Fragment-Based De†Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.

Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment-based, computer-assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best-in-class HtrA inhibitor. The results obtained reinforce the validity of ligand-based de novo design and binding-kinetics-guided optimization for the efficient discovery of pioneering lead structures and prototyping drug-like chemical probes with tailored bioactivity.

Peptide-Membrane Interaction between Targeting and Lysis.

Certain cationic peptides interact with biological membranes. These often-complex interactions can result in peptide targeting to the membrane, or in membrane permeation, rupture, and cell lysis. We investigated the relationship between the structural features of membrane-active peptides and these effects, to better understand these processes. To this end, we employed a computational method for morphing a membranolytic antimicrobial peptide into a nonmembranolytic mitochondrial targeting peptide by "directed simulated evolution." The results obtained demonstrate that superficially subtle sequence modifications can strongly affect the peptides' membranolytic and membrane-targeting abilities. Spectroscopic and computational analyses suggest that N- and C-terminal structural flexibility plays a crucial role in determining the mode of peptide-membrane interaction.

Tracheal sealing by auto-inflation in tracheal tube cuffs.

BACKGROUND: The purpose of this study was to determine if inspiratory pressure from intermittent positive pressure ventilation may be sufficient to inflate the cuff (thus 'auto-inflation') and thereby seal the trachea. METHODS: In a laboratory model we investigated the ability of cuffs of seven 5.0 mm internal diameter (ID) tracheal tubes (Sheridan CF, Mallinckrodt Hi-Contour, Mallinckrodt Sealguard, Mallinckrodt Safety-Flex, Portex Soft Seal, Rueschelit Super-Safety Clear and Microcuff PET) to seal the trachea by auto-inflation, i.e. by using the inspiratory pressure to expand and keep open the cuff within the trachea. A mechanical lung connected to a model trachea made from clear, rigid polyvinylchloride (PVC) (12 mm ID) was used to simulate changes in inspiratory pressures. Respirator settings were: fresh gas flow (air) 6 lxmin(-1); positive end-expiratory pressure 5 cmH(2)O; respiratory rate 20 brxmin(-1); I : E ratio = 1 : 2; inspiratory pressure 5, 10, 15, 20, and 25 cmH(2)O. Percentage of expiratory to inspiratory tidal volume (E : I V(t) volume ratio) was calculated. RESULTS: Using lubricated Mallinckrodt Seal Guard tube cuffs E : I V(t) volume ratio was almost 100% at a peak inspiratory pressure of 10 cmH(2)o whereas in tube cuffs particularly made of PVC an E : I ratio was achieved only at higher inspiratory pressures, if at all. CONCLUSIONS: Auto-inflation in the Mallinckrodt Seal Guard with high volume-low pressure polyurethane cuff can produce adequate tracheal sealing in the model trachea used. The implication is that such auto-inflation should decrease the risk of tracheal injury from acute or persistent cuff hyperinflation.

Prevention of postoperative nausea and vomiting in children following adenotonsillectomy, using tropisetron with or without low-dose dexamethasone.

PURPOSE: Postoperative nausea and vomiting (PONV) after adenotonsillectomy in children is, in spite of the prophylactic administration of tropisetron, still a frequent event. The aim of this study was to evaluate the benefit of the additional systemic administration of low-dose dexamethasone (0.15 mg x kg(-1)) for the prevention of PONV. METHODS: With hospital ethics committee approval, we investigated children undergoing adenotonsillectomy receiving tropisetron (0.1 mg x kg(-1); maximum dose, 2 mg) or tropisetron (0.1 mg x kg(-1); maximum dose, 2 mg) plus dexamethasone (0.15 mg x kg(-1); maximum dose, 6 mg) intraoperatively. The incidence of vomiting episodes and the need for postoperative analgesics were recorded. Patient data were analyzed using the t-test and the chi(2) test (significance level of P = 0.05). Data values are means +/- SD. RESULTS: Ninety children (39 girls and 51 boys), aged 5.6 +/- 2.8 years and weighing 21.9 +/- 8.8 kg, were enrolled in the study. The overall incidence of vomiting was 38.9% within the first 24 h (67 vomiting events) and 44.4% within 48 h postoperatively (87 vomiting events). The incidence of vomiting in the tropisetron-only group was 53.3% (24/45) at 24 h and 60% (27/45) at 48 h (24 h: P < 0.001 and 48 h: P = 0.04) and 24.4% (11/45) at 24 h and 28.9% (13/45) at 48 h in the tropisetron-dexamethasone group. The need for postoperative nalbuphine was double in patients treated with tropisetron-dexamethasone (0.61 mg +/- 0.36 mg x kg(-1) x 48 h(-1)) compared to that in patients receiving only tropisetron (0.31 mg +/- 0.28 mg x kg(-1) x 48 h(-1); P < 0.0001). CONCLUSION: A low-dose bolus of dexamethasone (0.15 mg x kg(-1)) in combination with tropisetron, compared to tropisetron alone, considerably reduced the incidence of vomiting in children following pediatric adenotonsillectomy.

Comparison of cuffed and uncuffed preformed oral pediatric tracheal tubes.

BACKGROUND: In preformed cuffed tracheal tubes the position of the cuff within the airway is given by its distance to the tube bend placed at the lower teeth. The aim of this study was to compare the design of cuffed and uncuffed preformed pediatric oral tracheal tubes with regard to anatomical landmarks. METHODS: Complete series of cuffed and uncuffed preformed oral pediatric tracheal tubes sized from internal diameter 3.0-7.0 mm if available were ordered from five different manufacturers. The distance from the bend to the distal tube tip and to the upper border of the cuff were measured and compared with anatomical airway landmarks in the developing child. RESULTS: Between cuffed and uncuffed tracheal preformed tubes up to 37 mm differences in the bend-to-tracheal tube tip distances were found for given age groups. Thus uncuffed preformed tracheal tubes were more at risk for inadvertent endobronchial intubation than cuffed preformed tracheal tubes. Comparison of bend-to-upper border of the cuff distances with teeth-to-vocal cord distances calculated from anatomical data revealed that several of the tracheal tube cuffs become positioned within the subglottic larynx or even within the vocal cords when inserted according to the bend. CONCLUSIONS: There is a need for improvement in cuffed preformed pediatric tracheal tubes, namely a standard bend-to-tracheal tube tip distance to allow a safe insertion depth, a short cuff placed on the tube shaft as distally as possible and an intubation depth mark to verify a proper position of the cuff in the trachea.