The crystallographic structure of NV protease with the C-terminal tail redesigned to mimic P4 to P1 of another substrate site provided further structural details on how the active site accommodates sequence variations in the substrates. Based on these structural

analyses, substrate-based aldehyde inhibitors were synthesized and screened for inhibition potency. Crystallographic structures of the protease in complex with each of the three most potent inhibitors were determined. These structures showed concerted conformational changes in the S4 and S2 pockets of the protease to accommodate variations in the P4 and P2 residues of the substrate/inhibitor, which could be a mechanism for how the learn more NV protease recognizes multiple sites in the polyprotein with differential affinities during virus replication. These structures further indicate that the mechanism of inhibition by these inhibitors involves covalent bond formation with the side chain of the conserved cysteine in the active site by nucleophilic addition, and such substrate-based

aldehydes could be effective protease inhibitors.”
“Baseline body mass index (BMI), baseline BMI status (normal, overweight, obese) and early (1 month) BMI increases were tested as predictors of 6- and 12- PF477736 in vivo month increases in glucose and lipid measures in 82 olanzapine (OLZ)- and 78 risperidone (RIS)-treated patients with schizophrenia, schizoaffective disorder, or bipolar disorder who participated in a 12-month randomized, prospective metabolic effects study. Baseline BMI predicted

greater fasting glucose and HgbA1c levels at 12 months for both treatments. Early BMI change predicted fasting glucose levels at 6 months, but not HgbA c or BMI, at either time point. For patients who received no concomitant mood stabilizers, early BMI change predicted 12 month HgbA1c values in the 012 group, and 6- (but not 12-) month fasting glucose and HgbA1c values in the RIS group. Neither baseline BMI nor early BMI change consistently predicted increases in lipids with either drug. OLZ-treated patients during with normal baseline BMI had greater increases in total cholesterol, triglycerides, and non-HDL-cholesterol than those who were overweight or obese. In conclusion, higher baseline BMI predicted adverse glycemic changes after 12 months with 012 and RIS. Individuals with normal baseline BMI may be most susceptible to OLZ-induced hyperlipidosis. Frequency of metabolic screening should be independent of baseline BMI or rapid increases in BMI. (C) 2011 Elsevier Ireland Ltd. All rights reserved.