h VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m 7 GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a K D (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC 50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC 50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection. Influenza is a potentially deadly infectious disease that has imposed a substantial burden in terms of morbidity and mortality on human populations (1). Recent statistics suggest that, each year in the United States, 5% to 20% of the population becomes infected with influenza virus, with more than 200,000 hospitalizations for respiratory and heart-related complications and an annual mortality rate ranging from ϳ3,000 to 49,000 deaths (2, 3).Vaccination has become the mainstay of efforts to minimize the impact of seasonal influenza (4, 5), and while generally effective in healthy adults, it is often less effective in elderly individuals, and there have been recent examples where predictions of which viral strains to include have been inadequate (6, 7). Further, the 2009 H1N1 pandemic demonstrated that the logistics required to rapidly isolate and identify the correct strain and to produce enough vaccine worldwide was quite challenging (8-10). The continued incidence of human infection by avian influenza virus strains, namely, either the highly pathogenic H5N1 or H7N7 subtypes or the recently emerging low pathogenic H7N9 and H10N9 strains, represents an additional challenge for vaccine development strategies (11-15) Antiviral agents may be used for the prophylaxis of influenza virus infection (mainly in high-risk settings) or in a treatment modality for the reduction of illness duration. They may also provide an option for rapid deployment during a pandemic situati...

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

1.3 C). When discharge/charge is carried out at a high current density of 10.5 A g − 1 (70 C), the thin fi lm electrodes retain a good discharge capacity of 120 mA h g − 1 , and the specifi c power density is over 28 kW kg − 1 .

Data have been assembled on the enthalpies of solvation of 373 compounds in water and 138 compounds in 1-octanol. It is shown that an Abraham solvation equation with five descriptors can be used to correlate the experimental solvation enthalpies to within standard deviations of 3.68 kJ/mol (water) and 2.66 kJ/mol (1-octanol). The derived correlations provide very accurate mathematical descriptions of the observed enthalpies of solvation, which in the case of water span a range of 150 kJ/mol. Division of the experimental values into a training set and a test set shows that there is no bias in predictions and that the predictive capability of the correlations is better than 4 kJ/mol.