An improved method for the chemical synthesis of RNA was developed utilizing a streamlined method for the preparation of phosphoramidite monomers and a single-step deprotection of the resulting oligoribonucleotide product using 1,2-diamines under anhydrous conditions. The process is compatible with most standard heterobase protection and employs a 2'-O-(1,1-dioxo-1λ(6)-thiomorpholine-4-carbothioate) as a unique 2'-hydroxyl protective group. Using this approach, it was demonstrated that the chemical synthesis of RNA can be as simple and robust as the chemical synthesis of DNA.
Bulky, flexible molecules such as peptides and peptidomimetics are often used as lead compounds during the drug discovery process. Pathophysiological events, e.g., the formation of amyloid fibrils in Alzheimer's disease, the conformational changes of prion proteins, or beta-secretase activity, may be successfully hindered by the use of rationally designed peptide sequences. A key step in the molecular engineering of such potent lead compounds is the prediction of the energetics of their binding to the macromolecular targets. Although sophisticated experimental and in silico methods are available to help this issue, the structure-based calculation of the binding free energies of large, flexible ligands to proteins is problematic. In this study, a fast and accurate calculation strategy is presented, following modification of the scoring function of the popular docking program package AutoDock and the involvement of ligand-based two-dimensional descriptors. Quantitative structure-activity relationships with good predictive power were developed. Thorough cross-validation tests and verifications were performed on the basis of experimental binding data of biologically important systems. The capabilities and limitations of the ligand-based descriptors were analyzed. Application of these results in the early phase of lead design will contribute to precise predictions, correct selections, and consequently a higher success rate of rational drug discovery.
Background
The investigation of food-drug and plant-drug interactions has become increasingly important. In case of antibiotics, it is essential to achieve and maintain a plasma concentration sufficient for the antimicrobial action. Although, on theoretical basis, the interaction of polyphenols and antibiotics may be hypothesized, experimental data are lacking to assess its clinical relevance. The aim of our study was to assess the interaction between one of the most widely used antibiotics, amoxicillin, and green tea, the most frequently consumed drink with high polyphenol content.
Methods
The effects of green tea on the plasma level of amoxicillin was studied in an in vivo experiment in rats. The plasma level of amoxicillin was monitored by LC-MS/MS for 240 min after oral administration. The polyphenol content of green tea was determined by the Folin-Ciocalteu method.
Results
The peak plasma concentration of amoxicillin significantly decreased upon its co-administration with green tea, although the AUC
0–240
of the antibiotic did not decrease significantly in the group treated with amoxicillin suspended in green tea.
Conclusions
Our results suggest a potentially relevant interaction between green tea and amoxicillin, worth being further studied in humans.
The optimization of PNA oligomer synthesis has been accomplished employing Fmoc/acyl-protected monomers on TentaGel and Wang resins. Among the tested activating agents (CMP, BET, HATU) the latter was of choice in solid phase syntheses. "Leakage" of TentaGel resin greatly hampers the solution and MS analyses. Synthesis and acyl group deprotection steps have been separately examined using Wang resin. Optimal conditions also worked well on the CPG support. HPLC and MS analyses of the PNA oligomers were carried out under various conditions.
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