Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higherorder NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.antiinfluenza | oligomerization | polymerase inhibitor | protein-protein interaction | cooperative inhibition

No abstract

No abstract

No abstract

H e a lt h c a r e s p e n d i n g i n t h e u n i t e d s tat e s grew 6.1 percent to $2.2 trillion, or $7,421 per person, in 2007 (Exhibits 1 and 2). The health spending share of gross domestic product (GDP) reached 16.2 percentan increase over the 16.0 percent share in 2006. This paper presents national health expenditure (NHE) estimates through 2007, with a focus on recent trends in the health care goods and services purchased, the sources of funds used to pay for those purchases, and the sponsors of U.S. health care spending. The NHE estimates measure the total annual spending for health care goods and services in the United States as well as spending for program administration; the net cost of private health insurance; government public health; and the amount invested in 2 4 6 J a n u a r y / F e b r u a r y 2 0 0 9 D a t a W a t c h