Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTCJ2X8)

• DTT Name: Hepatitis C virus Non-structural 5A (HCV NS5A)
• Synonyms: HCV NS5A
• Gene Name: HCV NS5A
• DTT Type: Successful target; [1]
• BioChemical Class: Hepacivirus polyprotein
• UniProt ID: POLG_HCV1
• TTD ID: T40555
• Sequence:
  SGSWLRDIWDWICEVLSDFKTWLKAKLMPQLPGIPFVSCQRGYKGVWRVDGIMHTRCHCG
  AEITGHVKNGTMRIVGPRTCRNMWSGTFPINAYTTGPCTPLPAPNYTFALWRVSAEEYVE
  IRQVGDFHYVTGMTTDNLKCPCQVPSPEFFTELDGVRLHRFAPPCKPLLREEVSFRVGLH
  EYPVGSQLPCEPEPDVAVLTSMLTDPSHITAEAAGRRLARGSPPSVASSSASQLSAPSLK
  ATCTANHDSPDAELIEANLLWRQEMGGNITRVESENKVVILDSFDPLVAEEDEREISVPA
  EILRKSRRFAQALPVWARPDYNPPLVETWKKPDYEPPVVHGCPLPPPKSPPVPPPRKKRT
  VVLTESTLSTALAELATRSFGSSSTSGITGDNTTTSSEPAPSGCPPDSDAESYSSMPPLE
  GEPGDPDLSDGSWSTVSSEANAEDVVCC
• 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

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Daclatasvir	DMSFK9V	Hepatitis C virus infection	1E51.1	Approved	[2]
Glecaprevir; pibrentasvir	DMF6Z5T	Hepatitis C virus infection	1E51.1	Approved	[1]

13 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-267	DMNQ869	Hepatitis C virus infection	1E51.1	Phase 3	[3]
MK-8742	DMK301H	Hepatitis C virus infection	1E51.1	Phase 3	[4]
Ravidasvir	DM1LFUN	Hepatitis C	1E51	Phase 2/3	[5]
ACH-3102	DM0RPY5	Hepatitis C virus infection	1E51.1	Phase 2	[6]
GS-5885	DMSL3DX	Hepatitis C virus infection	1E51.1	Phase 2	[7]
PPI-668	DM4EHVB	Hepatitis C virus infection	1E51.1	Phase 2	[6]
AZD-2836	DMT2FAP	Hepatitis C virus infection	1E51.1	Phase 1/2	[8]
AV4025	DME630T	Hepatitis C virus infection	1E51.1	Phase 1	[9]
AZD-7295	DM84WXZ	Hepatitis C virus infection	1E51.1	Phase 1	[8]
BMS-824383	DMPQ5XC	Hepatitis C virus infection	1E51.1	Phase 1	[2]
EDP-239	DMXW07J	Hepatitis C virus infection	1E51.1	Phase 1	[6]
MB-110	DMPE0KD	Hepatitis C virus infection	1E51.1	Phase 1	[10]
PPI-461	DMTOXLG	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
ACH-2928	DMSPW3N	Hepatitis C virus infection	1E51.1	Discontinued in Phase 1	[11]

References

• [1] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [2] 2011 Pipeline of Bristol-Myers Squibb.
• [3] Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. J Med Chem. 2014 Mar 13;57(5):2047-57.
• [4] Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem. 2013 Dec;8(12):1930-40.
• [5] Clinical pipeline report, company report or official report of Presidio Pharmaceuticals.
• [6] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [7] Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014 Mar 13;57(5):2033-46.
• [8] TARGETING THE NS5A PROTEIN OF HCV: AN EMERGING OPTION. Drugs Future. 2011 September; 36(9): 691-711.
• [9] Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025). J Med Chem. 2014 Sep 25;57(18):7716-30.
• [10] Clinical pipeline report, company report or official report of Microbio.
• [11] Company report (Achillion)