Target Information
Target General Information | Top | |||||
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Target ID |
T40492
(Former ID: TTDR00103)
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Target Name |
Hepatitis C virus NS3 helicase (HCV NS3)
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Synonyms |
HCV Hepacivirin; HCV NS3P; HCV p70
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Gene Name |
HCV NS3
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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 |
Peptidase
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UniProt ID | ||||||
EC Number |
EC 3.4.21.98
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Sequence |
APITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTAAQTFLATCINGVCWTVYHGAG
TRTIASPKGPVIQMYTNVDQDLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRG DSRGSLLSPRPISYLKGSSGGPLLCPAGHAVGIFRAAVCTRGVAKAVDFIPVENLETTMR SPVFTDNSSPPVVPQSFQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGA YMSKAHGIDPNIRTGVRTITTGSPITYSTYGKFLADGGCSGGAYDIIICDECHSTDATSI LGIGTVLDQAETAGARLVVLATATPPGSVTVPHPNIEEVALSTTGEIPFYGKAIPLEVIK GGRHLIFCHSKKKCDELAAKLVALGINAVAYYRGLDVSVIPTSGDVVVVATDALMTGYTG DFDSVIDCNTCVTQTVDFSLDPTFTIETITLPQDAVSRTQRRGRTGRGKPGIYRFVAPGE RPSGMFDSSVLCECYDAGCAWYELTPAETTVRLRAYMNTPGLPVCQDHLEFWEGVFTGLT HIDAHFLSQTKQSGENLPYLVAYQATVCARAQAPPPSWDQMWKCLIRLKPTLHGPTPLLY RLGAVQNEITLTHPVTKYIMTCMSADLEVVT Click to Show/Hide
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Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Ombitasvir + paritaprevir + ritonavir | Drug Info | Approved | Hepatitis C virus infection | [2] | |
Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
1 | BILN-2061 | Drug Info | Phase 2 | Hepatitis virus infection | [3] | |
2 | GS-9451 | Drug Info | Phase 2 | Chronic HCV-1 infection | [4] | |
3 | GS-9857 | Drug Info | Phase 2 | Hepatitis C virus infection | [5] | |
4 | ACH-2684 | Drug Info | Phase 1 | Hepatitis C virus infection | [6] | |
5 | VBY-376 | Drug Info | Phase 1 | Hepatitis C virus infection | [7] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | BMS-605339 | Drug Info | Terminated | Hepatitis C virus infection | [8] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Modulator | [+] 3 Modulator drugs | + | ||||
1 | Ombitasvir + paritaprevir + ritonavir | Drug Info | [1] | |||
2 | GS-9451 | Drug Info | [10] | |||
3 | ACH-2684 | Drug Info | [12] | |||
Inhibitor | [+] 35 Inhibitor drugs | + | ||||
1 | BILN-2061 | Drug Info | [9] | |||
2 | GS-9857 | Drug Info | [11] | |||
3 | VBY-376 | Drug Info | [13] | |||
4 | BMS-605339 | Drug Info | [14] | |||
5 | 2,4,6-Trihydroxy-3-nitro-N-tridecyl-benzamide | Drug Info | [15] | |||
6 | Ac-Glu-Cha-Cys | Drug Info | [16] | |||
7 | AcAsp-D-Gla-Leu-Ile-Cha-Cys | Drug Info | [15] | |||
8 | AcAsp-D-Glu-Leu-Glu-Cha-Cys | Drug Info | [16] | |||
9 | AcAsp-Gla-Leu-Ile-Cha-Cys | Drug Info | [16] | |||
10 | AcAsp-Glu-Cha-Val-Prb-Cpg | Drug Info | [15] | |||
11 | AcAsp-Glu-Cha-Val-Prb-Cys | Drug Info | [15] | |||
12 | AcAsp-Glu-Dif-Glu-Cha-Cys | Drug Info | [15] | |||
13 | AcAsp-Glu-Dif-Glu-Cha-Fab | Drug Info | [15] | |||
14 | AcAsp-Glu-Dif-Ile-Cha-Cys | Drug Info | [16] | |||
15 | AcAsp-Glu-Dif-Ile-Cha-Cys-Iqc-Nle-Thr-TyrNH2 | Drug Info | [15] | |||
16 | AcAsp-Glu-Dif-Ile-Cha-Cys-Pro-Cha-Asp-ValNH2 | Drug Info | [15] | |||
17 | AcAsp-Glu-Dif-Ile-Cha-Cys-Pro-Nle-Asp-ValNH2 | Drug Info | [15] | |||
18 | AcAsp-Glu-Dif-Lys-Cha-Cys | Drug Info | [16] | |||
19 | AcAsp-Glu-Leu-Glu-Cha-Cys | Drug Info | [16] | |||
20 | AcAsp-Glu-Met-Glu-Cha-Cys | Drug Info | [16] | |||
21 | AcAsp-Glu-Met-Glu-Glu-Cys | Drug Info | [15] | |||
22 | AcAsp-Glu-Met-Glu-Nal-Cyse | Drug Info | [16] | |||
23 | AcDif-Glu-Cha-Cys | Drug Info | [16] | |||
24 | AcDif-Ile-Cha-Cys | Drug Info | [16] | |||
25 | AcGlu-Asp-Val-Val-Leu-Cys-Iqc-Nle-Thr-TyrNH2 | Drug Info | [15] | |||
26 | AcGlu-Dif-Glu-Cha-Cys | Drug Info | [16] | |||
27 | AcGlu-Dif-Ile-Cha-Cys | Drug Info | [16] | |||
28 | Asp-D-Glu-Leu-Glu-Cha-Cys | Drug Info | [16] | |||
29 | Azapeptide | Drug Info | [17] | |||
30 | Boc-Ile-Leu-L-(difluoro)aminobutyric aid | Drug Info | [15] | |||
31 | Cbz-Ile-Leu-L-(difluoro)aminobutyric acid | Drug Info | [15] | |||
32 | GNF-PF-3464 | Drug Info | [18] | |||
33 | PATULIN | Drug Info | [15] | |||
34 | Ribavirin-TP | Drug Info | [19] | |||
35 | SCH-68631 | Drug Info | [15] |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: Vaniprevir | Ligand Info | |||||
Structure Description | Crystal structure of NS3/4A protease variant R155K in complex with vaniprevir | PDB:3SU4 | ||||
Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | Yes | [21] |
PDB Sequence |
GSVVIVGRIN
999 LSGDTAYAQQ1009 TRGEEGCQET1019 SQTGRDKNQV1029 EGEVQIVSTA1039 TQTFLATSIN 1049 GVLWTVYHGA1059 GTRTIASPKG1069 PVTQMYTNVD1079 KDLVGWQAPQ1089 GSRSLTPCTC 1099 GSSDLYLVTR1109 HADVIPVRRR1119 GDSRGSLLSP1129 RPISYLKGSA1139 GGPLLCPAGH 1149 AVGIFKAAVS1159 TRGVAKAVDF1169 IPVESLETTM1179 RS
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GLN1041
3.562
THR1042
3.858
PHE1043
3.396
VAL1055
4.134
HIS1057
3.065
GLY1058
3.587
VAL1078
3.368
ASP1079
3.520
LYS1080
4.422
ASP1081
3.485
ARG1123
3.390
ILE1132
3.711
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Ligand Name: (1R,2S,5S)-3-{(2S)-2-(2,3-dihydro-1H-inden-2-yl)-2-[({(1S)-2,2-dimethyl-1-[(2-oxopiperidin-1-yl)methyl]propyl}carbamoyl)amino]acetyl}-6,6-dimethyl-N-{(1S)-1-[oxo(prop-2-en-1-ylamino)acetyl]butyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide | Ligand Info | |||||
Structure Description | HCV NS3 Protease Domain with ketoamide inhibitor | PDB:3KN2 | ||||
Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [22] |
PDB Sequence |
APITAYAQQT
10 RGLLGCIITS20 LTGRDKNQVE30 GEVQIVSTAT40 QTFLATCING50 VCWTVYHGAG 60 TRTIASPKGP70 VIQMYTNVDQ80 DLVGWPAPQG90 SRSLTPCTCG100 SSDLYLVTRH 110 ADVIPVRRRG120 DSRGSLLSPR130 PISYLKGSSG140 GPLLCPAGHA150 VGLFRAAVCT 160 RGVAKAVDFI170 PVENLETTMR180 S
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Similarity Proteins
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Chemical Structure based Activity Landscape of Target | Top |
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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 |
Target Profiles in Patients | Top | |||||
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Drug Resistance Mutation (DRM) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy | |||||
REF 2 | FDA Approved Drug Products from FDA Official Website. 2015. Application Number: (ANDA) 207931. | |||||
REF 3 | ClinicalTrials.gov (NCT02226939) Antiviral Efficacy, Pharmacokinetics and Safety of BILN 2061 ZW in Patients With Cirrhosis and Chronic Hepatitis C. U.S. National Institutes of Health. | |||||
REF 4 | ClinicalTrials.gov (NCT01353248) GS 5885 Administered Concomitantly With GS-9451, Tegobuvir and Ribavirin (RBV) in Chronic Genotype 1 Hepatitis C Virus (HCV) Infection. U.S. National Institutes of Health. | |||||
REF 5 | ClinicalTrials.gov (NCT02202980) Efficacy and Safety of Oral Regimens for the Treatment of Chronic HCV Infection. U.S. National Institutes of Health. | |||||
REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034265) | |||||
REF 7 | ClinicalTrials.gov (NCT00557583) Evaluation of Safety and Pharmacokinetics of Single Doses of VBY-376 in Healthy Adults. U.S. National Institutes of Health. | |||||
REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030836) | |||||
REF 9 | 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. | |||||
REF 10 | Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients. Antimicrob Agents Chemother. 2012 October; 56(10): 5289-5295. | |||||
REF 11 | Clinical pipeline report, company report or official report of Gilead. | |||||
REF 12 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
REF 13 | Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel. Viruses. 2010 August; 2(8): 1752-1765. | |||||
REF 14 | 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. | |||||
REF 15 | Control of hepatitis C: a medicinal chemistry perspective. J Med Chem. 2005 Jan 13;48(1):1-20. | |||||
REF 16 | 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. | |||||
REF 17 | Azapeptides as inhibitors of the hepatitis C virus NS3 serine protease. Bioorg Med Chem Lett. 2002 Apr 8;12(7):1005-8. | |||||
REF 18 | 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. | |||||
REF 19 | ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy. Acta Biochim Pol. 2000;47(1):173-80. | |||||
REF 20 | Therapeutic applications of aptamers. Expert Opin Investig Drugs. 2008 Jan;17(1):43-60. | |||||
REF 21 | The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors. PLoS Pathog. 2012;8(7):e1002832. | |||||
REF 22 | P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile. Bioorg Med Chem Lett. 2010 Jan 15;20(2):567-70. |
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