Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus.

Abstract

The X-protein of the hepatitis B virus (HBV) is essential for virus infection and contributes to the development of HBV-induced hepatocellular carcinoma (HCC), a disease which causes more than one million deaths each year. Here we describe the design of a novel PROTAC (proteolysis targeting chimeric molecule) capable of simultaneously inducing the degradation of the X-protein, and antagonizing its function. The PROTAC was constructed by fusing the N-terminal oligomerization and C-terminal instability domains of the X-protein to each other, and rendering them cell-permeable by the inclusion of a polyarginine cell-penetrating peptide (CPP). It was predicted that the oligomerization domain would bind the X-protein, and that the instability domain would cause the X-protein to be targeted for proteasomal degradation. Addition of the PROTAC to HepG2 liver cancer cells, engineered to express full-length and C-terminally truncated forms of the X-protein, resulted in the degradation of both forms of the X-protein. A cell-permeable stand-alone form of the oligomerization domain was taken up by HepG2 cells, and acted as a dominant-negative inhibitor, causing inhibition of X-protein-induced apoptosis. In summary, the PROTAC described here induces the degradation of the X-protein, and antagonizes its function, and warrants investigation in a preclinical study for its ability to prevent or treat HBV infection and/or the development of HCC.

• Authors: Kristopher Montrose, Geoffrey W Krissansen
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 453 Issue 4 Pg. 735-40 (Oct 31 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 25305486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Oligopeptides
• Trans-Activators
• Viral Regulatory and Accessory Proteins
• hepatitis B virus X protein

Topics

• Amino Acid Sequence
• Apoptosis
• Drug Design
• Hep G2 Cells
• Humans
• Molecular Sequence Data
• Neoplasms, Experimental (metabolism, pathology)
• Oligopeptides (chemical synthesis, pharmacology)
• Precancerous Conditions (metabolism)
• Trans-Activators (antagonists & inhibitors, metabolism)
• Viral Regulatory and Accessory Proteins