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Elucidation of Postfusion Structures of the Measles Virus F Protein for the Structure-Based Design of Fusion
Aoi Takahara1, Toru Nakatsu1,2, Kazushige Hirata3,4
1Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Abstract:
Measles is a highly infectious disease and remains a major cause of childhood mortality worldwide. In some cases, the measles virus (MV) induces subacute sclerosing panencephalitis within several years of the acute infection. The infection of the target cells by MV is mediated by the F protein, in which two heptad repeat regions, HR1 and HR2, form a six-helix bundle before membrane fusion. We previously reported anti-MV peptides, which were designed from the HR region of the MV F protein. Here, we characterized the essential interactions between the HR1 and HR2 regions on the postfusion six-helix bundles of synthetic HR1 and HR2 peptides by crystallographic studies. Based on the crystal structures, we identified the minimal α-helix sequence for antiviral activity. Additionally, optimizing HR2 peptides by introducing α-helix-inducible motifs and maintaining key hydrogen bond networks at the N- and C-terminal regions led to the identification of highly potent antiviral peptides.
Insights
Researchers identified key interactions within the measles virus (MV) fusion (F) protein to develop potent antiviral peptides. These findings offer new strategies for combating measles infection and its severe complications.
Area of Science:
- Virology
- Structural Biology
- Medicinal Chemistry
Background:
- Measles virus (MV) is a highly infectious agent causing significant childhood mortality globally.
- MV infection can lead to severe neurological complications like subacute sclerosing panencephalitis.
- The MV fusion (F) protein mediates viral entry into target cells via a six-helix bundle structure formed by HR1 and HR2 regions.
Purpose of the Study:
- To characterize the essential interactions between the HR1 and HR2 regions of the MV F protein.
- To identify minimal sequences within the F protein HR regions responsible for antiviral activity.
- To design and optimize potent antiviral peptides targeting MV.
Main Methods:
- Crystallographic studies of synthetic HR1 and HR2 peptides to elucidate postfusion six-helix bundle structures.
- Analysis of crystal structures to identify critical amino acid sequences and interactions.
- Optimization of peptide sequences by incorporating alpha-helix-inducible motifs and preserving key hydrogen bonds.
Main Results:
- The crystal structures revealed essential interactions between HR1 and HR2 regions in the postfusion F protein.
- A minimal alpha-helix sequence critical for antiviral activity was identified.
- Optimized HR2 peptides demonstrated highly potent antiviral activity against MV.
Conclusions:
- Understanding the structural basis of MV F protein heptad repeat interactions is crucial for antiviral drug design.
- Optimized peptides targeting these interactions represent promising therapeutic candidates for measles.
- This research contributes to developing novel strategies against measles virus and its associated pathologies.
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