Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV‑1

Maarten Danial, Anna H. F. Andersen, Kaja Zuwala, Steffen Cosson, Camilla Frich Riber, Anton A. A. Smith, Martin Tolstrup, Graeme Moad, Alexander N. Zelikin, Almar Postma

In this paper 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 polymerization (RAFT) and comprises pendent sulfonated side chains as well as the reverse transcriptase prodrug lamivudine (3TC), which was 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 activity. In addition, the sulfonated polymers also 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.