Effects of singlet oxygen generated by a broad-spectrum viral fusion inhibitor on membrane nanoarchitecture

Hollmann, Axel; Gonçalves, Sónia; Augusto, Marcelo; Castanho, Miguel A. R. B.; Lee, Benhur; Santos, Nuno C.

doi:10.1016/j.nano.2015.02.014

Cited by 16 publications

(18 citation statements)

References 20 publications

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“…The results from the PIV5 infection system, taken together with the results from the HeV F cellular experiments, highlight the critical nature of fusion protein TM-TM interactions for maintenance of viral infectivity and demonstrate a potential for smallmolecule inhibitors that disrupt TM-TM interactions or modulators of lipid environment to serve as antiviral candidates. A study with paramyxoviruses found that a broad-spectrum small-molecule drug (JL103) could prevent membrane fusion by altering lipid architecture (37). Changes in the lipid environment caused by small-molecule inhibitors may be able to alter fusion protein TM-TM interactions and therefore disrupt fusion protein function.…”

Section: Discussionmentioning

confidence: 99%

A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

Barrett

Webb

Dutch

2019

J Virol

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Enveloped viruses utilize surface glycoproteins to bind and fuse with a target cell membrane. The zoonotic Hendra virus (HeV), a member of the family Paramyxoviridae, utilizes the attachment protein (G) and the fusion protein (F) to perform these critical functions. Upon triggering, the trimeric F protein undergoes a large, irreversible conformation change to drive membrane fusion. Previously, we have shown that the transmembrane (TM) domain of the F protein, separate from the rest of the protein, is present in a monomer-trimer equilibrium. This TM-TM association contributes to the stability of the prefusion form of the protein, supporting a role for TM-TM interactions in the control of F protein conformational changes. To determine the impact of disrupting TM-TM interactions, constructs expressing the HeV F TM with limited flanking sequences were synthesized. Coexpression of these constructs with HeV F resulted in dramatic reductions in the stability of F protein expression and fusion activity. In contrast, no effects were observed when the HeV F TM constructs were coexpressed with the nonhomologous parainfluenza virus 5 (PIV5) fusion protein, indicating a requirement for specific interactions. To further examine this, a TM peptide homologous to the PIV5 F TM domain was synthesized. Addition of the peptide prior to infection inhibited infection with PIV5 but did not significantly affect infection with human metapneumovirus, a related virus. These results indicate that targeted disruption of TM-TM interactions significantly impact viral fusion protein stability and function, presenting these interactions as a novel target for antiviral development. IMPORTANCE Enveloped viruses require virus-cell membrane fusion to release the viral genome and replicate. The viral fusion protein triggers from the pre-to the postfusion conformation, an essentially irreversible change, to drive membrane fusion. We found that small proteins containing the TM and a limited flanking region homologous to the fusion protein of the zoonotic Hendra virus reduced protein expression and fusion activity. The introduction of exogenous TM peptides may displace a TM domain, disrupting native TM-TM interactions and globally destabilizing the fusion protein. Supporting this hypothesis, we showed that a sequence-specific transmembrane peptide dramatically reduced viral infection in another enveloped virus model, suggesting a broader inhibitory mechanism. Viral fusion protein TM-TM interactions are important for protein function, and disruption of these interactions dramatically reduces protein stability.

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Section: Discussionmentioning

confidence: 99%

A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

Barrett

Webb

Dutch

2019

J Virol

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“…Novel lipophilic thiazolidine derivatives, such as LJ001 and JL103, are membrane-binding photosensitizers that produce singlet oxygen molecules to induce changes in the properties of lipid membranes and prevent fusion between viral and target cell membranes. They exhibit broad-spectrum activities against numerous enveloped viruses and may be active against CoVs [184][185][186][187] .…”

Section: Viral Envelope Membrane Nucleocapsid and Accessory Proteinmentioning

confidence: 99%

Coronaviruses — drug discovery and therapeutic options

Zumla

Chan

Azhar

et al. 2016

Nat Rev Drug Discov

1,591

1,721

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In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.

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“…13), are membrane-binding photosensitizers that produce singlet oxygen molecules to induce changes in the properties of lipid membranes and prevent fusion between viral and target cell membranes. They exhibit broad-spectrum activities against numerous enveloped viruses and may be active against CoVs [164][165][166][167]. In addition to the above-mentioned molecules, there are numerous peptide-based inhibitors of coronaviruses [168].…”

Section: Figure 13mentioning

confidence: 99%