Macromolecular prodrugs of ribavirin: towards a treatment for co-infection with HIV and HCV

Smith, Anders; Zuwała, Kaja; Kryger, Mille B. L.; Wohl, Benjamin M.; Guerrero‐Sánchez, Carlos; Tolstrup, Martin; Postma, Almar; Zelikin, Alexander N.

doi:10.1039/c4sc02754j

Cited by 27 publications

(28 citation statements)

References 24 publications

(43 reference statements)

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“…Without doubt, examples of strong, pronounced effects of molar mass on the biomedical properties of polymers are numerous and importance of this factor should not be overlooked. In our own prior work, with regards to the delivery of RBV, we found that high molar mass restricted the polymer cell entry and in doing so limited the observed therapeutic effects [39,65]. Not disregarding the importance of these observations, the data of this study strongly suggest chemical structure of the polymer is a dominant factor in its properties (at least in the experiments presented in this study) whereas polymer chain length is of secondary importance.…”

Section: Degree Of Polymerization Vs Polymer Structuresupporting

confidence: 50%

“…In our past studies, we developed broad-spectrum antiviral agents based on macromolecular prodrugs (MP) of ribavirin. When conjugated to polymers, ribavirin did not accumulate in the red blood cells which in vivo is the main side effect of the drug [37][38][39]. MP of ribavirin broadened the therapeutic window of the drug (in vitro) [37] and were effective against diverse viruses such as HCV (in a replicon cell culture model), measles, and influenza, in the latter case revealing antiviral effects in chicken embryo model [40,41].…”

Section: Introductionmentioning

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: Degree Of Polymerization Vs Polymer Structuresupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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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“…11,12 While this provides a higher therapeutic window between antiviral activity and cytotoxicity, these systems do not provide complete release and usually results in a lower efficacy against HIV infectivity. [11][12][13][14] Recently, a macromolecular prodrug anti-HIV system was devised that was capable of a rapid intracellular triggered release of an antiviral drug. In this system, the AZT drug was attached through a self-4 immolative, disulfanyl ethylcarbonate linker between the drug and a methacrylate polymer side chain.…”

Section: Introductionmentioning

confidence: 99%

“…7 For these reasons, AZT is often not recommended for treatment for first-line treatment of HIV. 8 Release of antiretroviral drugs from nanogels, 9 hydrogels, 10 or polymer conjugates [11][12][13][14] have all provided viable options for prolonging the circulation half-life and alleviating the cytotoxic side effects. While these systems effectively prolong the action of the antiviral released, drug release mechanisms rely on the presence of bonds that are intermediately stable to hydrolysis, such as ester linkages, to attach the drug to the polymer.…”

Section: Introductionmentioning

confidence: 99%

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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“…Upon further investigation of the polymer charge effect, it became clear that poly-anionic macromolecules inhibit viruses extracellularly by denying them cell entry in the first place [ 35 , 36 , 37 , 38 ], while poly-cationic macromolecules, on the other hand, are complexed with the genetic material of the virus [ 39 ]. Moreover, macromolecules play an essential role in controlling the release, distribution, and nonselective accumulation of the conjugated drugs [ 40 , 41 , 42 , 43 , 44 , 45 ].…”

Section: Macromolecular Prodrugsmentioning

confidence: 99%

Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years

2017

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Background: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. Methods: The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. Results: Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. Conclusions: Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned.

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Macromolecular prodrugs of ribavirin: towards a treatment for co-infection with HIV and HCV

Abstract: Macromolecular prodrugs of ribavirin were developed as blood safe formulations with capacity to fight inflammation and human immunodeficiency virus in vitro.

Cited by 27 publications

References 24 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

Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years

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