Macromolecular Antiviral Agents against Zika, Ebola, SARS, and Other Pathogenic Viruses

Abstract

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 molecular tweezer CLR01 inhibits Ebola and Zika virus infection

“…The MTT assay allows an indirect measurement of ZIKV infection as the tetrazolium dye is metabolized only in living, non-infected cells. To evaluate the effect of CLR01 on ZIKV more directly, infected cells were stained for the viral E protein and analyzed by confocal microscopy (Schandock et al, 2017). Upon treatment with 15 or 150 μM of CLR01, E protein-specific fluorescence could not be detected, whereas CLR03 had no effect, as expected ( Fig.…”

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

“…Identified lead candidate polymers exhibited antiviral activity against all the enveloped viral pathogens, including the Zika virus. For the latter, we presented evidence of direct contact between the polymer and the viral particle and concurrent inhibition of viral infectivity [21].…”

“…Finally, preventative antivirals that act through neutralization of viruses and/or blocking virus cell entry appear to be highly promising as broad-spectrum antiviral agents [19][20][21]. A notable class of such agents is polymers.…”

“…From a different perspective, we also focused on preventative measures and conducted a systematic study of polymers with anionic charge as inhibitors of virus cell entry [21]. Our broad study considered 14 polymers, infectious Zika virus, HIV, and HSV, as well as pseudotyped viral particles for Ebola, Lassa, Lyssa, SARS, and other viruses.…”

“…One intriguing possibility lies in the prospect of combining the curative and the preventative antiviral activity within the same macromolecular antiviral agent [40,44]. Such agents represent a combination therapy wherein the carrier exerts extracellular preventative effect [21] whereas the conjugated drug, once released inside the cell, is an intracellularly active therapeutic [37]. It is also possible that polyanions have an intracellular antiviral effect of their own, that is the inhibition of viral polymerases, [40,45,46] presumably through competitive electrostatic interaction with the protein.…”