Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Virus RNA-dependent RNA polymerase (Viru RdRP)
• Synonyms: HCV NS5B; HCV p68
• Gene Name: Viru RdRP
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: POLG_HCVJA
• TTD ID: T51843
• EC Number: EC 2.7.7.48
• Sequence:
  SMSYTWTGALITPCAAEESKLPINPLSNSLLRHHSMVYSTTSRSASLRQKKVTFDRLQVL
  DDHYRDVLKEMKAKASTVKARLLSIEEACKLTPPHSAKSKFGYGAKDVRSLSSRAVNHIR
  SVWEDLLEDTETPIDTTIMAKNEVFCVQPEKGGRKPARLIVFPDLGVRVCEKMALYDVVS
  TLPQAVMGPSYGFQYSPGQRVEFLVNTWKSKKCPMGFSYDTRCFDSTVTENDIRTEESIY
  QCCDLAPEARQAIRSLTERLYVGGPLTNSKGQNCGYRRCRASGVLTTSCGNTLTCYLKAT
  AACRAAKLQDCTMLVNGDDLVVICESAGTQEDAAALRAFTEAMTRYSAPPGDPPQPEYDL
  ELITSCSSNVSVAHDASGKRVYYLTRDPTTPLARAAWETVRHTPVNSWLGNIIMYAPTLW
  ARMILMTHFFSILLAQEQLEKALDCQIYGACYSIEPLDLPQIIERLHGLSAFSLHSYSPG
  EINRVASCLRKLGVPPLRVWRHRARSVRAKLLSQGGRAATCGKYLFNWAVKTKLKLTPIP
  AASQLDLSGWFVAGYNGGDIYHSLSRARPRWFMLCLLLLSVGVGIYLLPNR
• Function: Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity).

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AT-527	DMARIQK	Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[2]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FdG	DMYXA7E	Discovery agent	N.A.	Investigative	[1]
Guanosine-5'-Triphosphate	DMV2OJX	Discovery agent	N.A.	Investigative	[3]
Pyrimidinyl acylthiourea	DM7T2VQ	Discovery agent	N.A.	Investigative	[1]
Pyrophosphate 2-	DMZQ75M	Discovery agent	N.A.	Investigative	[4]
T-1105	DMGPQ0Y	Discovery agent	N.A.	Investigative	[1]
T-1106	DMPA2E9	Virus infection	1A24-1D9Z	Investigative	[1]
Thiadiazolo[2,3-a]pyrimidine	DMKRG2C	Discovery agent	N.A.	Investigative	[1]

References

• [1] Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106. Antimicrob Agents Chemother. 2009 Jan;53(1):202-9.
• [2] AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19. Antimicrob Agents Chemother. 2021 Mar 18;65(4):e02479-20.
• [3] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [4] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.