德国结构系统生物学中心Kay Grünewald研究小组取得一项新突破。他们提出了预融合糖蛋白B特异的纳米体可中和HSV-1和HSV-2。这一研究成果发表在2025年9月3日出版的国际学术期刊《自然》上。

在这里，该课题组人员展示了对预制离子特异性纳米体的分离，其中一个表现出很强的中和和跨物种活性。通过突变稳定化，课题组人员解决了单纯疱疹病毒1 gB的全长预制位结构，从而确定了结合表位。他们的分析显示了gB的膜嵌入区域和以前未解决的结构特征，包括一个新的铁离子环排列，提供了对铁离子所需的初始构象变化的见解。纳米体结合一个跨越三个结构域的表位，仅在预制状态下接近，使野生型HSV-2 gB保持这种构象，并使其天然预制结构得以确定。这也表明了中和模式和抗病毒干预的一个有吸引力的途径。

据悉，九种人类疱疹病毒，包括单纯疱疹病毒1型和2型、人类巨细胞病毒和EB病毒对全球公共卫生构成重大负担。它们的包膜包含至少十种不同的糖蛋白，这些糖蛋白是宿主细胞趋向性、附着和进入所必需的。其中最保守的糖蛋白B（gB）是必不可少的，因为它通过从卵泡前到卵泡后的构象进行广泛的重排来执行膜卵泡。目前，由于难以在结构上确定和修饰这种亚稳构象，还没有针对gB的抗病毒药物或针对其前置形态的中和抗体。

附：英文原文

Title: A nanobody specific to prefusion glycoprotein B neutralizes HSV-1 and HSV-2

Author: Vollmer, Benjamin, Ebel, Henriette, Rees, Renate, Nentwig, Julia, Mulvaney, Thomas, Schnemann, Jrgen, Krull, Jens, Topf, Maya, Grlich, Dirk, Grnewald, Kay

Issue&Volume: 2025-09-03

Abstract: The nine human herpesviruses, including herpes simplex virus1 and 2, human cytomegalovirus and Epstein–Barr virus, present a significant burden to global public health1. Their envelopes contain at least ten different glycoproteins, which are necessary for host cell tropism, attachment and entry2. The best conserved among them, glycoprotein B (gB), is essential as it performs membrane fusion by undergoing extensive rearrangements from a prefusion to postfusion conformation. At present, there are no antiviral drugs targeting gB or neutralizing antibodies directed against its prefusion form, because of the difficulty in structurally determining and using this metastable conformation. Here we show the isolation of prefusion-specific nanobodies, one of which exhibits strong neutralizing and cross-species activity. By mutational stabilization we solved the herpes simplex virus 1 gB full-length prefusion structure, which allowed the bound epitope to be determined. Our analyses show the membrane-embedded regions of gB and previously unresolved structural features3,4, including a new fusion loop arrangement, providing insights into the initial conformational changes required for membrane fusion. Binding an epitope spanning three domains, proximal only in the prefusion state, the nanobody keeps wild-type HSV-2 gB in this conformation and enabled its native prefusion structure to be determined. This also indicates the mode of neutralization and an attractive avenue for antiviral interventions.

DOI: 10.1038/s41586-025-09438-5

Source: https://www.nature.com/articles/s41586-025-09438-5