Viral Entry Inhibitors Targeting Six-Helical Bundle Core Against Highly Pathogenic Enveloped Viruses with Class I Fusion Proteins

2021 ◽  
Vol 28 ◽  
Author(s):  
Jing Pu ◽  
Joey Tianyi Zhou ◽  
Ping Liu ◽  
Fei Yu ◽  
Xiaoyang He ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Envelope Protein ◽  
Fusion Proteins ◽  
Viral Envelope ◽  
Class I ◽  
Highly Pathogenic ◽  
Hepatitis D ◽  
Enveloped Viruses ◽  
Helical Bundle ◽  
Entry Inhibitors

: TypeⅠ enveloped viruses bind to cell receptors through surface glycoproteins to initiate infection or undergo receptor-mediated endocytosis. They also initiate membrane fusion in the acidic environment of endocytic compartments, releasing genetic material into the cell. In the process of membrane fusion, envelope protein exposes fusion peptide, followed by insertion into the cell membrane or endosomal membrane. Further conformational changes ensue in which the type 1 envelope protein forms a typical six-helix bundle structure, shortening the distance between viral and cell membranes so that fusion can occur. Entry inhibitors targeting viral envelope proteins, or host factors, are effective antiviral agents and have been widely studied. Some have been used clinically, such as T20 and Maraviroc for human immunodeficiency virus 1 (HIV-1) or Myrcludex B for hepatitis D virus (HDV). This review focuses on entry inhibitors that target the six-helical bundle core against highly pathogenic enveloped viruses with class I fusion proteins, including retroviruses, coronaviruses, influenza A viruses, paramyxoviruses, and filoviruses.

scholarly journals The structure of a prokaryotic viral envelope protein expands the landscape of membrane fusion proteins

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kamel El Omari ◽  
Sai Li ◽  
Abhay Kotecha ◽  
Thomas S. Walter ◽  
Eduardo A. Bignon ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Envelope Protein ◽  
Fusion Proteins ◽  
Viral Envelope ◽  
Viral Envelope Protein ◽  
Membrane Fusion Proteins

Functional Domains within Fusion Proteins: Prospectives for Development of Peptide Inhibitors of Viral Cell Fusion

2000 ◽  
Vol 20 (6) ◽  
pp. 535-555 ◽  
Author(s):  
Yechiel Shai
Keyword(s):  
Membrane Fusion ◽  
Fusion Proteins ◽  
Peptide Inhibitors ◽  
Viral Envelope ◽  
Host Cells ◽  
Functional Domains ◽  
Fusion Event ◽  
Enveloped Viruses ◽  
Target Plasma ◽  
Shed Light

The entry of enveloped viruses into host cells is accomplished by fusion ofthe viral envelope and target plasma membrane and is mediated by fusionproteins. Recently, several functional domains within fusion proteins fromdifferent viral families were identified. Some are directly involved inconformational changes after receptor binding, as suggested by the recentrelease of crystallographically determined structures of a highly stablecore structure of the fusion proteins in the absence of membranes. However, in the presence of membranes, this core binds strongly to the membrane's surface and dissociates therein. Other regions, besides the N-terminal fusionpeptide, which include the core region and an internal fusion peptide inparamyxoviruses, are directly involved in the actual membrane fusion event, suggesting an “umbrella” like model for the membrane inducedconformational change of fusion proteins. Peptides resembling these regionshave been shown to have specific antiviral activity, presumably because theyinterfere with the corresponding domains within the viruses. Overall, thesestudies shed light into the molecular mechanism of membrane fusion induced byenvelope glycoproteins and suggest that fusion proteins from different viralfamilies share common structural and functional motifs.

scholarly journals Regulation of membrane fusion by the membrane-proximal coil of the t-SNARE during zippering of SNAREpins

2002 ◽  
Vol 158 (5) ◽  
pp. 929-940 ◽  
Author(s):  
Thomas J. Melia ◽  
Thomas Weber ◽  
James A. McNew ◽  
Lillian E. Fisher ◽  
Robert J. Johnston ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Fusion Proteins ◽  
The Other ◽  
Proximal Portion ◽  
Intrinsic State ◽  
Temporal Control ◽  
Helical Bundle ◽  
Proximal Half

We utilize structurally targeted peptides to identify a “tC fusion switch” inherent to the coil domains of the neuronal t-SNARE that pairs with the cognate v-SNARE. The tC fusion switch is located in the membrane-proximal portion of the t-SNARE and controls the rate at which the helical bundle that forms the SNAREpin can zip up to drive bilayer fusion. When the fusion switch is “off” (the intrinsic state of the t-SNARE), zippering of the helices from their membrane-distal ends is impeded and fusion is slow. When the tC fusion switch is “on,” fusion is much faster. The tC fusion switch can be thrown by a peptide that corresponds to the membrane-proximal half of the cognate v-SNARE, and binds reversibly to the cognate region of the t-SNARE. This structures the coil in the membrane-proximal domain of the t-SNARE and accelerates fusion, implying that the intrinsically unstable coil in that region is a natural impediment to the completion of zippering, and thus, fusion. Proteins that stabilize or destabilize one or the other state of the tC fusion switch would exert fine temporal control over the rate of fusion after SNAREs have already partly zippered up.

scholarly journals A Histidine Switch in Hemagglutinin-Neuraminidase Triggers Paramyxovirus-Cell Membrane Fusion

2008 ◽  
Vol 83 (4) ◽  
pp. 1727-1741 ◽  
Author(s):  
Anuja Krishnan ◽  
Santosh K. Verma ◽  
Prashant Mani ◽  
Rahul Gupta ◽  
Suman Kundu ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Membrane Fusion ◽  
Fusion Proteins ◽  
Sendai Virus ◽  
Biological Activities ◽  
Viral Envelope ◽  
Attachment Protein ◽  
Histidine Residues ◽  
Human Parainfluenza Virus ◽  
Mimicking Peptides

ABSTRACT Most paramyxovirus fusion proteins require coexpression of and activation by a homotypic attachment protein, hemagglutinin-neuraminidase (HN), to promote membrane fusion. However, the molecular mechanism of the activation remains unknown. We previously showed that the incorporation of a monohistidylated lipid into F-virosome (Sendai viral envelope containing only fusion protein) enhanced its fusion to hepatocytes, suggesting that the histidine residue in the lipid accelerated membrane fusion. Therefore, we explored whether a histidine moiety in HN could similarly direct activation of the fusion protein. In membrane fusion assays, the histidine substitution mutants of HN (H247A of Sendai virus and H245A of human parainfluenza virus 3) had impaired membrane fusion promotion activity without significant changes in other biological activities. Synthetic 30-mer peptides corresponding to regions of the two HN proteins containing these histidine residues rescued the fusion promoting activity of the mutants, whereas peptides with histidine residues substituted by alanine did not. These histidine-containing peptides also activated F-virosome fusion with hepatocytes both in the presence and in the absence of mutant HN in the virosome. We provide evidence that the HN-mimicking peptides promote membrane fusion, revealing a specific histidine “switch” in HN that triggers fusion.

scholarly journals Pseudotyping Autographa californica Multicapsid Nucleopolyhedrovirus (AcMNPV): F Proteins from Group II NPVs Are Functionally Analogous to AcMNPV GP64

2002 ◽  
Vol 76 (11) ◽  
pp. 5729-5736 ◽  
Author(s):  
Oliver Lung ◽  
Marcel Westenberg ◽  
Just M. Vlak ◽  
Douwe Zuidema ◽  
Gary W. Blissard
Keyword(s):  
Membrane Fusion ◽  
Envelope Protein ◽  
Protein Gene ◽  
Autographa Californica ◽  
Viral Envelope ◽  
Viral Attachment ◽  
F Protein ◽  
Viral Propagation ◽  
The Family ◽  
Vesicular Stomatitis

ABSTRACT GP64, the major envelope glycoprotein of budded virions of the baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), is involved in viral attachment, mediates membrane fusion during virus entry, and is required for efficient virion budding. Thus, GP64 is essential for viral propagation in cell culture and in animals. Recent genome sequences from a number of baculoviruses show that only a subset of closely related baculoviruses have gp64 genes, while other baculoviruses have a recently discovered unrelated envelope protein named F. F proteins from Lymantria dispar MNPV (LdMNPV) and Spodoptera exigua MNPV (SeMNPV) mediate membrane fusion and are therefore thought to serve roles similar to that of GP64. To determine whether F proteins are functionally analogous to GP64 proteins, we deleted the gp64 gene from an AcMNPV bacmid and inserted F protein genes from three different baculoviruses. In addition, we also inserted envelope protein genes from vesicular stomatitis virus (VSV) and Thogoto virus. Transfection of the gp64-null bacmid DNA into Sf9 cells does not generate infectious particles, but this defect was rescued by introducing either the F protein gene from LdMNPV or SeMNPV or the G protein gene from VSV. These results demonstrate that baculovirus F proteins are functionally analogous to GP64. Because baculovirus F proteins appear to be more widespread within the family and are much more divergent than GP64 proteins, gp64 may represent the acquisition of an envelope protein gene by an ancestral baculovirus. The AcMNPV pseudotyping system provides an efficient and powerful method for examining the functions and compatibilities of analogous or orthologous viral envelope proteins, and it could have important biotechnological applications.

A Dissection of Steps Leading to Viral Envelope Protein-Mediated Membrane Fusion

1991 ◽  
Vol 635 (1 Calcium Entry) ◽  
pp. 285-296 ◽  
Author(s):  
ROBERT BLUMENTHAL ◽  
CHRISTIAN SCHOCH ◽  
ANU PURI ◽  
MICHAEL J. CLAGUE
Keyword(s):  
Membrane Fusion ◽  
Envelope Protein ◽  
Viral Envelope ◽  
Viral Envelope Protein

scholarly journals Close Is Not Enough

2000 ◽  
Vol 150 (1) ◽  
pp. 105-118 ◽  
Author(s):  
James A. McNew ◽  
Thomas Weber ◽  
Francesco Parlati ◽  
Robert J. Johnston ◽  
Thomas J. Melia ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Membrane Fusion ◽  
Fusion Proteins ◽  
Active Role ◽  
Snare Complex ◽  
Active Process ◽  
Attachment Protein ◽  
Helical Bundle ◽  
Active Mechanism ◽  
Target Membrane

Is membrane fusion an essentially passive or an active process? It could be that fusion proteins simply need to pin two bilayers together long enough, and the bilayers could do the rest spontaneously. Or, it could be that the fusion proteins play an active role after pinning two bilayers, exerting force in the bilayer in one or another way to direct the fusion process. To distinguish these alternatives, we replaced one or both of the peptidic membrane anchors of exocytic vesicle (v)- and target membrane (t)-SNAREs (soluble N-ethylmaleimide-sensitive fusion protein [NSF] attachment protein [SNAP] receptor) with covalently attached lipids. Replacing either anchor with a phospholipid prevented fusion of liposomes by the isolated SNAREs, but still allowed assembly of trans-SNARE complexes docking vesicles. This result implies an active mechanism; if fusion occurred passively, simply holding the bilayers together long enough would have been sufficient. Studies using polyisoprenoid anchors ranging from 15–55 carbons and multiple phospholipid-containing anchors reveal distinct requirements for anchors of v- and t-SNAREs to function: v-SNAREs require anchors capable of spanning both leaflets, whereas t-SNAREs do not, so long as the anchor is sufficiently hydrophobic. These data, together with previous results showing fusion is inhibited as the length of the linker connecting the helical bundle-containing rod of the SNARE complex to the anchors is increased (McNew, J.A., T. Weber, D.M. Engelman, T.H. Sollner, and J.E. Rothman, 1999. Mol. Cell. 4:415–421), suggests a model in which one activity of the SNARE complex promoting fusion is to exert force on the anchors by pulling on the linkers. This motion would lead to the simultaneous inward movement of lipids from both bilayers, and in the case of the v-SNARE, from both leaflets.

scholarly journals Identification of the Fusion Peptide-Containing Region in Betacoronavirus Spike Glycoproteins

2016 ◽  
Vol 90 (12) ◽  
pp. 5586-5600 ◽  
Author(s):  
Xiuyuan Ou ◽  
Wangliang Zheng ◽  
Yiwei Shan ◽  
Zhixia Mu ◽  
Samuel R. Dominguez ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Cell Fusion ◽  
Fusion Proteins ◽  
Virus Entry ◽  
Amino Acid Sequences ◽  
Viral Envelope ◽  
Class I ◽  
Viral Fusion ◽  
Viral Fusion Proteins

ABSTRACTThe fusion peptides (FP) play an essential role in fusion of viral envelope with cellular membranes. The location and properties of the FPs in the spike (S) glycoproteins of different coronaviruses (CoV) have not yet been determined. Through amino acid sequence analysis of S proteins of representative CoVs, we identified a common region as a possible FP (pFP) that shares the characteristics of FPs of class I viral fusion proteins, including high Ala/Gly content, intermediate hydrophobicity, and few charged residues. To test the hypothesis that this region contains the CoV FP, we systemically mutated every residue in the pFP of Middle East respiratory syndrome betacoronavirus (MERS-CoV) and found that 11 of the 22 residues in the pFP (from G953 to L964, except for A956) were essential for S protein-mediated cell-cell fusion and virus entry. The synthetic MERS-CoV pFP core peptide (955IAGVGWTAGL964) induced extensive fusion of liposome membranes, while mutant peptide failed to induce any lipid mixing. We also selectively mutated residues in pFPs of two other β-CoVs, severe acute respiratory syndrome coronavirus (SARS-CoV) and mouse hepatitis virus (MHV). Although the amino acid sequences of these two pFPs differed significantly from that of MERS-CoV and each other, most of the pFP mutants of SARS-CoV and MHV also failed to mediate membrane fusion, suggesting that these pFPs are also the functional FPs. Thus, the FPs of 3 different lineages of β-CoVs are conserved in location within the S glycoproteins and in their functions, although their amino acid sequences have diverged significantly during CoV evolution.IMPORTANCEWithin the class I viral fusion proteins of many enveloped viruses, the FP is the critical mediator of fusion of the viral envelope with host cell membranes leading to virus infection. FPs from within a virus family, like influenza viruses or human immunodeficiency viruses (HIV), tend to share high amino acid sequence identity. In this study, we determined the location and amino acid sequences of the FPs of S glycoproteins of 3 β-CoVs, MERS-CoV, SARS-CoV, and MHV, and demonstrated that they were essential for mediating cell-cell fusion and virus entry. Interestingly, in marked contrast to the FPs of influenza and HIV, the primary amino acid sequences of the FPs of β-CoVs in 3 different lineages differed significantly. Thus, during evolution the FPs of β-CoVs have diverged significantly in their primary sequences while maintaining the same essential biological functions. Our findings identify a potential new target for development of drugs against CoVs.

Membrane Fusion

2000 ◽  
Vol 20 (6) ◽  
pp. 435-441 ◽  
Author(s):  
Richard M. Epand
Keyword(s):  
Membrane Fusion ◽  
Fusion Proteins ◽  
Molecular Level ◽  
Biological Membranes ◽  
Fusion Process ◽  
Viral Fusion ◽  
Enveloped Viruses ◽  
Single Protein ◽  
Process Studies ◽  
Analogous Mechanism

The fusion of biological membranes results in two bilayer-based membranes merging into a single membrane. In this process the lipids have to undergo considerable rearrangement. The nature of the intermediates that are formed during this rearrangement has been investigated. Certain fusion proteins facilitate this process. In many cases short segments of these fusion proteins have a particularly important role in accelerating the fusion process. Studies of the interaction of model peptides with membranes have allowed for increased understanding at the molecular level of the mechanism of the promotion of membrane fusion by fusion proteins. There is an increased appreciation of the roles of several independent segments of fusion proteins in promoting the fusion process. Many of the studies of the fusion of biological membranes have been done with the fusion of enveloped viruses with other membranes. One reason for this is that the number of proteins involved in viral fusion is relatively simple, often requiring only a single protein. For many enveloped viruses, the structure of their fusion proteins has certain common elements, suggesting that they all promote fusion by an analogous mechanism. Some aspects of this mechanism also appears to be common to intracellular fusion, although several proteins are involved in that process which is more complex and regulated than is fusion.

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