Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTT4SY6)

• DTT Name: Hepatitis B virus Polymerase (HBV P)
• Synonyms: Protein P
• Gene Name: HBV P
• DTT Type: Successful target; [1]
• BioChemical Class: DNA-directed DNA polymerase
• UniProt ID: Q67889_HBV
• TTD ID: T71501
• Sequence:
  MPLSYQHFRKLLLLDDGTGPLEEELPRLADEGLNRRVAEDLNLGNLNVSIPWTHKVGNFT
  GLYSSTVPVFNPHWKTPSFPNIHLHQDIIKKCEQFVGPLTVNEKRRLQLIMPARFYPKVT
  KYLPLDKGIKPYYPEHLVNHYFQTRHYLHTLWKAGILYKRETTHSASFCGSPYSWEQDLQ
  HGAESIHQQSSGILSRPPVGSSLQSKHRKSRLGLQSQQGHLARRQQGRSWSIRAGFHPTA
  RRPFGVEPSGSGHTTNFASKSASCLHQSPVRKAAYPSVSTFEKHSSSGHAVELHNLPPNS
  ARSKSERPVFPCWWLQFRNSKPCSDYCLSLIVNLREDWGPCDDHGEHHIRIPRTPARVRG
  GVFLVDKNPHNTAESRLVVDFSQFSRGNYRVSWPKFAVPNLPSLTNLLSSNLSWLSLDVS
  AAFYHIPLHPAAMPHLLVGSSGLSRYVARLSSNSRYFNNQHGTMQNLHDSCSRNLYVSLL
  LLYQTFGRKLHLYSHPIILGFRKIPMAVGLSPFLLAQFTSAICSVVRRAFPHCLGFSYMD
  DVVLGAKSVQHRESLYTAVTNFLLSLGIHLNPNKTKRWGYSLNFMGYIIGSWGTLPQDHI
  VQKIKHCFRKLPVNRPIDWKVWQRIVGLLGFAAPFTQCGYPALMPLYACIQAKQAFTFSP
  TYKAFLSKQYMNLYPVARQRPGLCQVFADATPTGWGLA
• Function: Multifunctional enzyme that converts the viral RNA genome into dsDNA in viral cytoplasmic capsids. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3'- to 5'-endonucleasic mode. Neo-synthesized pregenomic RNA (pgRNA) are encapsidated together with the P protein, and reverse-transcribed inside the nucleocapsid. Initiation of reverse-transcription occurs first by binding the epsilon loop on the pgRNA genome, and is initiated by protein priming, thereby the 5'-end of (-)DNA is covalently linked to P protein. Partial (+)DNA is synthesized from the (-)DNA template and generates the relaxed circular DNA (RC-DNA) genome. After budding and infection, the RC-DNA migrates in the nucleus, and is converted into a plasmid-like covalently closed circular DNA (cccDNA). The activity of P protein does not seem to be necessary for cccDNA generation, and is presumably released from (+)DNA by host nuclear DNA repair machinery.

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Telbivudine	DMSWUGE	Hepatitis B virus infection	1E51.0	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ATI-2173	DMT5QYJ	Hepatitis B	1E51	Phase 2	[2]
NCO-48	DMUSPW5	Hepatitis B virus infection	1E51.0	Phase 1	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Valtorcitabine	DMXQCBU	Hepatitis virus infection	1E50-1E51	Discontinued in Phase 2	[4]

References

• [1] Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success. Best Pract Res Clin Gastroenterol. 2008;22(6):1081-92.
• [2] ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e00836-20.
• [3] Safety, Tolerability and Pharmacokinetics of NCO-48 Fumarate in Healthy Subjects
• [4] Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J Pharm Sci. 2008 Mar;97(3):1109-34.