Abstract
Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre- and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.
Highlights
The paramyxovirus and pneumovirus families belong to the order Mononegavirales (1), which includes additional major human pathogen families such as the filoviruses and rhabdoviruses.Characteristic for the order are lipid-enveloped virions that contain a negative sense non-segmented (NNS) RNA genome
Another example for severe and unmitigated paramyxovirus disease is provided by Nipah virus (NiV), a zoonotic member of the family that belongs to the henipavirus genus
With a focus on pharmaceutical targeting of the viral entry machinery, we will discuss in the following the main stages of pneumo- and paramyxovirus F protein-mediated membrane fusion, examining the conformational rearrangements required for membrane merger
Summary
The paramyxovirus and pneumovirus families belong to the order Mononegavirales (1), which includes additional major human pathogen families such as the filoviruses and rhabdoviruses. No approved vaccine prophylaxis or antiviral therapeutic is currently available to protect against any HPIV infection or improve disease management Another example for severe and unmitigated paramyxovirus disease is provided by NiV, a zoonotic member of the family that belongs to the henipavirus genus. Medical and economic burden associated with paramyxo- and pneumovirus infections, a major and currently unmet clinical need exists to expedite the development of novel safe and effective therapeutics for improved disease management and outbreak control. With a focus on pharmaceutical targeting of the viral entry machinery, we will discuss in the following the main stages of pneumo- and paramyxovirus F protein-mediated membrane fusion, examining the conformational rearrangements required for membrane merger This structural framework of the viral entry process will be overlaid with known neutralizing epitopes and target sites for small-molecule entry inhibitors to better appreciate the underlying mechanism of inhibition, the structural basis for viral resistance, and the potential for counteracting viral escape through proactive ligand engineering
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