Drug Target

Both thalassemia and carnitine deficiency represent independent causes of erythropoietin resistance, and thus anemia, in uremic patients. We evaluated the unknown long-term effects of L-carnitine administration in β-thalassemic on chronic hemodialysis. We studied twelve subjects (M = 8; F = 4) affected by β-thalassemia minor (β-thal; HbA2 level = 6.6 ± 0.6%) and forty non-thalassemic subjects (M = 24; F = 16) as controls (C), on chronic hemodialysis treatment. Patients and controls were at target hemoglobin levels (11-12g/dl) prior to the study and underwent to i.v. L-carnitine administration for a one year period-time. Groups were comparable for age, gender, serum levels of hemoglobin (Hb), iron, ferritine, PTH and aluminum, transferrin saturation, and dialysis modalities. During the study both groups showed significant Hb increase and erythropoietin (EPO) decrease; as a difference, such changes emerged at the 3rd month in C but at the 8th month in β-thal. At start, during the dial...

The organization and mining of malaria genomic and post-genomic data is important to significantly increase the knowledge of the biology of its causative agents, and is motivated, on a longer term, by the necessity to predict and characterize new biological targets and new drugs. Biological targets are sought in a biological space designed from the genomic data from Plasmodium falciparum, but using also the millions of genomic data from other species. Drug candidates are sought in a chemical space containing the millions of small molecules stored in public and private chemolibraries. Data management should, therefore, be as reliable and versatile as possible. In this context, five aspects of the organization and mining of malaria genomic and post-genomic data were examined: 1) the comparison of protein sequences including compositionally atypical malaria sequences, 2) the high throughput reconstruction of molecular phylogenies, 3) the representation of biological processes, particularly metabolic pathways, 4) the versatile methods to integrate genomic data, biological representations and functional profiling obtained from Xomic experiments after drug treatments and 5) the determination and prediction of protein structures and their molecular docking with drug candidate structures. Recent progress towards a grid-enabled chemogenomic knowledge space is discussed.

Purpose: Ischemia reperfusion injury to skeletal muscle, following an acute arterial occlusion is important cause of morbidity and mortality. The aim of the present study was to determine and evaluate the effects of ascorbic acide, alpha-tocopherol and allopurinol on ischemia reperfusion injury in rabbit skeletal muscle. Methods: Forty-eight New Zealand white rabbits, all male, weighing between 2.5 to 3.0 (mean 2.8) kg, were used in the study. They were separated into four groups. Group I was the control group without any drugs. The other groups were treatment groups (groups II, III, and IV). Group II rabbits administrated 50 mg/kg ascorbic acide and 100 mg/kg alpha-tocopherol 3 days prior to ischemia, group III rabbits received 50 mg/kg allopurinol 2 days prior to ischemia, and group IV rabbits were administrated both 50 mg/kg ascorbic acide, 100 mg/kg alpha-tocopherol 3 days prior to ischemia and 50 mg/kg allopurinol 2 days prior to ischemia. Two hours ischemia and 2 hours reperfusion were underwent to the treatment groups. At the end of the reperfusion periods, muscle samples were taken from rectus femoris muscle for determination of superoxide dismutase, catalase and glutathione peroxidase activities as antioxidant enzymes, and malondialdehyde as an indicator of lipid peroxidation and xanthine oxidase levels as source hydroxyl radical. Besides, histopathological changes (edema, infl ammation, ring formation and splitting formation) were evaluated in the muscle specimens. Results: In the treatment groups; superoxide dismutase (U/mgprotein), catalase (U/mgprotein), and glutathione peroxidase (U/mgprotein) levels increased, malondialdehyde (nmol/mgprotein) and xanthine oksidase (mU/mgprotein) levels decreased compared to control I (p Ͻ 0.05). Increase of superoxide dismutase, catalase, and glutathione peroxidase levels were the highest and decrease of malondialdehyde and xanthine oxidase levels were the highest in group IV compared to groups II and III, but no signifi cant as statistically. Also amount of cellular injury in group II, III, and IV were lower than group I. Conclusions: Antioxidant medication may help lowering ischemia reperfusion injury. In our study, all drug medications are shown to be able to have an effective role for preventing ischemia reperfusion injury. Moreover, ascorbic acide + alphatocopherol + allopurinol group (group IV) may have a benefi cial effect to decrease the local and systemic damage due to ischemia-reperfusion injury.

Peptidoglycan is a sugar/amino acid polymer unique to bacteria and essential for division and cell shape maintenance. The d-amino acids that make up its cross-linked stem peptides are not abundant in nature and must be synthesized by bacteria de novo. d-Glutamate is present at the second position of the pentapeptide stem and is strictly conserved in all bacterial species. In Gram-negative bacteria, d-glutamate is generated via the racemization of l-glutamate by glutamate racemase (MurI). Chlamydia trachomatis is the leading cause of infectious blindness and sexually transmitted bacterial infections worldwide. While its genome encodes a majority of the enzymes involved in peptidoglycan synthesis, no murI homologue has ever been annotated. Recent studies have revealed the presence of peptidoglycan in C. trachomatis and confirmed that its pentapeptide includes d-glutamate. In this study, we show that C. trachomatis synthesizes d-glutamate by utilizing a novel, bifunctional homologue of diaminopimelate epimerase (DapF). DapF catalyzes the final step in the synthesis of meso-diaminopimelate, another amino acid unique to peptidoglycan. Genetic complementation of an Escherichia coli murI mutant demonstrated that Chlamydia DapF can generate d-glutamate. Biochemical analysis showed robust activity, but unlike canonical glutamate racemases, activity was dependent on the cofactor pyridoxal phosphate. Genetic complementation, enzymatic characterization, and bioinformatic analyses indicate that chlamydial DapF shares characteristics with other promiscuous/primordial enzymes, presenting a potential mechanism for d-glutamate synthesis not only in Chlamydia but also numerous other genera within the Planctomycetes-Verrucomicrobiae-Chlamydiae superphylum that lack recognized glutamate racemases.

Streptococcus pneumoniae is the causative agent of Pneumonia resulting in a substantial portion of childhood deaths in Bangladesh. Though drugs are in sufficient availability but the emergence of multi-drug resistant varieties of S. pneumoniae has led to the search for novel drug targets. The metabolic pathways of host (Homo sapiens) and pathogen (S. pneumoniae serotype-2) were compared where six biochemical pathways of S. pneumonia, distinct from human pathways, were identified. These comprised of 20 unique enzymes, which being non-homologous proteins in contrast to human host proteins, can be considered as probable drug targets. Among them, the 3D structure of an uncharacterized protein molecule was built in by homology modeling and the binding pockets of protein molecule responsible for specific functions were identified. These structural and functional characterizations of the protein, unique in S. pneumoniae in host condition, made the possibility for the sophisticated rational drug design.