Biology subjects

Fischer, W.

Publications and source records attributed to Fischer, W..

2 recordsLinked to original sources

bioRxiv2018

Targeting hepatitis C virus p7 channel activity reveals prospect for bimodal antiviral prophylaxis

Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or \"viroporins\", contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery.\n\nWe describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.

microbiology↗

bioRxiv2018

Structural transition and antibody binding of Ebola GP and Zika E proteins from pre-fusion to fusion-initiation state

Membrane fusion proteins are responsible for viral entry into host cells- a crucial first step in viral infection. These proteins undergo large conformational changes from pre-fusion to fusion initiation structures, and, despite differences in viral genomes and disease etiology, many fusion proteins are arranged as trimers. Structural information for both pre-fusion and fusion initiation states is critical for understanding virus neutralization by the host immune system. In the case of Ebola glycoprotein (GP) and Zika envelope protein (Zika E), pre-fusion state structures have been identified experimentally, but only partial structures of fusion initiation states have been described. While the fusion initiation structure is in an energetically unfavorable state that is difficult to solve experimentally, the existing structural information combined with computational approaches enabled the modeling of fusion initiation state structures of both proteins. These structural models provide an improved understanding of four different neutralizing antibodies in the prevention of viral host entry.

biophysics↗