Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor

Roymans, Dirk; Alnajjar, Sarhad; Battles, Michael B.; Sitthicharoenchai, Panchan; Furmanova-Hollenstein, Polina; Rigaux, Peter; Berg, Joke Van Den; Kwanten, Leen; Ginderen, Marcia Van; Verheyen, Nick; Vranckx, Luc; Jaensch, Steffen; Arnoult, Éric; Voorzaat, Richard; Gallup, Jack M.; Larios-Mora, Alejandro; Crabbe, Marjolein; Huntjens, Dymphy; Raboisson, Pierre; Langedijk, Johannes P. M.; Ackermann, Mark R.; McLellan, Jason S.; Vendeville, Sandrine; Koul, Anil

doi:10.1038/s41467-017-00170-x

Cited by 62 publications

(100 citation statements)

References 71 publications

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“…https://doi.org/10.1371/journal.ppat.1007944.g003 The epitope for each antibody is shown on the green protomer, and the epitope itself is colored purple for AM22, red for RSD5-GL, and blue for D25. (C) The amino 5K6C, 5K6F-5K6I, 5TOJ, and 5TOK [8,40,41,[45][46][47][48][49]). Conformational flexibility and transient exposure of different epitopes have been noted for other class I fusion proteins such as HIV-1 Env and MERS-CoV Spike [50][51][52][53][54].…”

Section: Discussionmentioning

confidence: 99%

Alternative conformations of a major antigenic site on RSV F

et al. 2019

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The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site Ø. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site Ø in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site Ø, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site Ø, each diverging at a conserved proline residue located in the middle of an α-helix. These data suggest that antigenic site Ø exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates.

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Section: Discussionmentioning

confidence: 99%

Alternative conformations of a major antigenic site on RSV F

et al. 2019

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“…During the last few years, a number of crystallographic structures of the prefusion RSV glycoprotein became available focusing on several benzimidazole-based or bioisosteres inhibitors as co-crystallized ligands [31][32][33]. A number of them highlighted a small number of contacts responsible for the inhibitor positioning at the exposed surface area of the protein, occupying one hydrophobic region of the biological target especially, including the F137 residue.…”

Section: Molecular Modelling Studiesmentioning

confidence: 99%

“…Herein we discuss this computational work with the aim of exploring an adequate RSV F protein inhibition activity of the newly synthesized antiviral compounds, by means of molecular docking simulations taking into account the X-ray crystallographic structure of the RSV F protein in complex with JNJ-53718678 (pdb code = 5KWW; resolution = 2.5 Å) [32]. This crystallographic data have been chosen based on the structural similarity shown by the reference compound JNJ-53718678 with the in-house, benzimidazole-based hydrazones and thiosemicarbazones.…”

Section: Molecular Modelling Studiesmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Novel (thio)semicarbazone-Based Benzimidazoles as Antiviral Agents against Human Respiratory Viruses

et al. 2020

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Respiratory RNA viruses are responsible for recurrent acute respiratory illnesses that still represent a major medical need. Previously we developed a large variety of benzimidazole derivatives able to inhibit these viruses. Herein, two series of (thio)semicarbazone-and hydrazone-based benzimidazoles have been explored, by derivatizing 5-acetyl benzimidazoles previously reported by us, thereby evaluating the influence of the modification on the antiviral activity. Compounds 6, 8, 16 and 17, bearing the 5-(thio)semicarbazone and 5-hydrazone functionalities in combination with the 2-benzyl ring on the benzimidazole core structure, acted as dual inhibitors of influenza A virus and human coronavirus. For respiratory syncytial virus (RSV), activity is limited to the 5-thiosemicarbazone (25) and 5-hydrazone (22) compounds carrying the 2-[(benzotriazol-1/2-yl)methyl]benzimidazole scaffold. These molecules proved to be the most effective antiviral agents, able to reach the potency profile of the licensed drug ribavirin. The molecular docking analysis explained the SAR of these compounds around their binding mode to the target RSV F protein, revealing the key contacts for further assessment. The herein-investigated benzimidazole-based derivatives may represent valuable hit compounds, deserving subsequent structural improvements towards more efficient antiviral agents for the treatment of pathologies caused by these human respiratory viruses.

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“…ALX-0171 is a trivalent nanobody that targets the RSV Fusion (F) protein for delivery via inhalation (Detalle et al, 2015). Fusion inhibitors, the second class of novel RSV inhibitors, block an essential conformational change of the RSV F protein, thereby inhibiting cell entry by preventing fusion between the virus envelope and the host-cell membrane (Roymans et al, 2017). Current fusion inhibitors include JNJ-678, presatovir (GS-5806), AK0529, and RV521 (Table 2).…”

Section: Emergence Of Drugs Against Respiratory Infectionsmentioning

confidence: 99%

Innovation and trends in the development and approval of antiviral medicines: 1987–2017 and beyond

2018

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2017 marked the 30th anniversary of the approval of zidovudine (AZT) as the first HIV/AIDS therapy. Since then, more than eighty antiviral drugs have received FDA approval, half of which treat HIV infection. Here, we provide a retrospective analysis of approved antiviral drugs, including therapeutics against other major chronic infections such as hepatitis B and C, and herpes viruses, over the last thirty years. During this time, only a few drugs were approved to treat acute viral infections, mainly influenza. Analysis of these approved antiviral drugs based on molecular class and mode of action shows that a large majority are small molecules and direct-acting agents as opposed to proteins, peptides, or oligonucleotides and host-targeting therapies. In addition, approvals of combination therapies accelerated over the last five years. We also provide a prospective study of future potential antiviral therapies, based on current clinical research pipelines across the pharmaceutical industry. Comparing past drug approvals with current clinical candidates hints at the future evolution in antiviral therapies and reveals how antiviral medicines are often discovered. Overall, this work helps forecast future trends and innovation in the field of antiviral research and development.

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Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor

Cited by 62 publications

References 71 publications

Alternative conformations of a major antigenic site on RSV F

Alternative conformations of a major antigenic site on RSV F

Synthesis and Biological Evaluation of Novel (thio)semicarbazone-Based Benzimidazoles as Antiviral Agents against Human Respiratory Viruses

Innovation and trends in the development and approval of antiviral medicines: 1987–2017 and beyond

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