Target Information
Target General Information | Top | |||||
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Target ID |
T40555
(Former ID: TTDC00322)
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Target Name |
Hepatitis C virus Non-structural 5A (HCV NS5A)
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Synonyms |
HCV NS5A
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Gene Name |
HCV NS5A
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Hepatitis virus infection [ICD-11: 1E50-1E51] | |||||
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).
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BioChemical Class |
Hepacivirus polyprotein
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UniProt ID | ||||||
Sequence |
SGSWLRDIWDWICEVLSDFKTWLKAKLMPQLPGIPFVSCQRGYKGVWRVDGIMHTRCHCG
AEITGHVKNGTMRIVGPRTCRNMWSGTFPINAYTTGPCTPLPAPNYTFALWRVSAEEYVE IRQVGDFHYVTGMTTDNLKCPCQVPSPEFFTELDGVRLHRFAPPCKPLLREEVSFRVGLH EYPVGSQLPCEPEPDVAVLTSMLTDPSHITAEAAGRRLARGSPPSVASSSASQLSAPSLK ATCTANHDSPDAELIEANLLWRQEMGGNITRVESENKVVILDSFDPLVAEEDEREISVPA EILRKSRRFAQALPVWARPDYNPPLVETWKKPDYEPPVVHGCPLPPPKSPPVPPPRKKRT VVLTESTLSTALAELATRSFGSSSTSGITGDNTTTSSEPAPSGCPPDSDAESYSSMPPLE GEPGDPDLSDGSWSTVSSEANAEDVVCC Click to Show/Hide
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Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 3 Approved Drugs | + | ||||
1 | Daclatasvir | Drug Info | Approved | Hepatitis C virus infection | [2] | |
2 | Glecaprevir; pibrentasvir | Drug Info | Approved | Hepatitis C virus infection | [1] | |
3 | Sofosbuvir + velpatasvir + voxilaprevir | Drug Info | Approved | Hepatitis C virus infection | [1] | |
Clinical Trial Drug(s) | [+] 13 Clinical Trial Drugs | + | ||||
1 | ABT-267 | Drug Info | Phase 3 | Hepatitis C virus infection | [3] | |
2 | MK-8742 | Drug Info | Phase 3 | Hepatitis C virus infection | [4] | |
3 | Ravidasvir | Drug Info | Phase 2/3 | Hepatitis C | [5] | |
4 | ACH-3102 | Drug Info | Phase 2 | Hepatitis C virus infection | [6] | |
5 | GS-5885 | Drug Info | Phase 2 | Hepatitis C virus infection | [7] | |
6 | PPI-668 | Drug Info | Phase 2 | Hepatitis C virus infection | [8] | |
7 | AZD-2836 | Drug Info | Phase 1/2 | Hepatitis C virus infection | [9] | |
8 | AV4025 | Drug Info | Phase 1 | Hepatitis C virus infection | [10] | |
9 | AZD-7295 | Drug Info | Phase 1 | Hepatitis C virus infection | [11] | |
10 | BMS-824383 | Drug Info | Phase 1 | Hepatitis C virus infection | [12] | |
11 | EDP-239 | Drug Info | Phase 1 | Hepatitis C virus infection | [13] | |
12 | MB-110 | Drug Info | Phase 1 | Hepatitis C virus infection | [14] | |
13 | PPI-461 | Drug Info | Phase 1 | Hepatitis C virus infection | [15] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | ACH-2928 | Drug Info | Discontinued in Phase 1 | Hepatitis C virus infection | [16] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 6 Inhibitor drugs | + | ||||
1 | Daclatasvir | Drug Info | [12] | |||
2 | Glecaprevir; pibrentasvir | Drug Info | [1] | |||
3 | Sofosbuvir + velpatasvir + voxilaprevir | Drug Info | [1] | |||
4 | Ravidasvir | Drug Info | [19] | |||
5 | BMS-824383 | Drug Info | [12] | |||
6 | MB-110 | Drug Info | [24] | |||
Modulator | [+] 11 Modulator drugs | + | ||||
1 | ABT-267 | Drug Info | [17] | |||
2 | MK-8742 | Drug Info | [18] | |||
3 | ACH-3102 | Drug Info | [20] | |||
4 | GS-5885 | Drug Info | [21] | |||
5 | PPI-668 | Drug Info | [20] | |||
6 | AZD-2836 | Drug Info | [22] | |||
7 | AV4025 | Drug Info | [23] | |||
8 | AZD-7295 | Drug Info | [22] | |||
9 | EDP-239 | Drug Info | [20] | |||
10 | PPI-461 | Drug Info | [20] | |||
11 | ACH-2928 | Drug Info | [25] |
Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
References | Top | |||||
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REF 1 | 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85. | |||||
REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. | |||||
REF 3 | ClinicalTrials.gov (NCT01773070) A Follow up Study Designed to Obtain Long Term Data on Subjects Who Either Achieved a Sustained Virologic Response or or Did Not Achieve a Sustained Virologic Response in an Abbott Sponsored Hepatitis C Study. U.S. National Institutes of Health. | |||||
REF 4 | ClinicalTrials.gov (NCT02204475) Grazoprevir (MK-5172)/Elbasvir (MK-8742) Versus Boceprevir/Pegylated Interferon/Ribavarin for Chronic Hepatitis C Infection (MK-5172-066). U.S. National Institutes ofHealth. | |||||
REF 5 | ClinicalTrials.gov (NCT03362814) Efficacy and Safety of Ravidasvir in Combination With Danoprevir/r and Ribavirin(RBV) in Treatment-naive, Non-cirrhotic, Chronic Hepatitis C Virus Genotype1 Infected Subjects.. U.S. National Institutes of Health. | |||||
REF 6 | ClinicalTrials.gov (NCT01849562) Safety, Tolerability and Efficacy of 12-weeks of Sovaprevir, ACH-3102 and Ribavirin in Treatment-naive GT-1 HCV Subjects. U.S. National Institutes of Health. | |||||
REF 7 | ClinicalTrials.gov (NCT01435226) GS-5885, GS-9451, Tegobuvir and Ribovirin in Treatment-Experienced Subjects With Chronic Genotype 1a Or 1b Hepatitis C Virus (HCV) Infection. U.S. National Institutesof Health. | |||||
REF 8 | ClinicalTrials.gov (NCT01859962) Study of PPI-668, BI 207127 and Faldaprevir, With and Without Ribavirin, in the Treatment of Chronic Hepatitis C. U.S. National Institutes of Health. | |||||
REF 9 | ClinicalTrials.gov (NCT00522808) A Study of the PK, Safety and Antiviral Activity of A-831 in HCV Carriers. U.S. National Institutes of Health. | |||||
REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800039148) | |||||
REF 11 | ClinicalTrials.gov (NCT00906256) Clinical Pharmacology Study of AZD7295 in Healthy Subjects. U.S. National Institutes of Health. | |||||
REF 12 | 2011 Pipeline of Bristol-Myers Squibb. | |||||
REF 13 | ClinicalTrials.gov (NCT01856426) Proof of Concept Study for Safety and Efficacy of EDP239 in Hepatitis C Subjects. U.S. National Institutes of Health. | |||||
REF 14 | ClinicalTrials.gov (NCT02617615) A Trial to Evaluate Safety, Tolerability, PK and Antiviral Activity of MB-110 in Hepatitis C Virus Infected Patients. U.S. National Institutes of Health. | |||||
REF 15 | 2011 Pipeline of Presidio. | |||||
REF 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032623) | |||||
REF 17 | Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. J Med Chem. 2014 Mar 13;57(5):2047-57. | |||||
REF 18 | Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem. 2013 Dec;8(12):1930-40. | |||||
REF 19 | Clinical pipeline report, company report or official report of Presidio Pharmaceuticals. | |||||
REF 20 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
REF 21 | 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. | |||||
REF 22 | TARGETING THE NS5A PROTEIN OF HCV: AN EMERGING OPTION. Drugs Future. 2011 September; 36(9): 691-711. | |||||
REF 23 | Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025). J Med Chem. 2014 Sep 25;57(18):7716-30. | |||||
REF 24 | Clinical pipeline report, company report or official report of Microbio. | |||||
REF 25 | Company report (Achillion) |
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