Multivalent benzoboroxole functionalized polymers as gp120 glycan targeted microbicide entry inhibitors.

dc.contributor.author

Jay, Julie I

dc.contributor.author

Lai, Bonnie E

dc.contributor.author

Myszka, David G

dc.contributor.author

Mahalingam, Alamelu

dc.contributor.author

Langheinrich, Kris

dc.contributor.author

Katz, David F

dc.contributor.author

Kiser, Patrick F

dc.coverage.spatial

United States

dc.date.accessioned

2011-06-21T17:27:00Z

dc.date.issued

2010-02-01

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.description.version

Version of Record

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/20014858

dc.identifier.eissn

1543-8392

dc.identifier.uri

https://hdl.handle.net/10161/4091

dc.language

eng

dc.language.iso

en_US

dc.publisher

American Chemical Society (ACS)

dc.relation.ispartof

Mol Pharm

dc.relation.isversionof

10.1021/mp900159n

dc.relation.journal

Molecular Pharmaceutics

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
dc.type

Journal article

duke.date.pubdate

2010-2-jan

duke.description.issue

1

duke.description.volume

7

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/20014858

pubs.begin-page

116

pubs.end-page

129

pubs.issue

1

pubs.organisational-group

Biomedical Engineering

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

Obstetrics and Gynecology

pubs.organisational-group

Pratt School of Engineering

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

7

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
274015900013.pdf
Size:
2.61 MB
Format:
Adobe Portable Document Format