Highly Active Macromolecular Prodrugs Inhibit Expression of the Hepatitis C Virus Genome in the Host Cells

Ruiz-Sanchis, Pau; Wohl, Benjamin M.; Smith, Anders; Zuwała, Kaja; Melchjorsen, Jesper; Tolstrup, Martin; Zelikin, Alexander N.

doi:10.1002/adhm.201400307

Cited by 26 publications

(32 citation statements)

References 22 publications

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“…We note that data in Fig. 7 are rather similar to the drug release data collected in our prior studies via HPLC [43,46,62] and this serves to validate the established herein NMR-based approach to monitor drug release. 1 H NMR based method to quantify drug release was applied to the macromolecular prodrugs based on other polyanions as well as a nonionic carrier, PHPMA, Fig.…”

Section: Drug Release Kineticssupporting

confidence: 76%

“…We also experimentally confirmed the link between ribavirin and the synthesis of nitric oxide in macrophages, with relevance to the treatment of hepatitis [42]. Key to successful delivery of ribavirin using MP was the development of a disulfide-containing linker that releases the drug from the prodrug upon cell entry [43].…”

Section: Introductionsupporting

confidence: 54%

“…Of these, the synthesis of the hydrophobic methacrylate monomer (monomer 1 in Fig. 2) was reported in our previous publications [43]. Acrylic counterparts were obtained via similar protocols with minor variations.…”

Section: Polymer Synthesismentioning

confidence: 99%

“…Polymers may thus exhibit significant differences in the drug release kinetics. We have previously investigated the release of RBV and other drugs conjugated to polymers via the same linkage as used in this study (disulfide trigger paired with a self-immolative linker) via HPLC [43,46,62]. Herein, we established an 1 H NMR-based method to quantify the release of RBV as illustrated in Fig.…”

Section: Drug Release Kineticsmentioning

confidence: 99%

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Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects

Zuwała

Riber

Løvschall

et al. 2018

Journal of Controlled Release

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Macromolecular (pro)drugs hold much promise as broad-spectrum antiviral agents as either microbicides or carriers for intracellular delivery of antiviral drugs. Intriguing opportunity exists in combining the two modes of antiviral activity in the same polymer structure such that the same polymer acts as a microbicide and also serves to deliver the conjugated drug (ribavirin) into the cells. We explore this opportunity in detail and focus on the polymer backbone as a decisive constituent of such formulations. Fourteen polyanions (polycarboxylates, polyphosphates and polyphosphonates, and polysulfonates) were analyzed for blood pro/anti coagulation effects, albumin binding and albumin aggregation, inhibitory activity on polymerases, cytotoxicity, and anti-inflammatory activity in stimulated macrophages. Ribavirin containing monomers were designed to accommodate the synthesis of macromolecular prodrugs with disulfide-exchange triggered drug release. Kinetics of drug release was fast in all cases however enhanced hydrophobicity of the polymer significantly slowed release of ribavirin. Results of this study present a comprehensive view on polyanions as backbone for macromolecular prodrugs of ribavirin as broad-spectrum antiviral agents.

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Section: Drug Release Kineticssupporting

confidence: 76%

Section: Introductionsupporting

confidence: 54%

Section: Polymer Synthesismentioning

confidence: 99%

Section: Drug Release Kineticsmentioning

confidence: 99%

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Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects

Zuwała

Riber

Løvschall

et al. 2018

Journal of Controlled Release

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“…The amount of 3TC prodrug released in the absence of a thiol trigger was very similar to values reported for polymers consisting of ribavirin when incubated in phosphate buffer for 48 hours. 48 Furthermore, 25 control experiments performed at pH 5.8 in the presence and absence of GSH showed that only ~10% of 3TC was released. These results indicated that the 3TC conjugated to the polymer via the disulfide SIL was stable at pH 7.4 in the absence of GSH as well as at pH 5.8 even in the presence of 5 mM GSH ( Figure S16).…”

Section: Lamivudine Release From Polymersmentioning

confidence: 97%

Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

et al. 2016

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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.

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Self‐Immolative Linkers Literally Bridge Disulfide Chemistry and the Realm of Thiol‐Free Drugs

Riber

Smith

Zelikin

2015

Adv Healthcare Materials

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The ultimate goal of controlled, intracellulardrug delivery is to get the drug to the target cell without spilling the contents in transit and then release the entire payload upon cell entry. One of the most powerful platforms to achieve this relies on the intracellular disulfide reshuffling as a trigger for drug release form the engineered prodrugs. However, utility of disulfide reshuffling for drug release is naturally applicable only to the thiol containing molecules-ultimately leaving nearly all commercialized drugs beyond the scope of this platform. This is a drastic limitation. A cunning new tool of organic chemistry is fast entering the mainstream of prodrug design: the self-immolative linkers. This platform allows overcoming the natural chemical barrier and makes it possible to link virtually any drug to its carrier via a disulfide bond and engineer a specific intracellular release. It is a game-changing accomplishment of modern organic chemistry. The scope and limitations of this novel opportunity for medicinal chemistry and nanomedicine are outlined.

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Highly Active Macromolecular Prodrugs Inhibit Expression of the Hepatitis C Virus Genome in the Host Cells

Cited by 26 publications

References 22 publications

Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects

Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects

Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

Self‐Immolative Linkers Literally Bridge Disulfide Chemistry and the Realm of Thiol‐Free Drugs

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