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Published on: March 24, 2017
Helical peptides with disordered regions for measles viruses provide new generalized insights into fusion inhibitors
Kazushige Hirata1,2, Aoi Takahara3, Satoshi Suzuki1
1Department of Infectious Diseases, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Abstract:
Despite effective vaccines, measles virus (MeV) outbreaks occur sporadically. Therefore, developing anti-MeV agents remains important for suppressing MeV infections. We previously designed peptide-based MeV fusion inhibitors, M1 and M2, that target MeV class I fusion protein (F protein). Here, we developed a novel fusion inhibitor, MEK35, that exerts potent activity against M1/M2-resistant MeV variants. Comparing MEK35 to M1 derivatives revealed that combining disordered and helical elements was essential for overcoming M1/M2 resistance. Moreover, we propose a three-step antiviral process for peptide-based fusion inhibitors: (i) disordered peptides interact with F protein; (ii) the peptides adopt a partial helical conformation and bind to F protein through hydrophobic interactions; and (iii) subsequent interactions involving the disordered region of the peptides afford a peptide-F protein with a high-affinity peptide-F protein interaction. An M1-resistant substitution blocks the second step. These results should aid the development of novel viral fusion inhibitors targeting class I F protein.
Insights
A new peptide fusion inhibitor, MEK35, effectively targets measles virus (MeV) variants resistant to prior treatments. Combining disordered and helical elements is key to overcoming MeV resistance and developing new antiviral therapies.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Measles virus (MeV) outbreaks persist despite vaccination, necessitating novel antiviral agents.
- Previous peptide inhibitors (M1, M2) target the MeV class I fusion (F) protein.
- Development of agents overcoming treatment resistance is crucial.
Purpose of the Study:
- To develop a novel fusion inhibitor effective against MeV variants resistant to M1/M2.
- To elucidate the structural requirements for overcoming M1/M2 resistance.
- To understand the mechanism of action for peptide-based fusion inhibitors.
Main Methods:
- Design and synthesis of a novel peptide fusion inhibitor, MEK35.
- Evaluation of MEK35 activity against M1/M2-resistant MeV variants.
- Comparative analysis of MEK35 and M1 derivatives to identify key structural features.
- Characterization of the proposed three-step antiviral mechanism.
Main Results:
- MEK35 demonstrated potent activity against M1/M2-resistant MeV variants.
- Combining disordered and helical peptide elements was essential for overcoming resistance.
- A three-step mechanism involving disordered and helical conformations was proposed for peptide-F protein interaction.
- An M1-resistant mutation was found to impede the second step of the proposed mechanism.
Conclusions:
- MEK35 represents a promising novel antiviral agent against resistant MeV strains.
- Structural insights into MEK35 aid in designing next-generation viral fusion inhibitors.
- Understanding the peptide-F protein interaction mechanism is vital for developing effective antivirals targeting class I fusion proteins.
