Abstract
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.
Highlights
Parainfluenza viruses are important agents of lower respiratory tract disease in children [1, 2], as well as in older adults and immunocompromised individuals [3]
As a control for specificity, we assessed the effect of the compounds on plaque formation by a closely related paramyxovirus, simian virus 5 (PIV5); this virus was not sensitive to the inhibitory effect of the three molecules, suggesting the inhibitory properties of the identified molecules were specific for HPIV3
The first step in paramyxovirus infection is binding of the receptor-binding protein (HN for HPIV3) to cell surface receptors
Summary
Parainfluenza viruses are important agents of lower respiratory tract disease in children [1, 2], as well as in older adults and immunocompromised individuals [3]. CSC11 and CSC7 Exert a Virucidal Effect—Because CSC11 and CSC7 do not interfere with HN receptor binding (Fig. 4), we hypothesized that their inhibition of viral entry might be attributable to a direct virucidal effect independent of the virus-target cell interaction.
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