scholarly journals Targeting the Fusion Process of SARS-CoV-2 Infection by Small Molecule Inhibitors

mBio ◽  
2022 ◽  
Author(s):  
Seung Bum Park ◽  
Parker Irvin ◽  
Zongyi Hu ◽  
Mohsin Khan ◽  
Xin Hu ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Host Cells ◽  
Fusion Process ◽  
Enveloped Viruses ◽  
Enveloped Virus ◽  
Fusion Inhibitors

SARS-CoV-2 is an enveloped virus that requires membrane fusion for entry into host cells. Since the fusion process is relatively conserved among enveloped viruses, we tested our HCV fusion inhibitors, dichlorcyclizine and fluoxazolevir, against SARS-CoV-2.

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 Small-Molecule Fusion Inhibitors Bind the pH-Sensing Stable Signal Peptide-GP2 Subunit Interface of the Lassa Virus Envelope Glycoprotein

2016 ◽  
Vol 90 (15) ◽  
pp. 6799-6807 ◽  
Author(s):  
Sundaresh Shankar ◽  
Landon R. Whitby ◽  
Hedi E. Casquilho-Gray ◽  
Joanne York ◽  
Dale L. Boger ◽  
...  
Keyword(s):  
Small Molecule ◽  
Envelope Glycoprotein ◽  
Small Molecule Inhibitors ◽  
Hemorrhagic Fever ◽  
Lassa Virus ◽  
Ph Sensing ◽  
Antiviral Therapies ◽  
Hemorrhagic Fevers ◽  
Fusion Inhibitors ◽  
Stable Signal

ABSTRACTArenavirus species are responsible for severe life-threatening hemorrhagic fevers in western Africa and South America. Without effective antiviral therapies or vaccines, these viruses pose serious public health and biodefense concerns. Chemically distinct small-molecule inhibitors of arenavirus entry have recently been identified and shown to act on the arenavirus envelope glycoprotein (GPC) to prevent membrane fusion. In the tripartite GPC complex, pH-dependent membrane fusion is triggered through a poorly understood interaction between the stable signal peptide (SSP) and the transmembrane fusion subunit GP2, and our genetic studies have suggested that these small-molecule inhibitors act at this interface to antagonize fusion activation. Here, we have designed and synthesized photoaffinity derivatives of the 4-acyl-1,6-dialkylpiperazin-2-one class of fusion inhibitors and demonstrate specific labeling of both the SSP and GP2 subunits in a native-like Lassa virus (LASV) GPC trimer expressed in insect cells. Photoaddition is competed by the parental inhibitor and other chemically distinct compounds active against LASV, but not those specific to New World arenaviruses. These studies provide direct physical evidence that these inhibitors bind at the SSP-GP2 interface. We also find that GPC containing the uncleaved GP1-GP2 precursor is not susceptible to photo-cross-linking, suggesting that proteolytic maturation is accompanied by conformational changes at this site. Detailed mapping of residues modified by the photoaffinity adducts may provide insight to guide the further development of these promising lead compounds as potential therapeutic agents to treat Lassa hemorrhagic fever.IMPORTANCEHemorrhagic fever arenaviruses cause lethal infections in humans and, in the absence of licensed vaccines or specific antiviral therapies, are recognized to pose significant threats to public health and biodefense. Lead small-molecule inhibitors that target the arenavirus envelope glycoprotein (GPC) have recently been identified and shown to block GPC-mediated fusion of the viral and cellular endosomal membranes, thereby preventing virus entry into the host cell. Genetic studies suggest that these inhibitors act through a unique pH-sensing intersubunit interface in GPC, but atomic-level structural information is unavailable. In this report, we utilize novel photoreactive fusion inhibitors and photoaffinity labeling to obtain direct physical evidence for inhibitor binding at this critical interface in Lassa virus GPC. Future identification of modified residues at the inhibitor-binding site will help elucidate the molecular basis for fusion activation and its inhibition and guide the development of effective therapies to treat arenaviral hemorrhagic fevers.

scholarly journals Characterization of Fusion Determinants Points to the Involvement of Three Discrete Regions of Both E1 and E2 Glycoproteins in the Membrane Fusion Process of Hepatitis C Virus

2007 ◽  
Vol 81 (16) ◽  
pp. 8752-8765 ◽  
Author(s):  
Dimitri Lavillette ◽  
Eve-Isabelle Pécheur ◽  
Peggy Donot ◽  
Judith Fresquet ◽  
Jennifer Molle ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Membrane Fusion ◽  
Conformational Changes ◽  
Lipid Membranes ◽  
Fusion Process ◽  
Fusion Peptides ◽  
Cellular Membranes ◽  
Enveloped Virus ◽  
Molecular Events

ABSTRACT Infection of eukaryotic cells by enveloped viruses requires the merging of viral and cellular membranes. Highly specific viral surface glycoproteins, named fusion proteins, catalyze this reaction by overcoming inherent energy barriers. Hepatitis C virus (HCV) is an enveloped virus that belongs to the genus Hepacivirus of the family Flaviviridae. Little is known about the molecular events that mediate cell entry and membrane fusion for HCV, although significant progress has been made due to recent developments in infection assays. Here, using infectious HCV pseudoparticles (HCVpp), we investigated the molecular basis of HCV membrane fusion. By searching for classical features of fusion peptides through the alignment of sequences from various HCV genotypes, we identified six regions of HCV E1 and E2 glycoproteins that present such characteristics. We introduced conserved and nonconserved amino acid substitutions in these regions and analyzed the phenotype of HCVpp generated with mutant E1E2 glycoproteins. This was achieved by (i) quantifying the infectivity of the pseudoparticles, (ii) studying the incorporation of E1E2 and their capacity to mediate receptor binding, and (iii) determining their fusion capacity in cell-cell and liposome/HCVpp fusion assays. We propose that at least three of these regions (i.e., at positions 270 to 284, 416 to 430, and 600 to 620) play a role in the membrane fusion process. These regions may contribute to the merging of viral and cellular membranes either by interacting directly with lipid membranes or by assisting the fusion process through their involvement in the conformational changes of the E1E2 complex at low pH.

scholarly journals Surfactin Inhibits Membrane Fusion during Invasion of Epithelial Cells by Enveloped Viruses

2018 ◽  
Vol 92 (21) ◽  
Author(s):  
Lvfeng Yuan ◽  
Shuai Zhang ◽  
Yongheng Wang ◽  
Yuchen Li ◽  
Xiaoqing Wang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Oral Administration ◽  
Membrane Fusion ◽  
Lipid Membrane ◽  
Antiviral Drugs ◽  
Fusion Inhibitor ◽  
Enveloped Viruses ◽  
Viral Membrane ◽  
Fusion Inhibitors ◽  
Naturally Occurring

ABSTRACT Because membrane fusion is a crucial step in the process by which enveloped viruses invade host cells, membrane fusion inhibitors can be effective drugs against enveloped viruses. We found that surfactin from Bacillus subtilis can suppress the proliferation of porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV) in epithelial cells at a relatively low concentration range (15 to 50 μg/ml), without cytotoxicity or viral membrane disruption. Membrane fusion inhibition experiments demonstrate that surfactin treatment significantly reduces the rate at which the virus fuses to the cell membrane. Thermodynamic experiments show that the incorporation of small amounts of surfactin hinders the formation of negative curvature by lamellar-phase lipids, suggesting that surfactin acts a membrane fusion inhibitor. A fluorescent lipopeptide similar to surfactin was synthesized, and its ability to insert into the viral membrane was confirmed by spectroscopy. In vivo experiments have shown that oral administration of surfactin to piglets protects against PEDV infection. In conclusion, our study indicates that surfactin is a membrane fusion inhibitor with activity against enveloped viruses. As the first reported naturally occurring wedge lipid membrane fusion inhibitor, surfactin is likely to be a prototype for the development of a broad range of novel antiviral drugs. IMPORTANCE Membrane fusion inhibitors are a rapidly emerging class of antiviral drugs that inhibit the infection process of enveloped viruses. They can be classified, on the basis of the viral components targeted, as fusion protein targeting or membrane lipid targeting. Lipid-targeting membrane fusion inhibitors have a broader antiviral spectrum and are less likely to select for drug-resistant mutations. Here we show that surfactin is a membrane fusion inhibitor and has a strong antiviral effect. The insertion of surfactin into the viral envelope lipids reduces the probability of viral fusion. We also demonstrate that oral administration of surfactin protects piglets from PEDV infection. Surfactin is the first naturally occurring wedge lipid membrane fusion inhibitor that has been identified and may be effective against many viruses beyond the scope of this study. Understanding its mechanism of action provides a foundation for the development of novel antiviral agents.

Recent Advances in the Development of Small-Molecule Compounds Targeting HIV- 1 gp41 as Membrane Fusion Inhibitors

2012 ◽  
Vol 9 (1) ◽  
pp. 20-26
Author(s):  
Norihito Kawashita ◽  
Yu-Shi Tian ◽  
U. Chandimal de Silva ◽  
Kousuke Okamoto ◽  
Tatsuya Takagi
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
Fusion Inhibitors ◽  
Recent Advances ◽  
Hiv 1

scholarly journals HIV fusion: Catch me if you can

2020 ◽  
Vol 295 (45) ◽  
pp. 15196-15197
Author(s):  
Solène Denolly ◽  
François-Loïc Cosset
Keyword(s):  
Cell Membrane ◽  
Membrane Fusion ◽  
Lipid Membrane ◽  
Electron Tomography ◽  
Fusion Process ◽  
Target Cells ◽  
Tirf Microscopy ◽  
Enveloped Viruses ◽  
Cryo Electron Tomography

The penetration of enveloped viruses into target cells requires the fusion of the lipid envelope of their virions with the host lipid membrane though a stepwise and highly sophisticated process. However, the intermediate steps in this process have seldom been visualized due to their rarity and rapidity. Here, using cryo-electron tomography, TIRF microscopy, and cell membrane–derived vesicles called blebs, Ward et al. visualize intermediates of the HIV-cell membrane fusion process and demonstrate how Serinc proteins prevent full fusion by interfering with this process.

scholarly journals Identification of an Intermediate Step in Foamy Virus Fusion

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1472
Author(s):  
Aurélie Dupont ◽  
Ivo M. Glück ◽  
Dorothee Ponti ◽  
Kristin Stirnnagel ◽  
Sylvia Hütter ◽  
...  
Keyword(s):  
Foamy Virus ◽  
Host Cells ◽  
Fusion Process ◽  
Productive Infection ◽  
Intermediate Step ◽  
Viral Glycoprotein ◽  
Enveloped Viruses ◽  
Essential Step ◽  
Foamy Viruses ◽  
Particle Level

Viral glycoprotein-mediated membrane fusion is an essential step for productive infection of host cells by enveloped viruses; however, due to its rarity and challenges in detection, little is known about the details of fusion events at the single particle level. Here, we have developed dual-color foamy viruses (FVs) composed of eGFP-tagged prototype FV (PFV) Gag and mCherry-tagged Env of either PFV or macaque simian FV (SFVmac) origin that have been optimized for detection of the fusion process. Using our recently developed tracking imaging correlation (TrIC) analysis, we were able to detect the fusion process for both PFV and SFVmac Env containing virions. PFV Env-mediated fusion was observed both at the plasma membrane as well as from endosomes, whereas SFVmac Env-mediated fusion was only observed from endosomes. PFV Env-mediated fusion was observed to happen more often and more rapidly than as for SFVmac Env. Strikingly, using the TrIC method, we detected a novel intermediate state where the envelope and capsids are still tethered but separated by up to 400 nm before final separation of Env and Gag occurred.

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 Structural Basis of SARS-CoV-2– and SARS-CoV–Receptor Binding and Small-Molecule Blockers as Potential Therapeutics

2021 ◽  
Vol 61 (1) ◽  
pp. 465-493 ◽  
Author(s):  
Hariharan Sivaraman ◽  
Shi Yin Er ◽  
Yeu Khai Choong ◽  
Edem Gavor ◽  
J. Sivaraman
Keyword(s):  
Small Molecule ◽  
Receptor Binding ◽  
Viral Entry ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Structural Basis ◽  
Virus Receptor ◽  
Fusion Inhibitors ◽  
Human Coronaviruses ◽  
Transmembrane Serine Protease

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other hosts is mediated by host–pathogen interactions, specifically virus–receptor binding. An in-depth understanding of the virus–receptor binding mechanism is a prerequisite for the discovery of vaccines, antibodies, and small-molecule inhibitors that can interrupt this interaction and prevent or cure infection. In this review, we discuss the viral entry mechanism, the known structural aspects of virus–receptor interactions (SARS-CoV-2 S/humanACE2, SARS-CoV S/humanACE2, and MERS-CoV S/humanDPP4), the key protein domains and amino acid residues involved in binding, and the small-molecule inhibitors and other drugs that have (as of June 2020) exhibited therapeutic potential. Specifically, we review the potential clinical utility of two transmembrane serine protease 2 (TMPRSS2)-targeting protease inhibitors, nafamostat mesylate and camostat mesylate, as well as two novel potent fusion inhibitors and the repurposed Ebola drug, remdesivir, which is specific to RNA-dependent RNA polymerase, against human coronaviruses, including SARS-CoV-2.

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