Viral pathogens continue to constitute a heavy burden on healthcare and socioeconomic systems. Efforts to create antiviral drugs repeatedly lag behind the advent of pathogens and growing understanding is that broad-spectrum antiviral agents will make strongest impact in future antiviral efforts. This work performs selection of synthetic polymers as novel broadly active agents and demonstrates activity of these polymers against Zika, Ebola, Lassa, Lyssa, Rabies, Marburg, Ebola, influenza, herpes simplex, and human immunodeficiency viruses. Results presented herein offer structure-activity relationships for these pathogens in terms of their susceptibility to inhibition by polymers, and for polymers in terms of their anionic charge and hydrophobicity that make up broad-spectrum antiviral agents. The identified leads cannot be predicted based on prior data on polymer-based antivirals and represent promising candidates for further development as preventive microbicides.
The requirement for new antiviral therapeutics is an ever present need. Particularly lacking are broad spectrum antivirals that have low toxicity. We develop such agents based on macromolecular prodrugs whereby both the polymer chain and the drug released from the polymer upon cell entry have antiviral effects. Specifically, macromolecular prodrugs were designed herein based on poly(methacrylic acid) and ribavirin. Structure-function parameter space was analyzed via the synthesis of 10 polymer compositions varied by molar mass and drug content. Antiviral activity was tested in cell culture against both low and high pathogenic strains of influenza. Lead compounds were successfully used to counter infectivity of influenza in chicken embryos. The lead composition with the highest activity against influenza was also active against another respiratory pathogen, respiratory syncytial virus, providing opportunity to potentially treat infection by the two pathogens with one antiviral agent. In contrast, structure-function activity against the herpes simplex virus was drastically different, revealing limitations of the broad spectrum antiviral agents based on macromolecular prodrugs.
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.
A number of unknown pharmaceutical preparations seized by Danish customs authorities were submitted for liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis. Comparison with reference standards unequivocally identified the content of the powders as analogs of the growth hormone secretagogues GHRP-2 (Pralmorelin), GHRP-6, Ipamorelin, and modified growth hormone releasing factor (modified GRF 1-29), which can be used as performance-enhancing substances in sports. In all cases, the detected modification involved the addition of an extra glycine amino acid at the N-terminus, and analytical methods targeting growth hormone secretagogues should hence be updated accordingly.
Synthetic
polymers make strong contributions as tools for delivery
of biological drugs and chemotherapeutics. The most praised characteristic
of polymers in these applications is complete lack of pharmacological
function such as to minimize the side effects within the human body.
In contrast, synthetic polymers with curative pharmacological activity
are truly rare. Moreover, such activity is typically nonspecific rather
than structure-defined. In this work, we present the discovery of
poly(ethylacrylic acid) (PEAA) as a polymer with a suit of structure-defined,
unexpected, pharmacological, and pharmacokinetic properties not observed
in close structural analogues. Specifically, PEAA reveals capacity
to bind to albumin with ensuing natural hepatic deposition in vivo
and exhibits concurrent inhibitory activity against the hepatitis
C virus and inflammation in hepatic cells. Our findings provide a
view on synthetic polymers as curative, functional agents and present
PEAA as a unique biomedical tool with applications related to health
of the human liver.
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