scholarly journals How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion

2018 ◽  
Author(s):  
Luke H. Chao ◽  
Jaebong Jang ◽  
Adam Johnson ◽  
Anthony Nguyen ◽  
Nathanael S. Gray ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Single Particle ◽  
Small Molecule Inhibitors ◽  
Viral Fusion ◽  
Viral Attachment ◽  
Target Membrane ◽  
Viral Membrane Fusion ◽  
Rate Limiting

AbstractDengue virus (DV) is a compact, icoshedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic “fusion loops”. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments. Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the contact zone between virus and target membrane creates a trimerization bottleneck. We have extended that work to dengue VLPs, from all four DV serotypes, finding an essentially similar mechanism. Small-molecule inhibitors of DV infection that target E block its fusion-inducing conformation change. We show that ∼15 bound molecules per particle (∼8.5 % occupancy) completely prevent fusion, in accord with the proposed mechanism and the likely inhibitor binding site on E.Impact statementSingle-particle studies of dengue-virus membrane fusion and the effect of small-molecule inhibitors of infection clarify the viral fusion mechanism.

scholarly journals How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Luke H Chao ◽  
Jaebong Jang ◽  
Adam Johnson ◽  
Anthony Nguyen ◽  
Nathanael S Gray ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Dengue Virus Infection ◽  
Viral Attachment ◽  
Target Membrane ◽  
Viral Membrane Fusion ◽  
Rate Limiting

Dengue virus (DV) is a compact, icosahedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic ‘fusion loops’. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments (Chao et al., 2014). Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the contact zone between virus and target membrane creates a trimerization bottleneck. We now report an extension of that work to dengue VLPs, from all four serotypes, finding an essentially similar mechanism. Small-molecule inhibitors of dengue virus infection that target E block its fusion-inducing conformational change. We show that ~12–14 bound molecules per particle (~20–25% occupancy) completely prevent fusion, consistent with the proposed mechanism.

scholarly journals Small-Molecule Inhibition of Viral Fusion Glycoproteins

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Han-Yuan Liu ◽  
Priscilla L. Yang
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
Viral Entry ◽  
Small Molecule Inhibitors ◽  
Fusion Reaction ◽  
Covalent Bond ◽  
Annual Review ◽  
Publication Date ◽  
Viral Fusion ◽  
Viral Glycoprotein

Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

scholarly journals Sequential conformational rearrangements in flavivirus membrane fusion

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Luke H Chao ◽  
Daryl E Klein ◽  
Aaron G Schmidt ◽  
Jennifer M Peña ◽  
Stephen C Harrison
Keyword(s):  
Membrane Fusion ◽  
Conformational Transition ◽  
Structural Features ◽  
Cell Entry ◽  
The West ◽  
Target Membrane ◽  
Trimer Formation ◽  
Conformational Rearrangements ◽  
Viral Cell Entry ◽  
Rate Limiting

The West Nile Virus (WNV) envelope protein, E, promotes membrane fusion during viral cell entry by undergoing a low-pH triggered conformational reorganization. We have examined the mechanism of WNV fusion and sought evidence for potential intermediates during the conformational transition by following hemifusion of WNV virus-like particles (VLPs) in a single particle format. We have introduced specific mutations into E, to relate their influence on fusion kinetics to structural features of the protein. At the level of individual E subunits, trimer formation and membrane engagement of the threefold clustered fusion loops are rate-limiting. Hemifusion requires at least two adjacent trimers. Simulation of the kinetics indicates that availability of competent monomers within the contact zone between virus and target membrane makes trimerization a bottleneck in hemifusion. We discuss the implications of the model we have derived for mechanisms of membrane fusion in other contexts.

Novel Small Molecule Inhibitors of Dengue Virus Replication

2009 ◽  
Vol 82 (2) ◽  
pp. A38
Author(s):  
Chelsea Byrd ◽  
Jessica Page ◽  
Chris Harver ◽  
Doug Grosenbach ◽  
Aklile Berhanu ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Virus Replication ◽  
Small Molecule ◽  
Small Molecule Inhibitors
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