Hepatitis B virus Direct Repeat 2 region (HBV DR2) (HBV DR2)

The Hepatitis B virus (HBV) Direct Repeat 2 (DR2) region is a highly conserved 12-nucleotide sequence (5'-TTCACCTCTGCC-3') located within the viral pregenomic RNA (pgRNA) and the minus-strand DNA [1, 2]. It serves as a critical cis-acting element required for the initiation of plus-strand DNA synthesis during the viral replication cycle [2, 16]. Specifically, after the synthesis of minus-strand DNA, an RNA primer containing the DR1 sequence translocates to the DR2 site on the minus-strand template [1, 7]. This "primer translocation" is essential for the formation of relaxed circular DNA (rcDNA), which is the mature genomic form packaged into infectious virions and subsequently converted into the persistent covalently closed circular DNA (cccDNA) reservoir in the host nucleus [2, 16]. As a therapeutic target, the DR2 region is primarily addressed through RNA-targeted strategies such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), which aim to degrade the pgRNA and inhibit the production of viral antigens like HBsAg [4, 5]. Drugs like ARC-520 and JNJ-3989 have been developed to target sequences encompassing or adjacent to the DR2 region to suppress viral load [5]. Additionally, the unique mechanism of primer translocation to the DR2 site is considered an attractive target for novel small-molecule inhibitors, as disrupting this step can prevent the formation of infectious rcDNA [2, 17]. Current nucleos(t)ide analogs (NRTIs), such as entecavir and tenofovir, indirectly affect the processes involving DR2 by inhibiting the viral polymerase that utilizes the DR2-primed template for DNA elongation [12, 13].

Other names

Direct Repeat 2DR2 motifDR2 sequenceHBV DR2 RNA element3'-proximal DR2 motif

RNA interference (siRNA/ASO), inhibition of primer translocation, and inhibition of viral polymerase (reverse transcriptase).