Type
Journal articleSubject
Administration, IntravaginalAnti-HIV Agents
Anti-Infective Agents
Binding Sites
Boronic Acids
CD4-Positive T-Lymphocytes
Female
HIV Envelope Protein gp120
HIV Infections
HIV-1
Humans
In Vitro Techniques
Models, Molecular
Molecular Structure
Polymers
Surface Plasmon Resonance
Vagina
Virus Internalization
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https://hdl.handle.net/10161/4091Published Version (Please cite this version)
10.1021/mp900159nPublication Info
Jay, Julie I; Lai, Bonnie E; Myszka, David G; Mahalingam, Alamelu; Langheinrich, Kris;
Katz, David F; & Kiser, Patrick F (2010). Multivalent benzoboroxole functionalized polymers as gp120 glycan targeted microbicide
entry inhibitors. Mol Pharm, 7(1). pp. 116-129. 10.1021/mp900159n. Retrieved from https://hdl.handle.net/10161/4091.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
David F. Katz
Nello L. Teer, Jr. Distinguished Professor of Biomedical Engineering, in the Edmund
T. Pratt, Jr. School of Engineering
Dr. Katz's research interests emphasize methods for prophylaxis against STD's, including
topical microbicides, and for contraception. Core perspectives and approaches include
mass transport phenomena and biofluid mechanics; rheology and imaging, both in vitro
and in vivo. These are integrated to fundamental biological, pathological, and clinical
processes and needs for improvement.
Context. According to the Joint United Nations Programme on

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