Antivirals interacting with hepatitis B virus core protein and core mutations may misdirect capsid assembly in a similar fashion.
Recently, heteroarylpyrimidines (HAP) have been identified as potent inhibitors of capsid maturation. Here we discuss the HAP mode of action comparing the aggregation phenotype of wild-type and mutant core proteins with the respective phenotype imposed by HAP or other agents interacting with core protein. Pertinent tests include core fusion protein-mediated transactivation in a two-hybrid system and capsid formation. The finding that transactivation appeared to be unaffected by HAP, or by mutations preventing assembly, is surprising and raises the question for the structure of the interacting hybrid core proteins: Are they monomers, dimers or even oligomers? A direct activity of core fusion monomers is not excluded but considered to be highly unlikely due to rapid homodimerisation. A role of core fusion dimers in transactivation would indicate distinct interactions with a differential sensitivity to HAP. Regarding significance of data gained in two-hybrid systems, caution is necessary, since the site of transactivation is the nucleus, whereas the real site of the core protein interactions during replication is the cytoplasm. Apparently, HAP leave the monomer-monomer interface of HBV core protein unaffected but prevent capsid maturation by interacting with a region known to be crucial for dimer multimerisation and formation of stable capsids. It is suggested to use antivirals as tools for the elucidation of early steps in genome replication and capsid assembly. A frame for this could be the hypothesis that the virus uses soluble core protein, namely intracellular maturation intermediates of HbeAg for a core targeted self-restriction of replication.
Hacker
Hans Jörg
HJ
Department of Virus-Host Interactions (F0600), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. h.hacker@dkfz.de
Deres
Karl
K
Mildenberger
Maria
M
Schröder
Claus H
CH
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000187:drug effects*; D005544:Forecasting; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009154:Mutation; D020798:Two-Hybrid System Techniques; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*; D019065:Virus Assembly / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D006512:Hepatitis B Core Antigens; D014758:Viral Core Proteins