Inhibition of histo-blood group antigen binding as a novel strategy to block norovirus infections.

Noroviruses (NoVs) are the most important viral pathogens that cause epidemic acute gastroenteritis. NoVs recognize human histo-blood group antigens (HBGAs) as receptors or attachment factors. The elucidation of crystal structures of the HBGA-binding interfaces of a number of human NoVs representing different HBGA binding patterns opens a new strategy for the development of antiviral compounds against NoVs through rational drug design and computer-aided virtual screening methods. In this study, docking simulations and virtual screening were used to identify hit compounds targeting the A and B antigens binding sites on the surface of the capsid P protein of a GII.4 NoV (VA387). Following validation by re-docking of the A and B ligands, these structural models and AutoDock suite of programs were used to screen a large drug-like compound library (derived from ZINC library) for inhibitors blocking GII.4 binding to HBGAs. After screening >2 million compounds using multistage protocol, 160 hit compounds with best predicted binding affinities and representing a number of distinct chemical classes have been selected for subsequent experimental validation. Twenty of the 160 compounds were found to be able to block the VA387 P dimers binding to the A and/or B HBGAs at an IC50<40.0 µM, with top 5 compounds blocking the HBGA binding at an IC50<10.0 µM in both oligosaccharide- and saliva-based blocking assays. Interestingly, 4 of the top-5 compounds shared the basic structure of cyclopenta [a] dimethyl phenanthren, indicating a promising structural template for further improvement by rational design.

Comparison of low-dose ketamine to midazolam for sedation during pediatric urodynamic study.

INTRODUCTION: Aim of sedation during pediatric urodynamic studies (UDS) is a calm and cooperative child while not affecting measurements. We compared the effectiveness of midazolam to low-dose ketamine infusion for sedation and their impact on urodynamics. MATERIALS AND METHODS: ASA-I children undergoing UDS were randomly assigned to group K (ketamine) loading dose (0.25 mg·kg(-1)) followed by infusion of 10-20 µg·kg(-1) ·min(-1) or group M (midazolam) loading dose of (0.02 mg·kg(-1)) followed by 1-2 µg·kg(-1) ·min(-1). The sedation scores and reactivity to catheterization were monitored by Children Hospital of Wisconsin Sedation Scale and Frankl Behavior Rating Scale, respectively. The UDS included two-channel filling cystometry in supine position followed by a free uroflowmetry in sitting position. The UDS was performed and interpreted in accordance with good urodynamic practice guidelines of International Continence Society (2002). RESULTS: A total of 34 children were enrolled. Group K children (n = 17) attained sedation earlier 6.80 (±3.36) min vs. 9.40 (±2.82) min; (P = 0.03) than group M (n = 17) and also recovered earlier 11.60 (±3.13) min vs. 19.67 (±5.49) min (P = 0.01). Reactivity scores during urinary and rectal catheterization were lower in group K (P = 0.03 and 0.01), respectively. Historical UDS data of 21 participants were available for comparison with effect of medication. None of the study drugs affected UDS parameters significantly. CONCLUSIONS: Midazolam or low-dose ketamine provide satisfactory sedation during pediatric UDS without impacting urodynamic values.