Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?

The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described.

No need to shout? Harbor porpoises (Phocoena phocoena) echolocate quietly in confined murky waters of the Wadden Sea.

Porpoise echolocation parameters may vary depending on their acoustic habitat and predominant behavior. Research was conducted in the Wadden Sea, an acoustically complex, tidally driven habitat with high particle resuspension. Source levels and echolocation parameters of wild harbor porpoises were estimated from time-of-arrival-differences of a six-element hydrophone array. The back-calculated peak-to-peak apparent source level of 169 ± 5 dB re 1 µPa was significantly lower than reported from Inner Danish Waters (-20 dB) and British Columbia (-9 dB) with narrower bandwidth. Porpoises therefore reduce their source level in the Wadden Sea under acoustically complex conditions suggesting an avoidance of cluttering.

Virial coefficients of anisotropic hard solids of revolution: The detailed influence of the particle geometry.

We provide analytical expressions for the second virial coefficients of differently shaped hard solids of revolution in dependence on their aspect ratio. The second virial coefficients of convex hard solids, which are the orientational averages of the mutual excluded volume, are derived from volume, surface, and mean radii of curvature employing the Isihara-Hadwiger theorem. Virial coefficients of both prolate and oblate hard solids of revolution are investigated in dependence on their aspect ratio. The influence of one- and two-dimensional removable singularities of the surface curvature to the mutual excluded volume is analyzed. The virial coefficients of infinitely thin oblate and infinitely long prolate particles are compared, and analytical expressions for their ratios are derived. Beyond their dependence on the aspect ratio, the second virial coefficients are influenced by the detailed geometry of the particles.

Dynamics of methanol in ionic liquids: validity of the Stokes-Einstein and Stokes-Einstein-Debye relations.

The validity of Stokes-Einstein (SE) and Stokes-Einstein-Debye (SED) relations for methanol in the physical environment of the ionic liquid (IL) 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide is studied by means of nuclear magnetic resonance (NMR) relaxation time experiments, viscosity measurements and molecular dynamics (MD) simulations. The reorientational correlation times of the hydroxyl groups of pure methanol and of methanol in the IL/methanol mixtures were determined. For that purpose an approach for estimating NMR deuteron quadrupole coupling constants, presented by Wendt and Farrar (Mol. Phys. 1998, 95, 1077-1081), was confirmed. The self-diffusion coefficients of methanol were taken from the MD simulations. The viscosities of all systems were then measured and the SE and SED relations validated. For pure methanol both relations are valid, whereas they become increasingly invalid with increasing IL concentration, as indicated by effective volumes and radii that are too low. The deviation from the SE and SED relations could be related to dynamical heterogeneities described by the non-Gaussian parameter α(t) obtained from MD simulations. For pure methanol, α(t) is close to zero in accord with the validity of both relations. With increasing IL concentration the dynamical heterogeneities of methanol increase strongly. The times t* at the maximum of α(t) increase linearly with the relative number of methanol monomers in the mixtures. Thus, the dynamical heterogeneities are largest for single methanol molecules fully embedded in the IL environment. In their own environment methanol molecules are highly mobile, whereas in the IL-rich region the mobility is strongly reduced leading to the non-validity of SE and SED relations.