Programmable Nanobody-Targeting Chimeras Enable Intracellular Viral Protein Degradation
Max Yu-Chen Pan1,2, Ting-Hui Lee1, Tzu-Ning Peng1
1Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 17, 2026
Summary
A new Nanobody-Targeting Chimera (Nab-TAC) platform efficiently clears hepatitis B virus (HBV) surface antigen (HBsAg) inside cells. This targeted protein degradation approach shows promise for a functional cure of chronic HBV infection.
Area of Science:
- Biotechnology
- Virology
- Drug Discovery
Background:
- Chronic hepatitis B virus (HBV) infection is a global health issue.
- Current therapies struggle to eliminate HBsAg, crucial for viral persistence.
- HBsAg clearance is key to overcoming immune tolerance in chronic HBV.
Purpose of the Study:
- To develop a novel platform for intracellular clearance of HBV antigens.
- To engineer a targeted protein degradation system for HBsAg removal.
- To assess the therapeutic potential of this platform for chronic HBV.
Main Methods:
- Developed a Nanobody-Targeting Chimera (Nab-TAC) platform using nanobodies.
- Utilized a split-luciferase screening platform to identify degradation modules.
- Engineered Nab-TAC constructs to target HBsAg within hepatocytes.
- Tested lead construct E3-FCGR3B in an HBV mouse model.
Main Results:
- Nab-TAC constructs efficiently degraded HBsAg in hepatocytes.
- The lead construct E3-FCGR3B achieved significant intrahepatic antigen clearance.
- Circulating HBsAg levels were markedly reduced in the HBV mouse model.
- Demonstrated modularity and versatility of the Nab-TAC platform.
Conclusions:
- Nab-TAC is a viable platform for targeted antiviral protein degradation.
- This approach offers a potential strategy for a functional cure of chronic HBV.
- Further development of Nab-TAC could lead to new HBV therapies.
Related Concept Videos
01:19Inhibitors of Virion Maturation and Assembly
As part of their replication cycle, certain viruses synthesize long precursor proteins called polyproteins within infected host cells. In human immunodeficiency virus (HIV), two major polyproteins are produced: Gag and Gag-Pol. The Gag polyprotein supplies the structural components of the virus, while Gag-Pol includes essential viral enzymes such as reverse transcriptase, integrase, and protease. After synthesis, these polyproteins move to the host cell membrane, where they assemble into an...
01:30Inhibitors of Viral Protein Synthesis
Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...