Bei Yang, PhDAssistant Professor

Our representative research achievements are briefed below:

1. Development and application of gene editing tools: DddA-derived cytosine base editor (DdCBE) couples TALE arrays and the dsDNA-specific cytidine deaminase DddA to target mitochondrial DNA (mtDNA) for editing, thus enabling the potential modeling and correction of pathogenic mtDNA mutations. Nevertheless, DdCBE and its derived variants manifest elusive editing windows and non-negligible off-target (OT) effects, limiting their application in high-precision-demanding research and clinical settings. To address this challenge and enable mechanistic-based optimization of DdCBE, we determined the cryo-EM structures of DdCBE in action, thus revealing its working mechanism and the structural determinants of its editing window. Based on the mechanistic insights, we then developed a “WinPred” model to guide TALE-recognition region and spacer length design and engineered a high-precision variant of DdCBE, i.e., aDdCBE with a 2~3 nt editing window and minimal off-target mutations. Further application of the WinPred model and aDdCBE enabled near single-nucleotide editing at multiple target sites and allowed faithful modelling of Leber hereditary optic neuropathy disease-related mutations (Mol Cell, 2025) (Fig. 1).

Fig.1| Structure-guided development of high-precision mitochondrial base editors

Beyond the development of gene-editing tools, we are also actively investigating their applications in the prevention and treatment of high-risk infectious and hereditary diseases. For instance, we developed a targeted base-editing strategy to disrupt transcription factor binding motifs in the promoter region of γ-globin in hematopoietic stem cells, thereby reactivating silenced γ-globin expression for β-thalassemia treatment (Cell Stem Cell, 2023). More recently, we explored the therapeutic potential of in vivo ASGR1 editing for the treatment of familial hypercholesterolemia (FH), a hereditary disorder associated with early-onset, life-threatening cardiovascular disease. We demonstrated that highly efficient and precise hepatic ASGR1 base editing could be safely achieved through LNP-mediated delivery of editing tools, resulting in robust and durable lipid lowering in an LDLR-deficient mouse model of FH (Molecular Therapy, 2026) (Fig.2).

Fig. 2| Gene therapy development for familial hypercholesterolemia

2. Rational immunogen design and vaccine development: Revealing conserved immune vulnerabilities in potential immunogens is essential for effective and broad-spectrum vaccine development. The trimeric Env protein on HIV-1 particles has long been the focus of AIDS vaccine design. However, its substantial sequence variability across HIV-1 subtypes and extensive glycosylation together impeded vaccine development for decades. To enable the application of state-of-the-art “epitope-focusing” vaccine strategy on HIV-1, we characterized the structural and immunogenic landscape of Env proteins from Asia prevalent HIV-1 subtypes, CRF01_AE and CRF07_BC. Our work identified CRF01_AE-specific features in the Env V1 region (Fig. 3A–B), uncovered their association with resistance to certain broadly neutralizing antibodies (bNAbs) (Fig. 3C–D), and revealed a novel neutralization mechanism of the first bNAb isolated from a CRF01_AE-infected individual (Fig. 3E) (Nat Commun, 2023). These findings expanded our understanding of Asia-prevalent HIV-1 subtypes and shed lights on future “epitope-focusing” HIV-1 vaccine design. Meanwhile, to better prepare for potential emergent coronaviruses, i.e., “HCoV-X”, we mapped the antigenic landscape of α-coronavirus spike proteins and revealed both conserved and divergent antigenic features across human coronaviruses, thus providing clues for future development of broadly effective coronavirus vaccines (Commun Biol, 2022).

Fig.3| Structural and immunogenic understanding of Envs from CRF subtypes

3. Drug targets identification and inhibitors screening: Compared to the huge health and economic burden imposed by Enterovirus infections on society, the countermeasures have fallen short. Viral 3C protease is one of the drug development focuses of Enterovirus, yet its protease active center has frustrated previous drug discovery efforts. Using an integrative approach which combines mass spectrometry and X-ray crystallography, we demonstrated that 1) the protease activity of 3C could be modulated allosterically and 2) 3C plays a regulatory role in enteroviruses genome replication by binding to the 5’NCR of viral genome. Notably, both the allosteric site and the 5'NCR-binding site on 3C are highly conserved and locate away from the protease active center, making them attractive broad-spectrum drug targets for enterovirus infection control (PNAS, 2020). In silico screening of 143,621 natural products against the allosteric site further identified dihydromyricetin (DHM), a natural product that can broadly binds and allosterically inhibits the protease activities of 3C proteins from multiple enteroviruses. Notably, DHM shows minimal cytotoxicity and potent antiviral efficacy in different cell models, exhibiting a selective index exceeding 700. These findings establish DHM as a unique, broad-spectrum allosteric inhibitor of Enterovirus3C proteases and underscore its potential as a promising candidate for the development of pan-enterovirus antivirals (Adv Biol, 2025).