Reoviridae-derived short trimerization domain for stabilizing homo-trimerization of vaccine immunogens and therapeutic proteins
Trimerization motifs play pivotal roles in structural biology and therapeutic protein engineering. Here, we describe a short trimerization motif (rFd1303) derived from the Reoviridae family reovirus σ1 protein. Compared with the widely used T4-Foldon, the rFd1303 increased recombinant protein yields. The rFd1303-fused immunogens of SARS-CoV-2 spike and influenza hemagglutinin elicited antibody responses comparable to T4-Foldon-fused controls in mice. Using this tag, we engineered a trimeric ACE2-Ig fusion protein (TriACE2-Ig) that remained stable after 30 days at room temperature and neutralized a broad range of ACE2-utilizing sarbecoviruses, including 19 SARS-CoV-2 variants, SARS-CoV, and pangolin coronaviruses GD and GX, with higher potency than monomeric ACE2-Ig. In the hamster model challenged with various SARS-CoV-2 variants, our data demonstrated that intranasal TriACE2-Ig administration markedly reduced viral loads, virus-induced body-weight loss, lung pathology, and decreased within-cage virus transmission. These findings highlight rFd1303 as a versatile trimerization platform for vaccine and therapeutic protein development. In this study, the authors engineer a short trimerization tag for vaccine and therapeutic protein development. The tag enables a trimeric ACE2 decoy that exhibits broad neutralizing activity against coronaviruses and confers protection in animal models.
Authors
- Tianying Zhang (ORCID: https://orcid.org/0000-0002-2477-329X)
- Yangtao Wu (ORCID: https://orcid.org/0000-0002-9429-266X)
- Shengxiang Ge (ORCID: https://orcid.org/0000-0002-7165-3004)
- Zehong Huang (ORCID: https://orcid.org/0000-0001-8167-6261)
- Qingbing Zheng (ORCID: https://orcid.org/0000-0002-7516-9965)
- Jijing Chen (ORCID: https://orcid.org/0000-0002-1270-9960)
- Shaojuan Wang
- Zikang Wang (ORCID: https://orcid.org/0000-0003-1406-1237)
- Ruojing Bai
- Yunda Hong (ORCID: https://orcid.org/0000-0003-2948-7652)
- Yi Guan (ORCID: https://orcid.org/0000-0001-6057-9243)
- Hai Jing Yu (ORCID: https://orcid.org/0000-0003-4086-8632)
- Lunzhi Yuan (ORCID: https://orcid.org/0000-0001-7480-0287)
- Zizheng Zheng (ORCID: https://orcid.org/0000-0003-0099-4212)
- Ningshao Xia (ORCID: https://orcid.org/0000-0003-0179-5266)
- Quan Yuan (ORCID: https://orcid.org/0000-0001-5487-561X)
- Jiahua Gao
- Jun Zhang (ORCID: https://orcid.org/0000-0002-6601-9180)
- Min Wei (ORCID: https://orcid.org/0000-0002-2649-9271)
- Hui Sun (ORCID: https://orcid.org/0009-0006-9866-9846)
- Huilin Guo
- Yuehua Chen (ORCID: https://orcid.org/0000-0003-4709-7623)
- Zhaoming Lu (ORCID: https://orcid.org/0000-0001-5190-1528)
- Yifan Yin (ORCID: https://orcid.org/0009-0005-0944-8797)
- Jinmiao Shi
- Qingfang Bu
- Youfeng Wang
- Jin Xiao
- Chen Zheng (ORCID: https://orcid.org/0000-0002-9544-0759)
- Jiayi Wu
- Yali Zhang
- Min Lin
- Ying Liu
- Jian Ma
- Yang Huang
- Zonglin Li
- Kai Wang
Institutions
- Xiamen University (CN)
- Shantou University (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1038/s41467-026-77926-x
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00