Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and 'easy to use' oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome inhibitors with in vivo efficacy in mouse models of leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). For the treatment of HAT, development compounds need to have excellent penetration to the brain to cure the meningoencephalic stage of the disease. Here we describe detailed biological and pharmacological characterization of triazolopyrimidine compounds in HAT specific assays. The TP class of compounds showed single digit nanomolar potency against Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense strains. These compounds are trypanocidal with concentration-time dependent kill and achieved relapse-free cure in vitro. Two compounds, GNF6702 and a new analog NITD689, showed favorable in vivo pharmacokinetics and significant brain penetration, which enabled oral dosing. They also achieved complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection of human African trypanosomiasis mouse models. Mode of action studies on this series confirmed the 20S proteasome as the target in T. brucei. These proteasome inhibitors have the potential for further development into promising new treatment for human African trypanosomiasis

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

Architecture of a nascent viral fusion pore

Enveloped viruses use specialized protein machinery to fuse the viral membrane with that of the host cell during cell invasion. In influenza virus, hundreds of copies of the haemagglutinin (HA) fusion glycoprotein project from the virus surface. Despite intensive study of HA and its fusion activity, the protein's modus operandi in manipulating viral and target membranes to catalyse their fusion is poorly understood. Here, the three-dimensional architecture of influenza virus–liposome complexes at pH 5.5 was investigated by electron cryo-tomography. Tomographic reconstructions show that early stages of membrane remodeling take place in a target membrane-centric manner, progressing from punctate dimples, to the formation of a pinched liposomal funnel that may impinge on the apparently unperturbed viral envelope. The results suggest that the M1 matrix layer serves as an endoskeleton for the virus and a foundation for HA during membrane fusion. Fluorescence spectroscopy monitoring fusion between liposomes and virions shows that leakage of liposome contents takes place more rapidly than lipid mixing at pH 5.5. The relation of ‘leaky' fusion to the observed prefusion structures is discussed

Electron mean free path for GaAs(100)-c(4x4) at very low energies

Electron mean free path (MFP) was determined by the angular resolved photoemission in 10-40 eV energy range for GaAs(100)-c(4 x 4) by the overlayer method. The investigation was based on the attenuation of the normal photoemission intensity of the Al 2p line from the molecular-beam-epitaxy grown GaAlAs layer buried four monolayers of GaAs below the surface. The energy dependence of the MFP shows a pronounced maximum at about 30 eV which is related to the corresponding section of the electron band structure of GaAs(100). (C) 2004 Elsevier B.V. All rights reserved

Photoemission from alpha and beta phases of the GaAs(001)-c(4 x 4) surface

We prepared alpha- and beta surface phases of GaAs(0 0 1)-c(4 x 4) reconstruction by molecular beam epitaxy (MBE) using As-4 and As-2 molecular beams, respectively, and examined them by angle-resolved ultraviolet photoelectron spectroscopy (UPS) and X-ray photoelectron spectroscopy (XPS) with synchrotron radiation as an excitation source. The UPS valence band spectra and the XPS 3d core level data show pronounced differences corresponding to the surface composition and the atomic structure of the two phases, as proposed in the literature. In UPS, the beta phase is characterized by an intensive surface state 0.5 eV below the top of the valence band at low photon energy, while an analogous peak in the alpha phase spectra is missing. The surface state is interpreted in terms of dangling bonds on As dimers. The As3d and Ga3d core level photoelectron lines exhibit phase-specific shapes as well as differences in the number, position and intensity of their deconvoluted components. The location of various atoms in the surface and subsurface layers is discussed; our photoemission results support models of the beta phase and the alpha phase with As-As dimers and Ga-As heterodimers, respectively. (C) 2009 Elsevier B.V. All rights reserved

Excitation of VLF quasi-electrostatic oscillations in the ionospheric plasma

A numerical solution of the dispersion equation for electromagnetic waves in a hot magnetized collisionless plasma has shown that, in a current-free ionospheric plasma, the distortion of the electron distribution function reproducing the downward flow of a thermal electron component and the compensating upward flow of the suprathermal electrons, which are responsible for the resulting heat flux, can destabilize quasi-electrostatic ion sound waves. The numerical analysis, performed with ion densities and electron temperature taken from the data recorded by the Interkosmos-24 (IK-24, Aktivny) satellite, is compared with a VLF spectrum registered at the same time on board. This spectrum shows a wide frequency band emission below the local ion plasma frequency. The direction of the electron heat flux inherent to the assumed model of VLF emission generation is discusse