Discovery and Characterization of Diazenylaryl Sulfonic Acids as Inhibitors of Viral and Bacterial Neuraminidases

Abstract

Viral neuraminidases are an established drug target to combat influenza. Severe complications observed in influenza patients are primarily caused by secondary infections with e.g., Streptococcus pneumoniae. These bacteria engage in a lethal synergism with influenza A viruses (IAVs) and also express neuraminidases. Therefore, inhibitors with dual activity on viral and bacterial neuraminidases are expected to be advantageous for the treatment of influenza infections. Here we report on the discovery and characterization of diazenylaryl sulfonic acids as dual inhibitors of viral and Streptococcus pneumoniae neuraminidase. The initial hit came from a virtual screening campaign for inhibitors of viral neuraminidases. For the most active compound,acid (NSC65847; 1), the K i -values measured in a fluorescence-based assay were lower than 1.5 µM for both viral and pneumococcal neuraminidases. The compound also inhibited N1 virus variants containing neuraminidase inhibitor resistance-conferring substitutions. Via enzyme kinetics and nonlinear regression modeling, 1 was suggested to impair the viral neuraminidases and pneumococcal neuraminidase with a mixed-type inhibition mode. Given its antiviral and antipneumococcal activity, 1 was identified as a starting point for the development of novel, dual-acting anti-infectives.

Perspectives towards antiviral drug discovery against Ebola virus

“…For comparison purposes between MD‐refined complex systems, binding‐free energy calculations using the molecular mechanics Poisson‐Boltzmann surface area/generalized born surface area can be incorporated in the workflow. Like these, numerous recent studies have been performed with the aid of MD simulations in search of direct antivirals and investigating drug resistance mechanisms …”

Lanostane Triterpenes from Gloeophyllum odoratum and Their Anti-Influenza Effects

“…3). Virus neutralization can be based on inhibitor binding to the viral envelope glycoproteins (i.e., hemagglutinin or neuraminidase, which are crucial for viral attachment and release, respectively) [23][24][25]. Hence, our data give first hints about possible targets of compound 3, which warrants ▶ Fig.…”

“…The assay time and temperature conditions of the plaque reduction assay were described recently [25,34] and slightly modified. Here, confluent MDCK cell monolayers grown in 12-well plates were inoculated with~30 pfu HK/68 in 500-µL test medium.…”

Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains

“…To identify potential inhibitors, our study virtually screened compounds from the National Cancer Institute (NCI) database. Previous virtual screening approaches have been applied to NCI molecular library 30 , 31 . Cheng et al .…”

“…Hoffmann et al . discovered a series of diazenylaryl sulfonic acids as NA inhibitors, which inhibited N1 NA with drug-resistant mutations 31 , including H274Y, N294S, Y155H, Q136L, I427Q and I427M. However, the physiochemical properties of the 150-cavity were not characterized, nor an analysis based on a dual H274Y/I222R mutation of an influenza virus.…”