A molecular epidemiological study of rabies epizootics in kudu (Tragelaphus strepsiceros) in Namibia

BACKGROUND: A panel of 37 rabies virus isolates were collected and studied, originating mainly from the northern and central regions of Namibia, between 1980 and 2003. RESULTS: These virus isolates demonstrated a high degree of genetic similarity with respect to a 400 bp region of the nucleoprotein gene, with the virus isolates originating from kudu antelope (n = 10) sharing 97.2–100% similarity with jackal isolates, and 97–100% similarity with those isolated from domestic dogs. Phylogenetic analysis suggested that these viruses were all of the canid rabies biotype of southern Africa. The viruses from kudu were closely associated with jackal isolates (n = 6), bat-eared fox isolates (n = 2) and domestic dog isolates (n = 2) at the genetic level and identical at the amino acid level, irrespective of the year of isolation. CONCLUSION: These data suggest that jackal and kudu may form part of the same epidemiological cycle of rabies in Namibian wildlife, and might demonstrate the close-relationship between rabies virus strains that circulate within Namibia and those that circulate between Namibia and its neighbouring countries such as Botswana and South Africa

A Comparative Study on the Experimentally Derived Electron Densities of three Protease Inhibitor Model Compounds

In order to contribute to a rational design of optimised protease inhibitors which can covalently block the nucleophilic amino acids of the proteases' active sites, we have chosen three model compounds (aziridine , oxirane and acceptor-substituted olefin ) for the examination of their electron-density distribution. Therefore, high-resolution low temperature (9, 27 and 100 K) X-ray diffraction experiments on single-crystals were carried out with synchrotron and conventional X-radiation. It could be shown by the analysis of the electron density using mainly Bader's Theory of Atoms in Molecules, Volkov's EPMM method for interaction energies, electrostatic potentials and Gatti's Source Function that aziridine is most suitable for drug design in this field. A regioselective nucleophilic attack at carbon atom C1 could be predicted and even hints about the reaction's stereoselectivity could be obtained. Moreover, the comparison between two data sets of aziridine (conventional X-ray source vs. synchrotron radiation) gave an estimate concerning the reproducibility of the quantitative results

Electron Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors

Three types of synthesised compounds, the aziridine 1, the epoxide 2 and the acceptor‐substituted olefin 3, were chosen as model compounds for electrophilic building blocks, which can covalently block the nucleophilic amino acids of the active sites of proteases (Cys in cysteine proteases or Asp in aspartate proteases). In order to rationally design optimised inhibitors and to understand the differences in inhibition properties of the scrutinised building blocks their structural and electronic properties were studied by ultra‐high resolution X‐ray diffraction and ab initio calculations to yield the experimental electron‐density distribution. It could be shown that the carbon atom C1 of the three‐membered heterocycle is the preferred electrophilic centre for attack of the nucleophiles, which is consistent with the results of corresponding chemical experiments with sulfur and oxygen nucleophiles

Can Experimental Electron-Density Studies be Used as a Tool to Predict Biologically Relevant Properties of Low-Molecular Weight Enzyme Ligands?

The case of protease inhibitor model compounds incorporating an aziridine or epoxide ring is used to exemplify how application of experimental electron‐density techniques can be used to explain the biological properties of low‐molecular weight enzyme ligands. This is furthermore seen in the light of a comparison of crystal and enzyme environments employing QM/MM computations to elucidate to which extent the properties in the crystal can be used to predict behavior in the biological surrounding