Highly potent compound that blocks Ebola virus entry discovered

A recent study has unveiled the mechanisms behind the diverse entry methods of the Ebola virus, known as Ebolavirus, across various species. The virus's glycoprotein, GP, undergoes significant conformational changes upon entering host cells through the endo-lysosomal pathway. The cleavage of GP by cathepsins and its subsequent binding to the NPC1 receptor are crucial steps leading to membrane fusion, allowing the virus to enter the host cell. However, the underlying molecular mechanisms governing these processes have been elusive.

In this study, researchers employed hydrogen/deuterium-exchange mass spectrometry and mass photometry to scrutinize the structural dynamics and energetic transitions of GP in two prominent species of Ebolavirus, Zaire (EBOV) and Sudan (SUDV). Their findings reveal the existence of allosteric axes that regulate the reorganization of GP cleavage sites, the opening of the receptor binding cavity, and the priming for fusion upon NPC1 engagement.

Notably, GP cathepsin cleavage and receptor binding mechanisms and kinetics differ between species, and their interactions are allosterically coupled in a species-specific manner. Furthermore, the study uncovers that the optimization of fusion priming in EBOV and SUDV GP follows distinct routes. These insights suggest that the structural dynamics and allosteric remodeling of GP play a pivotal role in the species-specific differences in Ebolavirus entry mechanisms.