Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus

Andries, Koen; Moeremans, M.; Gevers, Tom; Willebrords, R.; Sommen, Cois; Lacrampe, Jean; Janssens, Frans; Wyde, Philip R.

doi:10.1016/j.antiviral.2003.07.004

Cited by 100 publications

(100 citation statements)

References 18 publications

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“…Inhibitors of the HRSV F glycoprotein, such as palivizumab (Synagis), a humanized MAb (32), and low-molecular-weight compounds (2,15,52), have been the subject of intense research in recent years. Knowledge of their mode of action should contribute to improve their effectiveness and clinical use.…”

Section: Discussionmentioning

confidence: 99%

Neutralization of Human Respiratory Syncytial Virus Infectivity by Antibodies and Low-Molecular-Weight Compounds Targeted against the Fusion Glycoprotein

Magro

Andreu

Gómez‐Puertas

et al. 2010

J Virol

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Human respiratory syncytial virus (HRSV) fusion (F) protein is an essential component of the virus envelope that mediates fusion of the viral and cell membranes, and, therefore, it is an attractive target for drug and vaccine development. Our aim was to analyze the neutralizing mechanism of anti-F antibodies in comparison with other low-molecular-weight compounds targeted against the F molecule. It was found that neutralization by anti-F antibodies is related to epitope specificity. Thus, neutralizing and nonneutralizing antibodies could bind equally well to virions and remained bound after ultracentrifugation of the virus, but only the former inhibited virus infectivity. Neutralization by antibodies correlated with inhibition of cell-cell fusion in a syncytium formation assay, but not with inhibition of virus binding to cells. In contrast, a peptide (residues 478 to 516 of F protein [F478-516]) derived from the F protein heptad repeat B (HRB) or the organic compound BMS-433771 did not interfere with virus infectivity if incubated with virus before ultracentrifugation or during adsorption of virus to cells at 4°C. These inhibitors must be present during virus entry to effect HRSV neutralization. These results are best interpreted by asserting that neutralizing antibodies bind to the F protein in virions interfering with its activation for fusion. Binding of nonneutralizing antibodies is not enough to block this step. In contrast, the peptide F478-516 or BMS-433771 must bind to F protein intermediates generated during virus-cell membrane fusion, blocking further development of this process.Human respiratory syncytial virus (HRSV), a member of the Pneumovirus genus of the Paramyxoviridae family, is the main cause of severe lower respiratory tract infections in very young children (36), and it is a pathogen of considerable importance in the elderly (24, 26) and in immunocompromised adults (22). Currently, there is no effective vaccine against the virus although it is known that passive administration of neutralizing antibodies to individuals at high risk is an effective immunoprophylaxis (37,38).The HRSV genome is a single-stranded negative-sense RNA molecule of approximately 15 kb that encodes 11 proteins (16, 53). Two of these proteins are the main surface glycoproteins of the virion. These are (i) the attachment (G) protein, which mediates virus binding to cells (44), and (ii) the fusion (F) protein, which promotes both fusion of the viral and cell membranes at the initial stages of the infectious cycle and fusion of the membrane of infected cells with those of adjacent cells to form characteristic syncytia (72). These two glycoproteins are the only targets of neutralizing antibodies either induced in animal models (19,63,65,70) or present in human sera (62).The G protein is a highly variable type II glycoprotein that shares neither sequence identity nor structural features with the attachment protein of other paramyxoviruses (75). It is synthesized as a precursor of about 300 amino acids (depending on the strai...

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Section: Discussionmentioning

confidence: 99%

Neutralization of Human Respiratory Syncytial Virus Infectivity by Antibodies and Low-Molecular-Weight Compounds Targeted against the Fusion Glycoprotein

Magro

Andreu

Gómez‐Puertas

et al. 2010

J Virol

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“…7 Both RSV and parainfluenza-3 virus are an important cause of respiratory tract infections. 8,9 Among the heterocyclic rings containing bridgehead nitrogen atom, imidazo [2,1-b] activities.…”

Section: Introductionmentioning

confidence: 99%

Antibacterial, Antitubercular and Antiviral Activity Evaluations of Some Arylidenehydrazide Derivatives Bearing Imidazo[2,1-<i>b</i>]thiazole Moiety

Güzeldemirci

Karaman

Küçükbasmacı

2017

tjps

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ÖZObjectives: The aim of this study was to determine the probable antibacterial, antitubercular, and antiviral activities of some N 2 -arylidene-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl) acetic acid hydrazides (3a-j). Further structural optimization of the identified lead structures can lead us to new more active potential antibacterial, antitubercular, and antiviral agents. Materials and Methods:Antibacterial activities of the title compounds against Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922. These molecules were also evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) using the BACTEC 460 radiometric system and BACTEC 12B medium. Moreover, all the compounds (3a-j) were also evaluated against some DNA and RNA viruses in Madin-Darby Canine Kidney, Crandell-Rees Feline Kidney (CRFK), Vero, human embryonic lung (HEL) and HeLa cells. Results:Among the tested compounds, 3i displayed the highest efficacy against S. aureus and E. coli. Compound 3j, 5-nitro-2-furfurylidene derivative showed the highest antituberculosis activity (IC 50 : 6.16 μg/mL and IC 90 : 14.390 μg/mL). Compound 3i showed the most potent antiviral activity against feline corona virus in CRFK cell cultures (antiviral EC 50 : 7.5 μM and SI>13). Furthermore, compounds 3c and 3g displayed activity against herpes simplex virus-1 and vaccinia virus in HEL cell cultures (antiviral EC 50 values of 9; 16 and 20; 14 μM, respectively). Conclusion:On the basis of aforementioned results, it can be conluded that imidazo[2,1-b]thiazole derivatives bearing hydrazone moieties serve as promising chemical probes to design therapeutic agents with antibacterial, antitubercular, and antiviral properties.

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“…In addition to the approved monoclonal antibody palivizumab (Group, 1998), several small molecule inhibitors, e.g., disulfonated stilbenes (Razinkov et al, 2001), benzotriazoles (Cianci et al, 2004), benzimidazoles (Andries et al, 2003), and triphenol compounds (McKimm-Breschkin, 2000) that target F protein are also potent inhibitors of hRSV infectivity.…”

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confidence: 99%

Structural and Functional Aspects of the Small Hydrophobic (SH) Protein in the Human Respiratory Syncytial Virus

Gan¹,

Torres²

2011

Human Respiratory Syncytial Virus Infection

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Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus

Cited by 100 publications

References 18 publications

Neutralization of Human Respiratory Syncytial Virus Infectivity by Antibodies and Low-Molecular-Weight Compounds Targeted against the Fusion Glycoprotein

Neutralization of Human Respiratory Syncytial Virus Infectivity by Antibodies and Low-Molecular-Weight Compounds Targeted against the Fusion Glycoprotein

Antibacterial, Antitubercular and Antiviral Activity Evaluations of Some Arylidenehydrazide Derivatives Bearing Imidazo[2,1-<i>b</i>]thiazole Moiety

Structural and Functional Aspects of the Small Hydrophobic (SH) Protein in the Human Respiratory Syncytial Virus

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