Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease

Moscona, Anne

doi:10.1172/jci25669

Cited by 113 publications

(135 citation statements)

References 86 publications

(98 reference statements)

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…The timing of F-activation is critical for paramyxovirus entry (15,25,28,57,58). In the case of PIV5, a mutated F protein with a hyperactive fusion phenotype releases the fusion peptide before reaching the target cell, thus preventing fusion with the target cell (58).…”

Section: Discussionmentioning

confidence: 99%

“…Although F-activation is key for viral entry (19), triggering must occur only when F is close enough to then make contact with the target cell membrane. We suggest that this timing of activation represents a potential target for intervention with paramyxovirus infection (15,25,27).…”

mentioning

confidence: 94%

“…Binding to the target cell is mediated via interaction of the viral receptor-binding molecule (hemagglutinin-neuraminidase (HN) 3 ) with sialic acid-containing receptor molecules on the cell surface. The viral envelope then fuses directly with the plasma membrane of the cell, a process mediated by the viral fusion protein (F), releasing the viral nucleocapsid into the cytoplasm (13)(14)(15). During fusion, the F protein must undergo a structural rearrangement (16 -18) requiring an activation step, which must occur at the right time and place in order for fusion and entry to occur.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…Proteinaceous cellular receptors have been identified for some paramyxoviruses, including measles virus (13,14) and Nipah virus (15,16). Sialylated cell-surface proteins serve as receptors for other paramyxoviruses, such as parainfluenza virus (17,18). For all paramyxoviruses identified to date, the G or H/HN protein rather than the F protein is the receptor-binding moiety.…”

mentioning

confidence: 99%

Integrin αvβ1 promotes infection by human metapneumovirus

Cseke

Maginnis

Cox³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Human metapneumovirus (hMPV) is a recently described paramyxovirus that causes lower respiratory infections in children and adults worldwide. The hMPV fusion (F) protein is a membrane-anchored glycoprotein and major protective antigen. All hMPV F protein sequences determined to date contain an Arg-Gly-Asp (RGD) sequence, suggesting that F engages RGD-binding integrins to mediate cell entry. The divalent cation chelator EDTA, which disrupts heterodimeric integrin interactions, inhibits infectivity of hMPV but not the closely related respiratory syncytial virus (RSV), which lacks an RGD motif. Function-blocking antibodies specific for ␣v␤1 integrin inhibit infectivity of hMPV but not RSV. Transfection of nonpermissive cells with ␣v or ␤1 cDNAs confers hMPV infectivity, whereas reduction of ␣v and ␤1 integrin expression by siRNA inhibits hMPV infection. Recombinant hMPV F protein binds to cells, whereas ArgGly-Glu (RGE)-mutant F protein does not. These data suggest that ␣v␤1 integrin is a functional receptor for hMPV.receptor ͉ paramyxovirus ͉ fusion protein ͉ viral entry

show abstract

“…Human parainfluenza virus (HPIV3), a member of paramyxoviridae family is a respiratory pathogen affecting children worldwide causing croup, bronchiolitis, and pneumonia (Moscona, 2005;Reed et al, 1997). It is second only to respiratory syncytial virus (RSV) resulting in acute respiratory infections that require hospitalization of infants and children (Heilman, 1990;Murphy, 1988).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human parainfluenza virus type 3 infection by novel small molecules

Mao¹,

Thakur²,

Chattopadhyay³

et al. 2008

Antiviral Research

View full text Add to dashboard Cite

Human parainfluenza virus type 3 (HPIV3) is an important respiratory tract pathogen of infants and children. There are no vaccines or antivirals currently approved for prevention or treatment of HPIV3 infection. Towards developing an antiviral therapy to combat HPIV3 infection, we have established a green fluorescent protein (GFP)-tagged HPIV3 infected-cell assay and used it for screening of a small molecule library obtained from ChemBridge Diver. Two novel small molecules (C5 and C7) which shared structural similarities were identified and their inhibitory effects on HPIV3 were confirmed in CV-1 and human lung epithelium A549 cells by plaque assay, Western blot and Northern blot analyses. C5 and C7 effectively prevented the cytopathic effect in cells infected with HPIV3, achieving IC 50 values of 2.36μM and 0.08μM, respectively, for infectious virus production. The inhibition appears to be at the primary transcriptional level of HPIV3 life cycle based on sequential time course test, binding and internalization assays, and finally by a minigenome transcription assay in cells as well as measuring viral transcripts in cells in the presence of anisomycin. Interestingly, vesicular stomatitis virus (VSV), another member of mononegavirales order, was also inhibited by these compounds, whereas poliovirus-a picornavirus was not. Use of these inhibitors has a strong potential to develop novel antiviral agents against this important human pathogen.

show abstract

Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease

Cited by 113 publications

References 86 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

Integrin αvβ1 promotes infection by human metapneumovirus

Inhibition of human parainfluenza virus type 3 infection by novel small molecules

Contact Info

Product

Resources

About