Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTWXB3E)

• DTT Name: Hepatitis C virus NS3 helicase (HCV NS3)
• Synonyms: HCV Hepacivirin; HCV NS3P; HCV p70
• Gene Name: HCV NS3
• DTT Type: Successful target; [1]
• Related Disease: Hepatitis virus infection [ICD-11: 1E50-1E51]
• BioChemical Class: Peptidase
• UniProt ID: POLG_HCV1
• TTD ID: T40492
• EC Number: EC 3.4.21.98
• Sequence:
  APITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTAAQTFLATCINGVCWTVYHGAG
  TRTIASPKGPVIQMYTNVDQDLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRG
  DSRGSLLSPRPISYLKGSSGGPLLCPAGHAVGIFRAAVCTRGVAKAVDFIPVENLETTMR
  SPVFTDNSSPPVVPQSFQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGA
  YMSKAHGIDPNIRTGVRTITTGSPITYSTYGKFLADGGCSGGAYDIIICDECHSTDATSI
  LGIGTVLDQAETAGARLVVLATATPPGSVTVPHPNIEEVALSTTGEIPFYGKAIPLEVIK
  GGRHLIFCHSKKKCDELAAKLVALGINAVAYYRGLDVSVIPTSGDVVVVATDALMTGYTG
  DFDSVIDCNTCVTQTVDFSLDPTFTIETITLPQDAVSRTQRRGRTGRGKPGIYRFVAPGE
  RPSGMFDSSVLCECYDAGCAWYELTPAETTVRLRAYMNTPGLPVCQDHLEFWEGVFTGLT
  HIDAHFLSQTKQSGENLPYLVAYQATVCARAQAPPPSWDQMWKCLIRLKPTLHGPTPLLY
  RLGAVQNEITLTHPVTKYIMTCMSADLEVVT
• 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 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ombitasvir + paritaprevir + ritonavir	DML9TI0	Hepatitis C virus infection	1E51.1	Approved	[1]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BILN-2061	DM2J36F	Hepatitis virus infection	1E50-1E51	Phase 2	[2]
GS-9451	DMF910Q	Chronic HCV-1 infection	1E51.1	Phase 2	[3]
GS-9857	DMYU6P5	Hepatitis C virus infection	1E51.1	Phase 2	[4]
ACH-2684	DMW6X0O	Hepatitis C virus infection	1E51.1	Phase 1	[5]
VBY-376	DMU263R	Hepatitis C virus infection	1E51.1	Phase 1	[6]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-605339	DMY7ZRA	Hepatitis C virus infection	1E51.1	Terminated	[7]

32 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2,4,6-Trihydroxy-3-nitro-N-tridecyl-benzamide	DMTVL9N	Discovery agent	N.A.	Investigative	[8]
Ac-Glu-Cha-Cys	DM6T09B	Discovery agent	N.A.	Investigative	[9]
AcAsp-D-Gla-Leu-Ile-Cha-Cys	DMT74F5	Discovery agent	N.A.	Investigative	[8]
AcAsp-D-Glu-Leu-Glu-Cha-Cys	DMDC71B	Discovery agent	N.A.	Investigative	[9]
AcAsp-Gla-Leu-Ile-Cha-Cys	DMXQATR	Discovery agent	N.A.	Investigative	[9]
AcAsp-Glu-Cha-Val-Prb-Cpg	DMHZ5W3	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Cha-Val-Prb-Cys	DMDH5EJ	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Dif-Glu-Cha-Cys	DMEB8UA	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Dif-Glu-Cha-Fab	DMPQ8Z9	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Dif-Ile-Cha-Cys	DM6IP17	Discovery agent	N.A.	Investigative	[9]
AcAsp-Glu-Dif-Ile-Cha-Cys-Iqc-Nle-Thr-TyrNH2	DM3W68X	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Dif-Ile-Cha-Cys-Pro-Cha-Asp-ValNH2	DMCIJ6Q	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Dif-Ile-Cha-Cys-Pro-Nle-Asp-ValNH2	DMA7ZSY	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Dif-Lys-Cha-Cys	DM6PZ45	Discovery agent	N.A.	Investigative	[9]
AcAsp-Glu-Leu-Glu-Cha-Cys	DMKDZH4	Discovery agent	N.A.	Investigative	[9]
AcAsp-Glu-Met-Glu-Cha-Cys	DMOMI91	Discovery agent	N.A.	Investigative	[9]
AcAsp-Glu-Met-Glu-Glu-Cys	DMIVFZE	Discovery agent	N.A.	Investigative	[8]
AcAsp-Glu-Met-Glu-Nal-Cyse	DMBGHX7	Discovery agent	N.A.	Investigative	[9]
AcDif-Glu-Cha-Cys	DMKDEWH	Discovery agent	N.A.	Investigative	[9]
AcDif-Ile-Cha-Cys	DM1DWCP	Discovery agent	N.A.	Investigative	[9]
AcGlu-Asp-Val-Val-Leu-Cys-Iqc-Nle-Thr-TyrNH2	DMAI43O	Discovery agent	N.A.	Investigative	[8]
AcGlu-Dif-Glu-Cha-Cys	DM0BV9I	Discovery agent	N.A.	Investigative	[9]
AcGlu-Dif-Ile-Cha-Cys	DMK6HGI	Discovery agent	N.A.	Investigative	[9]
Asp-D-Glu-Leu-Glu-Cha-Cys	DMEW37R	Discovery agent	N.A.	Investigative	[9]
Azapeptide	DM3BXUJ	Discovery agent	N.A.	Investigative	[10]
Boc-Ile-Leu-L-(difluoro)aminobutyric aid	DMG35MJ	Discovery agent	N.A.	Investigative	[8]
Cbz-Ile-Leu-L-(difluoro)aminobutyric acid	DMI53WR	Discovery agent	N.A.	Investigative	[8]
GNF-PF-3464	DMWAKHD	Discovery agent	N.A.	Investigative	[11]
PATULIN	DM0RV9C	Discovery agent	N.A.	Investigative	[8]
Ribavirin-TP	DM09NGV	Discovery agent	N.A.	Investigative	[12]
SCH-68631	DM4CI57	Discovery agent	N.A.	Investigative	[8]
SE RNA	DMYSKI0	Human immunodeficiency virus infection	1C62	Investigative	[13]

References

• [1] HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy
• [2] Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology. 2005 Apr;41(4):832-5.
• [3] Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients. Antimicrob Agents Chemother. 2012 October; 56(10): 5289-5295.
• [4] Clinical pipeline report, company report or official report of Gilead.
• [5] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [6] Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel. Viruses. 2010 August; 2(8): 1752-1765.
• [7] Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis C virus infection. J Med Chem.2014 Mar 13;57(5):1708-29.
• [8] Control of hepatitis C: a medicinal chemistry perspective. J Med Chem. 2005 Jan 13;48(1):1-20.
• [9] Inhibition of hepatitis C virus NS3 protease activity by product-based peptides is dependent on helicase domain. Bioorg Med Chem Lett. 2001 Jan 22;11(2):203-6.
• [10] Azapeptides as inhibitors of the hepatitis C virus NS3 serine protease. Bioorg Med Chem Lett. 2002 Apr 8;12(7):1005-8.
• [11] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [12] ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy. Acta Biochim Pol. 2000;47(1):173-80.
• [13] Therapeutic applications of aptamers. Expert Opin Investig Drugs. 2008 Jan;17(1):43-60.