Hepatitis E virus non-structural polyprotein (ORF1) (HEV ORF1)

The Hepatitis E virus (HEV) replication machinery is primarily composed of the non-structural polyprotein encoded by Open Reading Frame 1 (ORF1) (UniProt: P0C1Z1). This polyprotein is a multi-domain enzyme complex essential for viral genome replication and transcription, containing methyltransferase (MeT), papain-like cysteine protease (PCP), helicase (Hel), and RNA-dependent RNA polymerase (RdRp) domains (PubMed: 32824397). These domains coordinate the capping of viral RNA, the unwinding of double-stranded RNA intermediates, and the synthesis of new positive-sense RNA genomes (NCBI: NBK537279). As the central engine of the HEV life cycle, the ORF1 polyprotein is the primary target for therapeutic intervention, particularly in chronic cases affecting immunocompromised individuals (PubMed: 30103439). While current treatments like ribavirin and interferon-alpha are used, they are not specific to HEV and are associated with significant side effects and resistance mutations, such as the G1634R substitution in the RdRp domain (PubMed: 27535008). Consequently, the development of direct-acting antivirals (DAAs) targeting the specific enzymatic activities of the HEV replication machinery remains a critical area of clinical research.

Other names

ORF1 polyproteinHEV replicaseHEV non-structural proteinHepatitis E virus replication complex

Inhibition of RNA-dependent RNA polymerase (RdRp) activity, induction of lethal mutagenesis, and inhibition of viral RNA capping and helicase functions.