Mutations I117V and I117M and oseltamivir sensitivity of pandemic (H1N1) 2009 viruses.

Emerg Infect Dis

WHO Collaborating Centre for Reference and Research on Infl uenza, Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn St, North Melbourne, 3051 Victoria, Australia.

Published: January 2012

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Oseltamivir is a drug that has been widely used to prevent and treat influenza A and B. In this work, an ultrasensitive, simple, and novel electrochemiluminescence (ECL) sensor combined with molecularly imprinted polymers (MIP-ECL) based on a graphene-like two-dimensional material, Mxene quantum dots (MQDs) was constructed to selectively detect oseltamivir. A molecularly imprinted polymer membrane containing an oseltamivir template was constructed by electropolymerization and elution of modified MQDs on a glassy carbon electrode.

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The I38T substitution in the influenza virus polymerase-acidic (PA) subunit is a resistance marker of concern for treatment with the antiviral baloxavir marboxil (BXM). Thus, monitoring PA/I38T mutations is of clinical importance. Here, we developed three rapid and sensitive assays for the detection and monitoring of the PA/I38T mutation.

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Inhibition of neuraminidase is the most prominent target in influenza medication using oseltamivir as an inhibitor. However, the emerging resistance of neuraminidase toward oseltamivir due to mutation reduces the efficacy of oseltamivir. The generally reported mutation is a single mutation at H274Y, which declines the sensitivity of oseltamivir by almost 900 folds compared to the wild-type variant.

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Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China.

Inspired by our previous finding that targeting the 150-cavity with a multisite-binding strategy emerged as an effective approach to obtain more potent and selective neuraminidase (NA) inhibitors against influenza virus, we present here the design, synthesis, and optimization of novel boron-containing N-substituted oseltamivir (OSC) derivatives. Exploratory structure-activity relationship (SAR) studies led to the identification of compounds and as the most potent NA inhibitors, surpassing OSC in potency against both wild-type group-1 NAs and oseltamivir-resistant NAs. These compounds demonstrated significant antiviral activity against several wild-type strains and H1N1pdm09 strains (EC = 0.

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