Structures of the prefusion form of measles virus fusion protein in complex with inhibitors

Area of Science:

• Virology
• Structural Biology
• Neuroscience

Background:

• Measles virus (MeV) is a highly contagious pathogen causing significant childhood illness and death.
• MeV can rarely cause persistent central nervous system infections leading to fatal neurodegenerative diseases like SSPE and MIBE.
• Specific MeV fusion (F) protein substitutions are implicated in pathogenesis, causing protein destabilization and hyperfusogenicity.

Purpose of the Study:

• To determine the crystal structures of the prefusion MeV-F protein.
• To investigate the binding of inhibitors to the MeV-F protein.
• To understand the structural basis for MeV-induced neurodegeneration and identify potential therapeutic targets.

Main Methods:

• X-ray crystallography was used to obtain the structures of the prefusion MeV-F protein alone and in complex with inhibitors.
• Small compound AS-48 and a fusion inhibitor peptide were used as inhibitors.
• Structural analysis focused on the binding site of the inhibitors and its relation to disease-associated mutations.

Main Results:

• The crystal structures of prefusion MeV-F alone and in complex with AS-48 or a fusion inhibitor peptide were determined.
• Both inhibitors bind to the same hydrophobic pocket in the MeV-F protein, located between the head and stalk regions.
• This binding site overlaps with the location of substitutions found in MeV isolates from neurodegenerative disease patients.
• The identified inhibitors demonstrated suppression of membrane fusion mediated by hyperfusogenic MeV-F mutants.

Conclusions:

• The structural insights into MeV-F protein-inhibitor complexes provide a basis for developing novel therapeutics.
• Targeting the identified hydrophobic pocket could be a promising strategy to combat MeV-induced neurodegenerative diseases.
• Further development of inhibitors based on these structures may lead to effective treatments for these intractable conditions.