Sialylneolacto-N-tetraose c (LSTc)-bearing Liposomal Decoys Capture Influenza A Virus

Hendricks, Gabriel; Weirich, Kimberly L.; Viswanathan, Karthik; Li, Jing; Shriver, Zachary; Ashour, Joseph; Ploegh, Hidde L.; Kurt-Jones, Evelyn A.; Fygenson, Deborah Kuchnir; Finberg, Robert W.; Comolli, James C.; Wang, Jennifer

doi:10.1074/jbc.m112.437202

Cited by 78 publications

(68 citation statements)

References 49 publications

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“…Viruses were quantified on MDCK cells to determine infectious titers (expressed in PFU per milliliter) as described previously (12). In brief, six 10-fold serial dilutions were performed on the viral samples, followed by 1 h of binding at 37°C on confluent MDCK cells in 12-well plates.…”

Section: Methodsmentioning

confidence: 99%

Evolution of the Influenza A Virus Genome during Development of Oseltamivir ResistanceIn Vitro

Renzette

Caffrey

Zeldovich

et al. 2014

J Virol

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f Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y resistance mutation fixed reproducibly within the population. The presence of the H274Y mutation in the viral population, at either a low or a high frequency, led to measurable changes in the neuraminidase inhibition assay. Surprisingly, fixation of the resistance mutation was not accompanied by alterations of viral population diversity or differentiation, and oseltamivir did not alter the selective environment. While the neighboring K248E mutation was also a target of positive selection prior to H274Y fixation, H274Y was the primary beneficial mutation in the population. In addition, once evolved, the H274Y mutation persisted after the withdrawal of the drug, even when not fixed in viral populations. We conclude that only selection of H274Y is required for oseltamivir resistance and that H274Y is not deleterious in the absence of the drug. These collective results could offer an explanation for the recent reproducible rise in oseltamivir resistance in seasonal H1N1 IAV strains in humans.

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Section: Methodsmentioning

confidence: 99%

Evolution of the Influenza A Virus Genome during Development of Oseltamivir ResistanceIn Vitro

Renzette

Caffrey

Zeldovich

et al. 2014

J Virol

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“…HS is a promising candidate for use as a decoy receptor. Decoy receptors have been shown to attenuate infections by diverting the targeted pathogen away from susceptible tissues in several infection models (Asher et al, 2005; Dennehy et al, 2007; Hendricks et al, 2013; Zibert et al, 1992). …”

Section: Introductionmentioning

confidence: 99%

“…Decoys may make individual low affinity interactions with a particular pathogen, but multimerization generates many more interactions, increasing the overall avidity of the virus–decoy interaction. This principle is illustrated with sialic acid decoys for influenza virus (Gambaryan et al, 2002; Hendricks et al, 2013; Mammen et al, 1995). HS-binding viruses can be inhibited with soluble heparin, a natural polymer that acts as a decoy.…”

Section: Introductionmentioning

confidence: 99%

Heparin octasaccharide decoy liposomes inhibit replication of multiple viruses

et al. 2015

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Heparan sulfate (HS) is a ubiquitous glycosaminoglycan that serves as a cellular attachment site for a number of significant human pathogens, including respiratory syncytial virus (RSV), human parainfluenza virus 3 (hPIV3), and herpes simplex virus (HSV). Decoy receptors can target pathogens by binding to the receptor pocket on viral attachment proteins, acting as ‘molecular sinks’ and preventing the pathogen from binding to susceptible host cells. Decoy receptors functionalized with HS could bind to pathogens and prevent infection, so we generated decoy liposomes displaying HS-octasaccharide (HS-octa). These decoy liposomes significantly inhibited RSV, hPIV3, and HSV infectivity in vitro to a greater degree than the original HS-octa building block. The degree of inhibition correlated with the density of HS-octa displayed on the liposome surface. Decoy liposomes with HS-octa inhibited infection of viruses to a greater extent than either full-length heparin or HS-octa alone. Decoy liposomes were effective when added prior to infection or following the initial infection of cells in vitro. By targeting the well-conserved receptor-binding sites of HS-binding viruses, decoy liposomes functionalized with HS-octa are a promising therapeutic antiviral agent and illustrate the utility of the liposome delivery platform.

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“…High molecular‐weight scaffolds displaying a large number of low affinity SA derived ligands were used to achieve high HA avidity. Over the years several carrier systems were employed as scaffolds ranging from polymers,6, 8, 9 dendrimers,10, 11, 12, 13 liposomes,5, 14 proteins,15 to gold nanoparticles 16. The most affine binders reported to date consist of SA tethered to linear polyacrylamide polymers 6.…”

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confidence: 99%

Multivalent Peptide–Nanoparticle Conjugates for Influenza‐Virus Inhibition

et al. 2017

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To inhibit binding of the influenza A virus to the host cell glycocalyx, we generate multivalent peptide–polymer nanoparticles binding with nanomolar affinity to the virus via its spike protein hemagglutinin. The chosen dendritic polyglycerol scaffolds are highly biocompatible and well suited for a multivalent presentation. We could demonstrate in vitro that by increasing the size of the polymer scaffold and adjusting the peptide density, viral infection is drastically reduced. Such a peptide–polymer conjugate qualified also in an in vivo infection scenario. With this study we introduce the first non‐carbohydrate‐based, covalently linked, multivalent virus inhibitor in the nano‐ to picomolar range by ensuring low peptide‐ligand density on a larger dendritic scaffold.

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Sialylneolacto-N-tetraose c (LSTc)-bearing Liposomal Decoys Capture Influenza A Virus

Cited by 78 publications

References 49 publications

Evolution of the Influenza A Virus Genome during Development of Oseltamivir ResistanceIn Vitro

Evolution of the Influenza A Virus Genome during Development of Oseltamivir ResistanceIn Vitro

Heparin octasaccharide decoy liposomes inhibit replication of multiple viruses

Multivalent Peptide–Nanoparticle Conjugates for Influenza‐Virus Inhibition

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