Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Hepatitis C virus Serine protease NS4A (HCV NS4A)
• Synonyms: HCV p8
• Gene Name: HCV NS4A
• DTT Type: Clinical trial target; [1]
• UniProt ID: POLG_HCV1
• TTD ID: T34997
• Sequence:
  STWVLVGGVLAALAAYCLSTGCVVIVGRVVLSGKPAIIPDREVLYREFDEMEECSQHLPY
  IEQGMMLAEQFKQKALGLLQTASRQAEVIAPAVQTNWQKLETFWAKHMWNFISGIQYLAG
  LSTLPGNPAIASLMAFTAAVTSPLTTSQTLLFNILGGWVAAQLAAPGAATAFVGAGLAGA
  AIGSVGLGKVLIDILAGYGAGVAGALVAFKIMSGEVPSTEDLVNLLPAILSPGALVVGVV
  CAAILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTAILSSLTVTQLL
  RRLHQWISSECTTPC
• 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

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TG-2349	DMZ571Y	Hepatitis C virus infection	1E51.1	Phase 2	[1]
MK-6325	DMV8BI4	Hepatitis C virus infection	1E51.1	Phase 1	[2]
PHX-1766	DMERJ6V	Hepatitis C virus infection	1E51.1	Phase 1	[3]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GS-9132	DMXB4T9	Hepatitis C virus infection	1E51.1	Discontinued in Phase 1/2	[1]
IDX-320	DMAYLS3	Hepatitis C virus infection	1E51.1	Discontinued in Phase 1/2	[4]

References

• [1] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [2] Synthesis of bis-macrocyclic HCV protease inhibitor MK-6325 via intramolecular sp -sp Suzuki-Miyaura coupling and ring closing metathesis. Org Lett. 2015 Mar 20;17(6):1533-6.
• [3] Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design. Antivir Ther. 2012;17(2):365-75.
• [4] Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.Antivir Ther.2012;17(4):633-42.