Structure-based design of inhibitors of NS3 serine protease of hepatitis C virus

We have designed small focused combinatorial library of hexapeptide inhibitors of NS3 serine protease of the hepatitis C virus (HCV) by structure-based molecular design complemented by combinatorial optimisation of the individual residues. Rational residue substitutions were guided by the structure and properties of the binding pockets of the enzyme's active site. The inhibitors were derived from peptides known to inhibit the NS3 serine protease by using unusual amino acids and alpha-ketocysteine or difluoroaminobutyric acid, which are known to bind to the S1 pocket of the catalytic site. Inhibition constants (Ki) of the designed library of inhibitors were predicted from a QSAR model that correlated experimental Ki of known peptidic inhibitors of NS3 with the enthalpies of enzyme-inhibitor interaction computed via molecular mechanics and the solvent effect contribution to the binding affinity derived from the continuum model of solvation. The library of the optimised inhibitors contains promising drug candidates-water-soluble anionic hexapeptides with predicted Ki* in the picomolar range.     

Structural Study of the Partially Disordered Full‐Length δ Subunit of RNA Polymerase from Bacillus subtilis

The partially disordered δ subunit of RNA polymerase was studied by various NMR techniques. The structure of the well‐folded N‐terminal domain was determined based on inter‐proton distances in NOESY spectra. The obtained structural model was compared to the previously determined structure of a truncated construct (lacking the C‐terminal domain). Only marginal differences were identified, thus indicating that the first structural model was not significantly compromised by the absence of the C‐terminal domain. Various ¹⁵N relaxation experiments were employed to describe the flexibility of both domains. The relaxation data revealed that the C‐terminal domain is more flexible, but its flexibility is not uniform. By using paramagnetic labels, transient contacts of the C‐terminal tail with the N‐terminal domain and with itself were identified. A propensity of the C‐terminal domain to form β‐type structures was obtained by chemical shift analysis. Comparison with the paramagnetic relaxation enhancement indicated a well‐balanced interplay of repulsive and attractive electrostatic interactions governing the conformational behavior of the C‐terminal domain. The results showed that the δ subunit consists of a well‐ordered N‐terminal domain and a flexible C‐terminal domain that exhibits a complex hierarchy of partial ordering.     

Acid-catalyzed decomposition of stable 1-(2,1-benzisothiazol-3-yl)-3-phenyltriazenes

The acid-catalyzed decomposition of unusually stable 1-(2,1-benzisothiazol-3-yl)-3-phenyltriazenes in either aqueous perchloric acid or an aqueous mixture of perchloric and acetic acid was studied under pseudo-first order reaction conditions at 25 °C. Different products were obtained according to substitution on nitrogen N-3. For a triazene carrying hydrogen, the corresponding 3-amino-2,1-benzisothiazole and benzenediazonium salts were formed whereas in the case of substitution by an alkyl group (methyl and n-butyl) the 2,1-benzisothiazole-3-diazonium salt and N-alkylaniline were obtained. The observed rate constant (k_obs) of the acid-catalyzed decomposition increased, initially, nonlinearly with increasing concentration of acid. Subsequently, k_obs decreased slightly and at high acid concentration, increased steeply once again. An A-S_E2 mechanism in which protonation of the triazene nitrogen proceeds simultaneously with cleavage of the N–N bond is proposed. Tautomerism of 1-(2,1-benzisothiazol-3-yl)-3-phenyltriazene was investigated using ¹H NMR spectroscopy.     

Synthesis and properties of YBa2Cu3O7-δ – Y2Ba4CuWO10.8 superconducting composites

YBa₂Cu₃O_7-δ (YBCO) is a well-known high-temperature superconductor. However, its critical current density and thus maximum trapped magnetic field can be improved significantly by introducing the secondary phases (artificial pinning centers). In this contribution, we successfully prepared YBCO single-grain bulks with Y₂Ba₄CuWO_10.8 phase serving as a source of pinning centers. This phase was prepared by solid-state reaction and further refined by milling. In the next step single-grain YBCO bulks with homogeneously distributed Y₂Ba₄CuWO_10.8 were prepared by top-seeded melt growth. Precursors as well as the final product were characterized by XRD, SEM and EDS. The phase composition of YBCO bulks containing Y₂Ba₄CuWO_10.8 was analyzed using Rietveld analysis. Thermal stability of YBCO bulk was studied by STA. Furthermore, PPMS was used to study electrical resistivity and critical current density. Bulk superconducting properties such as levitation force and trapped field ability were also measured.     

Multi-component adsorption of Ag(I), Cd(II) and Cu(II) by natural carbonaceous materials

Adsorption of silver, cadmium and copper from aqueous solutions by natural carbonaceous materials was investigated. The studied series of natural materials (spruce wood, pine bark, cork, peat, fusinite, lignite, oxidised lignite, bituminous coal and anthracite) was extended to include industrial carbon-rich materials: coke, activated carbon F-400 and Multisorb 100. Adsorption was tested on a single-component system and on the binary and ternary mixtures. All the materials used differ in their ability to adsorb selected metals. The adsorption of metals is significantly affected by the presence of other ions in solution. Total metal uptake was considerably higher in a mixture than single-ion adsorption. Chemical reactions, such as precipitation and reduction of metallic silver, play a role in metal uptake by bituminous coal, coke and activated carbon.