Influenza as a molecular walker

Hamming, P. H. Erik; Overeem, Nico J.; Huskens, Jurriaan

doi:10.1039/c9sc05149j

Cited by 35 publications

(34 citation statements)

References 65 publications

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“…Both proteins are able to interact with SAs, but while HA is known to promote IAV attachment to the cell membrane, NA is known to possess SA cleavage activity and is therefore believed to promote IAV egress (after the virus replication cycle has been completed). [28][29][30] The interplay between HA and NA is known to be important for completion of the virus life cycle and started Figure 1. Synthesis of mucin-inspired virus binding (MuVib) inhibitors based on high-molecular weight hPG.…”

Section: Resultsmentioning

confidence: 99%

Mucin‐Inspired, High Molecular Weight Virus Binding Inhibitors Show Biphasic Binding Behavior to Influenza A Viruses

Wallert

Nie

Anilkumar

et al. 2020

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Multivalent binding inhibitors are a promising new class of antivirals that prevent virus infections by inhibiting virus binding to cell membranes. The design of these inhibitors is challenging as many properties, for example, inhibitor size and functionalization with virus attachment factors, strongly influence the inhibition efficiency. Here, virus binding inhibitors are synthesized, the size and functionalization of which are inspired by mucins, which are naturally occurring glycosylated proteins with high molecular weight (MDa range) and interact efficiently with various viruses. Hyperbranched polyglycerols (hPGs) with molecular weights ranging between 10 and 2600 kDa are synthesized, thereby hitting the size of mucins and allowing for determining the impact of inhibitor size on the inhibition efficiency. The hPGs are functionalized with sialic acids and sulfates, as suggested from the structure of mucins, and their inhibition efficiency is determined by probing the inhibition of influenza A virus (IAV) binding to membranes using various methods. The largest, mucin‐sized inhibitor shows potent inhibition at pm concentrations, while the inhibition efficiency decreases with decreasing the molecular weight. Interestingly, the concentration‐dependent IAV inhibition shows a biphasic behavior, which is attributed to differences in the binding affinity of the inhibitors to the two IAV envelope proteins, neuraminidase, and hemagglutinin.

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Section: Resultsmentioning

confidence: 99%

Mucin‐Inspired, High Molecular Weight Virus Binding Inhibitors Show Biphasic Binding Behavior to Influenza A Viruses

Wallert

Nie

Anilkumar

et al. 2020

Small

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“…Therefore, we compared the motility of IAV with the behavior of artificial and simulated molecular walkers and argued that directional motility is intrinsic to receptor-cleaving multivalent particles, rather than a result of asymmetric organization alone. 93 The enhancement of directionality by asymmetric organization in filamentous viruses would allow motility over longer distances, which is consistent with the observation that the filamentous phenotype is more abundant in patient samples than in viruses from eggs or in cell cultures without mucus. 94 Underneath the mucus layer, the periciliary layer forms an even stricter barrier.…”

Section: Binding and Cleaving In The Mucussupporting

confidence: 83%

“…We and others proposed therefore that IAV must use an active molecular walk to cross the periciliary layer ( Figure 2.5b). 93,95…”

Section: Binding and Cleaving In The Mucusmentioning

confidence: 99%

Multivalent and dynamic interactions of the influenza virus at lipid membrane interfaces

Overeem

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“…Interaction with cell receptors is a key element for the activation of viral infective mechanisms, either directly or by conducting the viral particle to cell regions where these systems can be activated [36,37]. On the other hand, receptor destruction plays an important role in the release of the new viral particles.…”

Section: Discussionmentioning

confidence: 99%

“…The equilibrium between the receptor-binding and -destroying activities is a key element for the infective process, not only in terms of the "input/output" ratio of viral particles, but also in the initial interaction of the pathogen with the cell surface [37,40]. In ISAV, if the primary receptor (5N-4O sialic acids) binding via HE is not affected by the HPR length/esterase activity, possibly a secondary viral protein-cellular ligand interaction is regulated by those elements.…”

Section: Discussionmentioning

confidence: 99%

Interaction of the Amino-Terminal Domain of the ISAV Fusion Protein with a Cognate Cell Receptor

2020

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The infectious salmon anemia virus (ISAV), etiological agent of the disease by the same name, causes major losses to the salmon industry. Classified as a member of the Orthomyxoviridae family, ISAV is characterized by the presence of two surface glycoproteins termed hemagglutinin esterase (HE) and fusion protein (F), both of them directly involved in the initial interaction of the virus with the target cell. HE mediates receptor binding and destruction, while F promotes the fusion process of the viral and cell membranes. The carboxy-terminal end of F (F2) possesses canonical structural characteristics of a type I fusion protein, while no functional properties have been proposed for the amino-terminal (F1) region. In this report, based on in silico modeling, we propose a tertiary structure for the F1 region, which resembles a sialic acid binding domain. Furthermore, using recombinant forms of both HE and F proteins and an in vitro model system, we demonstrate the interaction of F with a cell receptor, the hydrolysis of this receptor by the HE esterase, and a crucial role for F1 in the fusion mechanism. Our interpretation is that binding of F to its cell receptor is fundamental for membrane fusion and that the esterase in HE modulates this interaction.

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Influenza as a molecular walker

Abstract: The neuraminidase on the surface of influenza viruses make the virus a receptor-cleaving molecular walker, similar to molecular spiders.

Cited by 35 publications

References 65 publications

Mucin‐Inspired, High Molecular Weight Virus Binding Inhibitors Show Biphasic Binding Behavior to Influenza A Viruses

Mucin‐Inspired, High Molecular Weight Virus Binding Inhibitors Show Biphasic Binding Behavior to Influenza A Viruses

Multivalent and dynamic interactions of the influenza virus at lipid membrane interfaces

Interaction of the Amino-Terminal Domain of the ISAV Fusion Protein with a Cognate Cell Receptor

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