HBx-Derived Constrained Peptides Inhibit the Secretion of Hepatitis B Virus Antigens

Hepatitis B virus (HBV) infection is the primary cause of cirrhosis and liver cancer. Protein-protein interactions (PPIs) between HBV x protein (HBx) and its host targets, including Bcl-2, are important for cell death and viral replication. No modulators targeting these PPIs have been reported yet. Here, we developed HBx-derived constrained peptides generated by a facile macrocyclization method by joining two methionine side chains of unprotected peptides with chemoselective alkylating linkers. The resulting constrained peptides with improved cell permeability and binding affinity were effective anti-HBV modulators by blocking the secretion of viral antigens. This study clearly demonstrated HBx as a potentially important PPI target and the potential application of this efficient peptide macrocyclization strategy for targeting key PPIs.