HYPOTHESIS | doi:10.20944/preprints202003.0183.v1
Subject: Life Sciences, Biophysics Keywords: Ebolavirus glycoprotein; Electrostatic interaction; Salt bridging network; Two Achilles' heels
Online: 11 March 2020 (10:32:02 CET)
Ebolavirus has a membrane envelope decorated by trimers of a glycoprotein (GP), which is responsible for host cell attachment and membrane fusion. Therefore, GP is a primary target for antiviral drugs development. Here, this article reports the first, to my knowledge, set of structural analysis of all Ebolavirus GP structures as of March 10, 2020, and also a brief update of the structurally identified electrostatic features of the Ebolavirus GP structures in both apo (unliganded) state and also in bound states with a series of small compounds, including a variety of approved drugs. With this comprehensive set of structural analysis, this article puts forward a hypothesis of two Achilles' heels of Ebolavirus GP structure, where the formation of two interfacial salt bridges, instead of destabilizing the prefusion conformation of Ebolavirus GP, constitutes a positive contribution towards the structural rigidification of the prefusion conformation of the Ebolavirus GP structure, thereby acting against GP-mediated Ebolavirus cell entry and/or preventing fusion between the viral and endosome membranes.
REVIEW | doi:10.20944/preprints201902.0209.v1
Subject: Life Sciences, Virology Keywords: Ebolavirus; Filoviridae; VSV; retroviral vectors; virus like particles; pseudovirus; antivirals; small molecules; viral entry.
Online: 21 February 2019 (13:13:34 CET)
Ebola Virus Disease (EVD) is one of the most lethal transmissible infections characterized by a high fatality rate, and caused by members of the Filoviridae family. The recent large outbreak of EVD in West Africa (2013-2016), highlighted the worldwide danger of this disease and its impact on global public health and economy. The development of highly needed anti-Filoviridae antivirals has been so far hampered by the shortage of tools to study their life cycle in vitro, and therefore screen for potential active compounds outside a biosafety level-4 (BSL-4) containment. Importantly, the development of surrogate models to in vitro study of Filoviridae entry in a BSL-2 setting, such as viral pseudotypes and Ebola virus like particles, tremendously boosted both our knowledge on viral life cycle and the identification of promising anti-Filoviridae compounds interfering with viral entry. In this context, the combination of such surrogate systems with large-scale small molecule compounds and haploid genetic screenings, as well as rational drug design and drug repurposing approaches will prove priceless in our quest for the development of a treatment for EVD.