A Recombinant Sialidase Fusion Protein Effectively Inhibits Human Parainfluenza Viral Infection In Vitro and In Vivo

Moscona, Anne; Porotto, Matteo; Palmer, Samantha G.; Tai, Caroline G.; Aschenbrenner, Lori; Triana‐Baltzer, Gallen; Li, Qi-Xiang; Wurtman, David F.; Niewiesk, Stefan; Fang, Fang

doi:10.1086/653621

Cited by 78 publications

(89 citation statements)

References 40 publications

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“…The irreversible loss of infectivity of HPIV3 virions caused by exposure to premature F-triggering agents points to the possibility of developing a new class of antivirals to combat the severe disease and high lethality associated with paramyxoviruses. We contend that both inhibition testing and mechanistic studies are likely to reflect the authentic biology if carried out in tissue resembling the natural host, and for this reason we employ the human airway epithelium model that closely reflects the in vivo behavior of HPIV3 (28) and HPIV3 antiviral molecules (47). The efficacy of the premature triggering antiviral strategy in a physiologically relevant ex vivo system that mimics the human airway supports the notion that this strategy may be useful clinically.…”

Section: Discussionmentioning

confidence: 88%

“…The HAE model was previously used to characterize the cell specificity of respiratory syncytial virus (45) and HPIV3 (46), studies that confirmed the model replicates those paramyxovirus-HAE interactions occurring in the human lung. We also recently employed this system to test a sialidase-based inhibitor, and showed a direct correlation between the HAE and in vivo results (47). We therefore hypothesized that peptide efficacy in this ex vivo model would correlate with in vivo efficacy.…”

Section: Compounds That Interact With the Active Site Of Hn Arementioning

confidence: 99%

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Premature Activation of the Paramyxovirus Fusion Protein before Target Cell Attachment with Corruption of the Viral Fusion Machinery

Farzan

Palermo

Yokoyama

et al. 2011

Journal of Biological Chemistry

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Paramyxoviruses, including the childhood pathogen human parainfluenza virus type 3, enter host cells by fusion of the viral and target cell membranes. This fusion results from the concerted action of its two envelope glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). The receptor-bound HN triggers F to undergo conformational changes that render it competent to mediate fusion of the viral and cellular membranes. We proposed that, if the fusion process could be activated prematurely before the virion reaches the target host cell, infection could be prevented. We identified a small molecule that inhibits paramyxovirus entry into target cells and prevents infection. We show here that this compound works by an interaction with HN that results in F-activation prior to receptor binding. The fusion process is thereby prematurely activated, preventing fusion of the viral membrane with target cells and precluding viral entry. This first evidence that activation of a paramyxovirus F can be specifically induced before the virus contacts its target cell suggests a new strategy with broad implications for the design of antiviral agents.

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Section: Discussionmentioning

confidence: 88%

Section: Compounds That Interact With the Active Site Of Hn Arementioning

confidence: 99%

Premature Activation of the Paramyxovirus Fusion Protein before Target Cell Attachment with Corruption of the Viral Fusion Machinery

Farzan

Palermo

Yokoyama

et al. 2011

Journal of Biological Chemistry

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“…We are developing a formulation suitable for inhalation, to deliver the antiviral agent directly to the target host tissue. We contend that a combination of an agent like Fludase, a sialidase fusion protein which interferes with receptor binding and is currently in clinical trials for adults with HPIV (28), and fusion inhibitor peptides may be a feasible combination treatment for respiratory viruses and would reduce the likelihood of eliciting resistance.…”

Section: Discussionmentioning

confidence: 99%

Circulating Clinical Strains of Human Parainfluenza Virus Reveal Viral Entry Requirements for In Vivo Infection

Palmer

DeVito

Jenkins

et al. 2014

J Virol

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Human parainfluenza viruses (HPIVs) cause widespread respiratory infections, with no vaccines or effective treatments. We show that the molecular determinants for HPIV3 growth in vitro are fundamentally different from those required in vivo and that these differences impact inhibitor susceptibility. HPIV infects its target cells by coordinated action of the hemagglutininneuraminidase receptor-binding protein (HN) and the fusion envelope glycoprotein (F), which together comprise the molecular fusion machinery; upon receptor engagement by HN, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. Peptides derived from key regions of F can potently inhibit HPIV infection at the entry stage, by interfering with the structural transition of F. We show that clinically circulating viruses have fusion machinery that is more stable and less readily activated than viruses adapted to growth in culture. Fusion machinery that is advantageous for growth in human airway epithelia and in vivo confers susceptibility to peptide fusion inhibitors in the host lung tissue or animal, but the same fusion inhibitors have no effect on viruses whose fusion glycoproteins are suited for growth in vitro. We propose that for potential clinical efficacy, antivirals should be evaluated using clinical isolates in natural host tissue rather than lab strains of virus in cultured cells. The unique susceptibility of clinical strains in human tissues reflects viral inhibition in vivo. IMPORTANCEAcute respiratory infection is the leading cause of mortality in young children under 5 years of age, causing nearly 20% of childhood deaths worldwide each year. The paramyxoviruses, including human parainfluenza viruses (HPIVs), cause a large share of these illnesses. There are no vaccines or drugs for the HPIVs. Inhibiting entry of viruses into the human cell is a promising drug strategy that blocks the first step in infection. To develop antivirals that inhibit entry, it is critical to understand the first steps of infection. We found that clinical viruses isolated from patients have very different entry properties from those of the viruses generally studied in laboratories. The viral entry mechanism is less active and more sensitive to fusion inhibitory molecules. We propose that to interfere with viral infection, we test clinically circulating viruses in natural tissues, to develop antivirals against respiratory disease caused by HPIVs.

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“…To assess the potential for lung delivery of the lipid-conjugated HRC peptides, we used an ex vivo mucosal tissue model consisting of normal, human-derived tracheal/bronchial epithelial cells that have been cultured to form a highly differentiated model that closely resembles the human airway epithelium (HAE) tissue of the respiratory tract. We have used HAE for evaluating entry inhibitors (47)(48)(49)(50)(51). In previous work, we found that the monomeric (HRC2) and dimeric (HRC4) peptides conjugated to cholesterol both reach the basolateral face in similar concentrations (29).…”

Section: Figmentioning

confidence: 99%

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence

Figueira

Palermo

Veiga

et al. 2017

J Virol

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Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo. We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The selfassembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides.IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides.

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A Recombinant Sialidase Fusion Protein Effectively Inhibits Human Parainfluenza Viral Infection In Vitro and In Vivo

Cited by 78 publications

References 40 publications

Premature Activation of the Paramyxovirus Fusion Protein before Target Cell Attachment with Corruption of the Viral Fusion Machinery

Premature Activation of the Paramyxovirus Fusion Protein before Target Cell Attachment with Corruption of the Viral Fusion Machinery

Circulating Clinical Strains of Human Parainfluenza Virus Reveal Viral Entry Requirements for In Vivo Infection

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence

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