A high-throughput target-based screening approach for the identification and assessment of mycothione reductase inhibitors.

Unlabelled: The World Health Organization's goal to combat tuberculosis (TB) is hindered by the emergence of anti-microbial resistance, therefore necessitating the exploration of new drug targets. Multidrug regimens are indispensable in TB therapy as they provide synergetic bactericidal effects, shorten treatment duration, and reduce the risk of resistance development. The research within our European RespiriTB consortium explores energy metabolism to identify new drug candidates that synergize with bedaquiline, with the aim of discovering more efficient combination drug regimens.

Efficient and Accurate Potential Energy Surfaces of Puckering in Sugar-Modified Nucleosides.

Puckering of the sugar unit in nucleosides and nucleotides is an important structural aspect that directly influences the helical structure of nucleic acids. The preference for specific puckering modes in nucleic acids can be analyzed via conformational analysis, but the large amount of conformations and the accuracy of the analysis leads to an extensive amount of computational time. In this paper, we show that the combination of geometry optimizations with the HF-3c method with single point energies at the RI-MP2 level results in accurate results for the puckering potential energy surface (PES) of DNA and RNA nucleosides while significantly reducing the necessary computational time.

Stable Hairpin Structures Formed by Xylose-Based Nucleic Acids.

Xenobiology explores synthetic nucleic acid polymers as alternative carriers of genetic information to expand the central dogma. The xylo- and deoxyxylo-nucleic acids (XyNA and dXyNA), containing 3' epimers of riboses and deoxyriboses, are considered to be potential candidates for an orthogonal system. In this study, thermal and spectroscopic analyses show that XyNA and dXyNA form stable hairpins.

New Metal-Free Route towards Imidazole-Substituted Uridine.

Nucleosides with a bi(hetero)aryl nucleobase have unique potential applications as antiviral drugs and molecular probes. The need for transition metal catalysis to synthesize these nucleosides from pre-functionalized building blocks and the use of nucleobase protection groups results in expensive and tedious syntheses. Herein we report that 5-imidazolyl-uracil can be obtained by scalable Van Leusen imidazole synthesis and regioselectively introduced on ribose to obtain the desired nucleoside in a 5 step synthesis (total yield 55 %).

Oligonucleotide promoted peptide bond formation using a tRNA mimicking approach.

TransferRNA's role in protein translation is the prime example of an Informational Leaving Group (ILG). A simplified model produced oligophenylalanine with a modified uracil as an ILG in the presence of specific oligonucleotides. Our preliminary studies contribute to the importance of hybrid species in bridging the gap between peptides and nucleic acids.

Theoretical Analysis of a Self-Replicator With Reduced Template Inhibition Based on an Informational Leaving Group.

The first non-enzymatic self-replicating systems, as proposed by von Kiedrowski (Angew Chem Int Ed Engl 25(10):932-935, 1986) and Orgel (Nature 327(6120):346-347, 1987), gave rise to the analytical background still used today to describe artificial replicators. What separates a self-replicating from an autocatalytic system is the ability to pass on structural information (Orgel, Nature 358(6383):203-209, 1992). Utilising molecular information, nucleic acids were the first choice as prototypical examples.

NMR study on the interaction of the conserved CREX 'stem-loop' in the Hepatitis E virus genome with a naphthyridine-based ligand.

A 2-amino-1,8-naphthyridine derivative that is described to bind single guanine bulges in RNA-DNA and RNA-RNA duplexes was synthesized and its interaction with the single G bulge in the conserved CREX of the Hepatitis E Virus (HEV) genome was explored by NMR and molecular modeling. Results indicate that the ligand intercalates in the internal loop, though none of the expected hydrogen bonds with the single G in the bulge could be demonstrated.

Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization.

Background: Fatty acid vesicles are an important part of protocell models currently studied. As protocells can be considered as pre-biological precursors of cells, the models try to contribute to a better understanding of the (cellular) origin of life and emphasize on 2 major aspects: compartmentalization and replication. It has been demonstrated that lipid-based membranes are amenable to growth and division (shell replication).