Peptide aptamer-mediated inhibition of target proteins by sequestration into aggresomes.
Peptide aptamers (PAs) can be employed to block the intracellular function of target proteins. Little is known about the mechanism of PA-mediated protein inhibition. Here, we generated PAs that specifically bound to the duck hepatitis B virus (HBV) core protein. Among them, PA34 strongly blocked duck HBV replication by inhibiting viral capsid formation. We found that PA34 led to a dramatic intracellular redistribution of its target protein into perinuclear inclusion bodies, which exhibit the typical characteristics of aggresomes. As a result, the core protein is efficiently removed from the viral life cycle. Corresponding findings were obtained for bioactive PAs that bind to the HBV core protein or to the human papillomavirus-16 (HPV16) E6 protein, respectively. The observation that PAs induce the specific sequestration of bound proteins into aggresomes defines a novel mechanism as to how this new class of intracellular inhibitors blocks the function of their target proteins.
Tomai
Evangelia
E
Molecular Therapy of Virus-Associated Cancers Group (F065), German Cancer Research Center, D-69120 Heidelberg, Germany.
Butz
Karin
K
Molecular Therapy of Virus-Associated Cancers Group (F065), German Cancer Research Center, D-69120 Heidelberg, Germany.
Lohrey
Claudia
C
Molecular Therapy of Virus-Associated Cancers Group (F065), German Cancer Research Center, D-69120 Heidelberg, Germany.
von Weizsäcker
Fritz
F
Medizinische Universitätsklinik II, D-79106 Freiburg, Germany.
Zentgraf
Hanswalter
H
Electron Microcopy Group (F090), German Cancer Research Center, D-69120 Heidelberg, Germany.
Hoppe-Seyler
Felix
F
Molecular Therapy of Virus-Associated Cancers Group (F065), German Cancer Research Center, D-69120 Heidelberg, Germany. Electronic address: hoppe-seyler@dkfz.de.
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D052158:Aptamers, Peptide / Q000737:chemistry*; D045744:Cell Line, Tumor; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000378:metabolism; D014746:Vimentin / Q000737:chemistry; D014779:Virus Replication
D000998:Antiviral Agents; D052158:Aptamers, Peptide; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D010455:Peptides; D011506:Proteins; D012097:Repressor Proteins; D014746:Vimentin