Toremifene interacts with and destabilizes the Ebola virus glycoprotein

Area of Science:

• Structural Biology
• Virology
• Drug Discovery

Background:

• Ebola viruses (EBOVs) cause fatal outbreaks with no approved treatments.
• The EBOV glycoprotein (GP) mediates viral entry and is a key drug target.

Purpose of the Study:

• To determine the unliganded structure of EBOV GP.
• To elucidate the high-resolution structures of EBOV GP complexed with toremifene and ibuprofen.
• To understand the mechanism of inhibition by these drugs.

Main Methods:

• X-ray crystallography
• Thermal shift assays

Main Results:

• Determined the first unliganded structure of EBOV GP.
• Identified a binding cavity for toremifene and ibuprofen between GP1 and GP2 subunits.
• Toremifene binding significantly destabilized GP, while ibuprofen showed a marginal effect.

Conclusions:

• Drug binding to EBOV GP inhibits viral entry by destabilizing the glycoprotein.
• These findings provide a structural basis for developing novel anti-EBOV therapeutics targeting GP.