Following the roadmap toward an effective Ebola virus treatment

Two Achilles' Heels of the Ebolavirus Glycoprotein?

“…Moreover, this article puts forward a set of small molecule-induced perturbation of interfacial electrostatic interaction network within experimentally determined ebola GP structures, and hypothesizes that these small compounds inhibit viral cell entry and/or membrane-fusion by binding to the glycoprotein, inducing a minor conformational perturbation, leading to the establishment of two inter-chain salt bridges, i.e., B_LYS_510-A_GLU_292 ( Figures 2, 3 and 4) and B_LYS_588-A_ASP_47 ( Figures 5, 6 and 7), restraining the conformational flexibility of the approximate structural region in the orange box (Figures 2 and 3) and the approximate structural region in the red box ( Figure 5) against GP-mediated Ebolavirus cell entry and/or membrane-fusion [14][15][16][115][116][117][118]. Along with previously reported details of the protein-inhibitor interactions of these complexes, this hypothesis may facilitate the design of more potent inhibitors of Ebolavirus cell entry [119][120][121][122][123][124][125]125,[144][145][146][147][148][149] and the discovery of novel antiviral compounds [54,[150][151][152][153][154][155][156] to prepare us for future outbreaks.…”

“…While the recent structural studies [14][15][16][115][116][117] painted an overall experimental picture of the Ebolavirus GP molecule, allowing conformational changes induced by antibody and receptor binding to be deciphered, in-depth structural and functional details, including its mechanism of inhibition, i.e., action mode of mediating virus cell entry [118][119][120][121][122][123][124][125] and possible conformational dynamics associated with it, are still to be investigated further, both experimentally and computationally [126,127]. As previously reported, the protein-drug interactions with both GP1 and GP2 are predominately hydrophobic [14][15][16][115][116][117], thus, from a structural point of view, this article aims to extract all electrostatic features embedded in all experimentally determined Ebolavirus GP structures currently available as of March 10, 2020.…”