[show abstract][hide abstract] ABSTRACT: Enveloped viruses commonly employ membrane fusion during cell penetration in order to deliver their genetic material across the cell boundary. Large conformational changes in the proteins embedded in the viral membrane play a fundamental role in the membrane fusion process. Despite the tremendously wide variety of viruses that contain membranes, it appears that they all contain membrane fusion protein machinery with a remarkably conserved mechanism of action. Much of our current biochemical understanding of viral membrane fusion has been derived from high-resolution structural studies and solution-based in vitro assays in which viruses fuse with liposomes or cells. Recently, single-particle experiments have been used to provide measurements of details not available in the bulk assays. Here we focus our discussion on the key dynamical aspects of fusion protein structure, along with some of the experimental and computational techniques presently being used to investigate viral-mediated membrane fusion.
[show abstract][hide abstract] ABSTRACT: Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar(-/-) ) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans.
[show abstract][hide abstract] ABSTRACT: Retroviruses cause a variety of the most serious diseases of man and animals. A new class of antiretroviral drugs, so-called 'entry inhibitors', block virus entry into the host cell. Until now, antiretroviral drug have been designed and evaluated in com-plex natural virus-cell systems, but the complexity impedes detailed insights into the underlying molecular mechanisms of virus-cell interaction. Therefore, we propose to engineer a novel model system which reduces the complexity of the components involved in virus-cell interaction. The proposed artificial model system will provide an in vitro testbed for antiretroviral drug design and validation. The system will combine the advantages of natural and artificial models by consisting of artificial lipo-somes equipped with a minimal cellular machinery providing nothing but the components needed for the molecular processes in virus-cell interaction. We are able to refer to data of several 'entry inhibitors' tested in a natural virus-cell system, and we already established liposome containers separated from the surrounding by a lipid membrane that enclose sugars, and ami-no acids. Here, we present results of encapsulating nucleotides and organic and inorganic ions. Further, we discuss how to proceed on the way towards a novel liposome-based testbed for antiretroviral drug design and validation.
International Conference on Engineering and Meta-Engineering (ICEME); 04/2010
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