Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the generalpopulation declines and as populations of immunocompromised individuals, who cannot be vaccinated,increase. There are no approved therapeutics for MeV. Neutralizing antibodies targeting viral fusionare one potential therapeutic approach but have not yet been structurally characterized or advanced toclinical use. We present cryo-electron microscopy (cryo-EM) structures of prefusion F alone [2.1-angstrom (& Aring;) resolution], F complexed with a fusion-inhibitory peptide (2.3-& Aring; resolution), F complexedwith the neutralizing and protective monoclonal antibody (mAb) 77 (2.6-& Aring; resolution), and an additionalstructure of postfusion F (2.7-& Aring; resolution). In vitro assays and examination of additional EM classesshow that mAb 77 binds prefusion F, arrests F in an intermediate state, and prevents transition to thepostfusion conformation. These structures shed light on antibody-mediated neutralization that involvesarrest of fusion proteins in an intermediate state
A neutralizing antibody prevents postfusion transition of measles virus fusion protein
Della Marca, RobertaMembro del Collaboration Group
;Porotto, Matteo
;
2024
Abstract
Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the generalpopulation declines and as populations of immunocompromised individuals, who cannot be vaccinated,increase. There are no approved therapeutics for MeV. Neutralizing antibodies targeting viral fusionare one potential therapeutic approach but have not yet been structurally characterized or advanced toclinical use. We present cryo-electron microscopy (cryo-EM) structures of prefusion F alone [2.1-angstrom (& Aring;) resolution], F complexed with a fusion-inhibitory peptide (2.3-& Aring; resolution), F complexedwith the neutralizing and protective monoclonal antibody (mAb) 77 (2.6-& Aring; resolution), and an additionalstructure of postfusion F (2.7-& Aring; resolution). In vitro assays and examination of additional EM classesshow that mAb 77 binds prefusion F, arrests F in an intermediate state, and prevents transition to thepostfusion conformation. These structures shed light on antibody-mediated neutralization that involvesarrest of fusion proteins in an intermediate stateI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.