Triple activity of lamivudine releasing sulfonated polymers against HIV-1

Danial, Maarten, Andersen, Anna H. F., Zuwala, Kaja, Cosson, Steffen, Riber, Camilla Frith, Smith, Anton A. A., Tolstrup, Martin, Moad, Graeme, Zelikin, Alexander N. and Postma, Almar (2016) Triple activity of lamivudine releasing sulfonated polymers against HIV-1. Molecular Pharmaceutics, 13 7: 2397-2410. doi:10.1021/acs.molpharmaceut.6b00156

Author Danial, Maarten
Andersen, Anna H. F.
Zuwala, Kaja
Cosson, Steffen
Riber, Camilla Frith
Smith, Anton A. A.
Tolstrup, Martin
Moad, Graeme
Zelikin, Alexander N.
Postma, Almar
Title Triple activity of lamivudine releasing sulfonated polymers against HIV-1
Journal name Molecular Pharmaceutics   Check publisher's open access policy
ISSN 1543-8392
Publication date 2016-07-05
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acs.molpharmaceut.6b00156
Open Access Status Not yet assessed
Volume 13
Issue 7
Start page 2397
End page 2410
Total pages 14
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Abstract In this article a library of polymeric therapeutic agents against the human immunodeficiency virus (HIV) is presented. The library of statistical copolymers of varied molar mass was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The synthesized polymers comprise pendent hydroxyl and sulfonated side chains as well as the reverse transcriptase prodrug lamivudine (3TC) attached via a disulfide self-immolative linker. The glutathione mediated release of 3TC is demonstrated as well as the antiviral efficacy against HIV entry and polymerase activity. Although a high degree of polymer sulfonation is required for effective HIV entry inhibition, polymers with approximately ∼50% sulfonated monomer demonstrated potent kinase independent reverse transcriptase inhibition. In addition, the sulfonated polymers demonstrate activity against DNA-DNA polymerase, which suggests that these polymers may exhibit activity against a broad spectrum of viruses. In summary, the polymers described provide a triple-active arsenal against HIV with extracellular activity via entry inhibition and intracellular activity by kinase-dependent lamivudine-based and kinase-independent sulfonated polymer based inhibition. Since these sulfonated copolymers are easily formulated into gels, we envision them to be particularly suited for topical application to prevent the mucosal transmission of viruses, particularly HIV.
Keyword Antiviral
Drug delivery
Self-immolative linker
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Australian Institute for Bioengineering and Nanotechnology Publications
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