tetano
Editor, Senior Moderator
ACS Infect Dis. 2017 Dec 21. doi: 10.1021/acsinfecdis.7b00120. [Epub ahead of print]
[h=1]A Broad Spectrum Inhibitor of Influenza A and B Viruses Targeting the Viral Nucleoprotein.[/h] White KM, Abreu P, Wang H, De Jesus PD, Manicassamy B, Garc?a-Sastre A, Chanda SK, DeVita RJ, Shaw ML.
[h=3]Abstract[/h] S119 was a top hit from an ultra-high through-put screen performed to identify novel inhibitors of influenza virus replication. It showed a potent antiviral effect (IC50 = 20 nM) and no detectable cytotoxicity (CC50 >500 μM) to yield a selectivity index greater than 25,000. Upon investigation, we found that S119 selected for resistant viruses carrying mutations in the viral nucleoprotein (NP). These resistance mutations highlight a likely S119 binding site overlapping with, but not identical to that found for the compound nucleozin. Mechanism of action studies revealed that S119 affects both the oligomerization state and cellular localization of the NP protein which impacts on viral transcription, replication and protein expression. Through a hit-to-lead structure-activity relationship (SAR) study, we found an analog of S119, named S119-8, which had increased breadth of inhibition against influenza A and B viruses accompanied by only a small loss in potency. Finally, in vitro viral inhibition assays showed a synergistic relationship between S119-8 and oseltamivir when they were combined, indicating the potential for future drug cocktails.
PMID: 29268608 DOI: 10.1021/acsinfecdis.7b00120
[h=1]A Broad Spectrum Inhibitor of Influenza A and B Viruses Targeting the Viral Nucleoprotein.[/h] White KM, Abreu P, Wang H, De Jesus PD, Manicassamy B, Garc?a-Sastre A, Chanda SK, DeVita RJ, Shaw ML.
[h=3]Abstract[/h] S119 was a top hit from an ultra-high through-put screen performed to identify novel inhibitors of influenza virus replication. It showed a potent antiviral effect (IC50 = 20 nM) and no detectable cytotoxicity (CC50 >500 μM) to yield a selectivity index greater than 25,000. Upon investigation, we found that S119 selected for resistant viruses carrying mutations in the viral nucleoprotein (NP). These resistance mutations highlight a likely S119 binding site overlapping with, but not identical to that found for the compound nucleozin. Mechanism of action studies revealed that S119 affects both the oligomerization state and cellular localization of the NP protein which impacts on viral transcription, replication and protein expression. Through a hit-to-lead structure-activity relationship (SAR) study, we found an analog of S119, named S119-8, which had increased breadth of inhibition against influenza A and B viruses accompanied by only a small loss in potency. Finally, in vitro viral inhibition assays showed a synergistic relationship between S119-8 and oseltamivir when they were combined, indicating the potential for future drug cocktails.
PMID: 29268608 DOI: 10.1021/acsinfecdis.7b00120