Meola Annalisa, Vernuccio Riccardo, Battini Leandro, Albericio Guillermo, Delgado Pilar, Bamford Rebecca, Pokorny Laura, Broutin Manon, Martínez León Alejandro, Gallien Sébastien, Gil María, Noriega María A, Guivel-Benhassine Florence, Porrot Françoise, Postal Jeanne, Buchrieser Julian, Hubert Mathieu, Haouz Ahmed, Lafaye Pierre, Esteban Mariano, Hub Jochen S, Mahévas Matthieu, Chappert Pascal, Mercer Jason, Garcia-Arriaza Juan, Schwartz Olivier, Guardado-Calvo Pablo
Structural biology of infectious diseases G5+ unit, Institut Pasteur, Université Paris Cité, Paris, France.
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain.
Cell. 2025 Aug 18. doi: 10.1016/j.cell.2025.07.040.
Monkeypox virus (MPXV) is a poxvirus endemic to Central and West Africa with high epidemic potential. Poxviruses enter host cells via a conserved entry-fusion complex (EFC), which mediates viral fusion to the cell membrane. The EFC is a promising therapeutic target, but the absence of structural data has limited the development of fusion-inhibiting treatments. Here, we investigated A16/G9, a subcomplex of the EFC that controls fusion timing. Using cryo-electron microscopy, we showed how A16/G9 interacts with A56/K2, a viral fusion suppressor that prevents superinfection. Immunization with A16/G9 elicited a protective immune response in mice. Using X-ray crystallography, we characterized two neutralizing antibodies and engineered a chimeric antibody that cross-neutralizes several poxviruses more efficiently than 7D11, the most potent antibody targeting the EFC described to date. These findings highlight the potential of A16/G9 as a candidate for subunit vaccines and identify regions of the EFC as targets for antiviral development.
猴痘病毒（MPXV）是一种在中非和西非流行的痘病毒，具有很高的流行潜力。痘病毒通过保守的进入融合复合体（EFC）进入宿主细胞，该复合体介导病毒与细胞膜融合。EFC是一个有前景的治疗靶点，但缺乏结构数据限制了融合抑制治疗的发展。在这里，我们研究了EFC的一个控制融合时机的亚复合体A16/G9。利用冷冻电子显微镜，我们展示了A16/G9如何与A56/K2相互作用，A56/K2是一种防止超级感染的病毒融合抑制剂。用A16/G9免疫可在小鼠中引发保护性免疫反应。利用X射线晶体学，我们鉴定了两种中和抗体，并设计了一种嵌合抗体，该嵌合抗体比7D11更有效地交叉中和多种痘病毒，7D11是迄今为止描述的针对EFC的最有效的抗体。这些发现突出了A16/G9作为亚单位疫苗候选物的潜力，并确定了EFC的区域作为抗病毒开发的靶点。
