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Updated: Jun 22, 2025
Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics DCAF
Published on: September 17, 2019
A neutralizing antibody prevents postfusion transition of measles virus fusion protein
Dawid S Zyla1, Roberta Della Marca2,3,4, Gele Niemeyer1,5
1Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Abstract:
Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the general population declines and as populations of immunocompromised individuals, who cannot be vaccinated, increase. There are no approved therapeutics for MeV. Neutralizing antibodies targeting viral fusion are one potential therapeutic approach but have not yet been structurally characterized or advanced to clinical use. We present cryo-electron microscopy (cryo-EM) structures of prefusion F alone [2.1-angstrom (Å) resolution], F complexed with a fusion-inhibitory peptide (2.3-Å resolution), F complexed with the neutralizing and protective monoclonal antibody (mAb) 77 (2.6-Å resolution), and an additional structure of postfusion F (2.7-Å resolution). In vitro assays and examination of additional EM classes show that mAb 77 binds prefusion F, arrests F in an intermediate state, and prevents transition to the postfusion conformation. These structures shed light on antibody-mediated neutralization that involves arrest of fusion proteins in an intermediate state.
Insights
Measles virus (MeV) poses a growing threat due to declining vaccination rates. Researchers structurally characterized neutralizing antibodies, revealing how they block viral fusion for potential new MeV therapies.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Measles virus (MeV) is a significant public health concern, exacerbated by decreasing vaccination coverage and increasing immunocompromised populations.
- Currently, no effective therapeutics exist for MeV infections.
- Neutralizing antibodies targeting the viral fusion (F) protein are a promising therapeutic avenue but lack structural characterization.
Purpose of the Study:
- To structurally characterize the measles virus fusion (F) protein in its prefusion and postfusion states.
- To elucidate the mechanism of neutralization by a protective monoclonal antibody (mAb) 77 targeting MeV.
- To provide structural insights for the development of novel MeV therapeutics.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures of the MeV F protein.
- Structures were solved for prefusion F alone, F complexed with a fusion-inhibitory peptide, and F complexed with mAb 77.
- In vitro assays were conducted to validate the functional effects of mAb 77 binding.
Main Results:
- High-resolution cryo-EM structures of prefusion and postfusion MeV F proteins were obtained (2.1-2.7 Å resolution).
- Monoclonal antibody 77 was shown to bind the prefusion F protein.
- mAb 77 was observed to arrest the F protein in an intermediate state, preventing its transition to the postfusion conformation.
Conclusions:
- The structural data reveals the mechanism by which mAb 77 neutralizes MeV by stabilizing an intermediate fusion conformation.
- These findings provide a structural basis for designing fusion-inhibiting therapeutics against measles.
- The study highlights the potential of targeting viral fusion proteins for antiviral drug development.
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