Bioinformatics of thymidine metabolism in Trypanosoma evansi: exploring nucleoside deoxyribosyltransferase (NDRT) as a drug target.

Trypanosoma evansi, the causative agent of surra or camel trypanosomiasis, is characterized by the widest geographic distribution and host range among the known trypanosomes. Its zoonotic importance and increasing evidence of drug resistance necessitate the discovery of new drug targets. The drug discovery process entails finding an exploitable difference between the host and the parasite. In this study, the thymidine metabolic pathways in camel and T. evansi were compared by analyzing their metabolic maps, protein sequences, domain and motif contents, phylogenetic relationships, and 3D structure models. The two organisms were revealed to recycle thymidine differently: performed by thymidine phosphorylase in camels (Camelus genus), this role in T. evansi was associated with nucleoside deoxyribosyltransferase (NDRT), a unique trypanosomal enzyme absent in camels. Thymidine in T. evansi seems to be governed by thymine through NDRT, whereas in camels, thymidine can be produced from thymidylate via 5'-nucleotidase. As a result, NDRT may be a promising drug target against T. evansi.

Bioinformatics of thymidine metabolism in Trypanosoma evansi: exploring nucleoside deoxyribosyltransferase (NDRT) as a drug target

@#Trypanosoma evansi, the causative agent of surra or camel trypanosomiasis, is characterized by the widest geographic distribution and host range among the known trypanosomes. Its zoonotic importance and increasing evidence of drug resistance necessitate the discovery of new drug targets. The drug discovery process entails finding an exploitable difference between the host and the parasite. In this study, the thymidine metabolic pathways in camel and T. evansi were compared by analyzing their metabolic maps, protein sequences, domain and motif contents, phylogenetic relationships, and 3D structure models. The two organisms were revealed to recycle thymidine differently: performed by thymidine phosphorylase in camels (Camelus genus), this role in T. evansi was associated with nucleoside deoxyribosyltransferase (NDRT), a unique trypanosomal enzyme absent in camels. Thymidine in T. evansi seems to be governed by thymine through NDRT, whereas in camels, thymidine can be produced from thymidylate via 5'-nucleotidase. As a result, NDRT may be a promising drug target against T. evansi.

Crystal structure, vibrational spectroscopy and optical properties of a one-dimensional organic-inorganic hybrid perovskite of [NH3CH2CH(NH3)CH2]BiCl5.

In this work the crystal structure by single crystal X-ray measurement and optical properties of 1D propane-1,2-diammonium pentachlorobismuthate [NH3CH2CH(NH3)CH3]BiCl5 organic-inorganic hybrid perovskite are presented. It is prepared by mixing ethanolic solution of equimolar ratios (1:1) of its basic components. The title compound crystallized in the noncentrosymmetric orthorhombic space group Pca21 with Z = 8 molecules per unit cell. The unit-cell parameters are a = 19.8403 (7) Å, b = 6.3303 (2) Å, c = 19.0314 (7) Å. The vibrational spectra are studied by Raman and infrared spectroscopy. The optical properties show a strong absorption in the ultraviolet region, the band gap energy Eg is found to be 3.15 eV. Cathodoluminescence measurements are also discussed.

Pharmacokinetics and oral bioavailability of amoxicillin in chicken infected with caecal coccidiosis.

Chicken infected with caecal coccidiosis (Eimeria tenella) was used to evaluate the effect of coccidiosis on the pharmacokinetic and bioavailability of amoxicillin. The level of amoxicillin was estimated by high-performance chromatography (HPLC) to calculate the pharmacokinetic parameters and oral bioavailability. For i.v. injection of amoxicillin, Vd and CL were 0.29 and 0.27 (mg/kg)/(µg/mL)/h, respectively. Compared with healthy chicken, intravenous injection of amoxicillin in the infected chicken showed higher distribution and elimination constants, delayed clearance and statistically significant higher AUC and MRT. Oral administration in healthy chicken was accompanied by rapid absorption and high bioavailability with Tmax , Cmax and F about 1.03 h, 3.26 µg/mL and 40.2, respectively. Furthermore, oral administration in the infected chicken produced higher mean absorption time, delayed Tmax, lower Cmax, smaller AUC value and lower bioavailability (16.76). Based on these results, monitoring and adjustment of amoxicillin dosing could be practiced during the presence of coccidiosis. The measured Cmax values suggest the administration of 1.3-folds of the normal dose to maintain the normal maximal serum concentrations of amoxicillin in chicken infected with caecal coccidiosis.

Association of host tropism of Middle East syndrome coronavirus with the amino acid structure of host cell receptor dipeptidyl peptidase 4.

The Middle East syndrome coronavirus (MERS-CoV) is a recently emerging betacoronavirus with high fatality. Recently, dipeptidyle peptidase (CD26, DPP4) was identified as the host cell receptor for MERS-CoV. Interestingly, despite of common presence of DPP4 receptors the binding and infection of various cells shows imminent variability. In this report, we provide a tool for prediction of the host tropism of the virus based on the host receptor binding interface. We found out that, in the binding of MERS-CoV to cells the amino acid residues in lancets 4 and 5 of DPP4 receptor, namely K267, Q286, T288, R317, R336, Q344 A291, L294, and I295 are involved. Changes in these residues correspond to profound decrease in virus binding to cells. The nine residues at the interface between the virus spikes and the lancets 4 and 5 of host DPP4 can be used as a predictive tool for the host tropism and virus affinity to host cell receptors.

Current and future asthma therapies.

Corticosteroids (CST) are the gold standard for asthma management and for several decades have been considered the cornerstone for asthma control. With the recent advent of genomic and structural analysis technologies, the molecular basis of the side effects, toxicity and resistance mechanisms of drug treatment are better understood. With respect to CST, there is consistent evidence that while CST therapy improves asthma symptoms, it does not alter the natural course of asthma or offer clear long-lasting improvement of respiratory performance. Therefore, the development of drugs capable of minimizing or avoiding CST side effects, toxicity and resistance could be the way forward for establishing new asthma therapies. This review summarizes the molecular basis of corticosteroid mechanisms of action and the related mechanisms influencing side effects and resistance. The future of CST adjunctive or replacement therapy is also briefly discussed.

The Binding Interactions of the Macrolide Endectocide Ivermectin with the Antibiotics Ampicillin, Chloramphenicol and Tetracycline HCL.

Ivermectin, chloramphenicol, ampicillin and tetracycline HCl are common drugs in human and veterinary practice. The purpose of this study is to investigate the possible binding interactions between ivermectin and the antibiotics chloramphenicol, ampicillin and tetracycline HCl. Isothermal titration calorimetry was used to determine the binding interactions between ivermectin and these antibiotics. Results indicated that, about three molecules of ampicillin can bind to one molecule of ivermectin and about one molecule of chloramphenicol with one molecule of ivermectin. However, no binding stoichiometry can be detected with tetracycline HCl-ivermectin titration. Furthermore, the binding interactions were accompanied by various biophysical and biochemical mechanisms. This is the first report of such interactions of ivermectin with chloramphenicol, ampicillin and tetracycline HCl. There are possible binding interactions of ivermectin with chloramphenicol and ampicillin. Further studies are required for detecting the impact of this binding on biological aspects of drug actions.

Mutational, inhibitory and microcalorimetric analyses of Plasmodium falciparum TMP kinase. Implications for drug discovery.

Plasmodium falciparum thymidylate kinase (PfTMK) can tolerate a range of substrates, which distinguishes it from other thymidylate kinases. The enzyme not only phosphorylates TMP and dUMP but can also tolerate bulkier purines, namely, dGMP, GMP, and dIMP. In order to probe the flexibility of PfTMK in accommodating ligands of various sizes, we developed 6 mutant enzymes and subjected these to thermodynamic, inhibitory and catalytic evaluation. Kinase activity was markedly affected by introducing a larger lysine residue instead of A111. The lack of the hydroxyl group after inducing mutation of Y107F affected enzyme activity, and had a more severe impact on dGMP kinase activity. PfTMK can be inhibited by both purine and pyrimidine nucleosides, raising the possibility of developing highly selective drugs. Thermodynamic analysis revealed that enthalpic forces govern both purine and pyrimidine nucleoside monophosphate binding, and the binding affinity of both substrates was highly comparable. The heat produced due to dGMP binding is lower than that attributable to TMP. This indicates that additional interactions occur with TMP, which may be lost with larger dGMP. Targeting PfTMK not only affects thymidine nucleotide synthesis but may also affect purine nucleotides, and thus the enzyme represents an attractive antimicrobial target.

Aortic translocation for D-TGA associated with LVOTO and VSD.

Aortic translocation is a useful surgical option in certain difficult subsets of transposition of great arteries with ventricular septal defect and left ventricular outflow tract obstruction. We report here the use of this technique with pulmonary homograft reconstruction of right ventricular pulmonary artery continuity in a child with transposition of the great arteries, left ventricular outflow tract obstruction, and restrictive ventricular septal defect.

The challenge of valve surgery in a developing population.

Between August 1988 and October 1992, 1,052 patients underwent 1,522 valve procedures in our institution. Their mean age was 32.69 years (range 1-90). The etiology was rheumatic in 724 (68.8%), congenital in 120 (11.4%), degenerative in 99 (9.4%), infective in 58 (5.5%) and ischemic in 17 (1.6%). The mean preoperative functional class (NYHA) was 2.95 and 780 (74.1%) were in sinus rhythm. Repair was possible in 885 (58.1%) valves. The rate of repair versus replacement was 94.5% for the tricuspid, 56.2% for the mitral and 43.6% for the aortic valve. The total hospital mortality was 4.18%. For isolated mitral surgery it was 2.94%, for isolated aortic 4.12% and for isolated tricuspid 15%. Double valve surgery carried a mortality of 3% and triple valve surgery 13%. Hospital mortality for isolated mitral and isolated aortic surgery was lower for repair than for replacement (1.5% vs. 5% and 0 vs. 6.8%). The follow-up was 94.65% complete. The total incidence of embolic events was 2.93% with an actuarial freedom at 48 months of 92.71 +/- 5.35% for repair, 88.22 +/- 6.26% for replacement and 90.31 +/- 5.65% for patients with repair and replacement. Late mortality was 4.5%. The actuarial survival excluding hospital deaths was 94.89 +/- 2.10% for repair, 86.84 +/- 2.84% for replacement and 91.33 +/- 2.73% for the mixed group. The reoperation rate was higher for repair (13%) than for replacement (0.1%). This rate was highest for the rheumatic mitral patients with an age below 20 years (25.2%).(ABSTRACT TRUNCATED AT 250 WORDS)