Target Information

Target General Infomation
Target ID
T40492
Former ID
TTDR00103
Target Name
Nonstructural protein NS3
Synonyms
HCV NS3 RNA helicase; Hepacivirin; Hepatitis C Virus RNA Helicase; Hepatitis C virus NS3 serine proteinase; NS3; NS3 protease; NS3 protein; Nonstructural protein 3; ORF-C; P70; Protease/helicase NS3; RNA helicase; Ribonucleic acid (RNA) helicase; SM protein
Target Type
Successful
Disease Chronic HCV infection [ICD9: 070.4, 070.5, 070.70; ICD10: B17.1, B18.2]
HCV infection [ICD9: 070.4, 070.5, 070.70; ICD10: B17.1, B18.2]
Hepatitis virus infection [ICD9: 573.3; ICD10: K75.9]
Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26]
Unspecified [ICD code not available]
Function
NS5B is an RNA-dependent RNA polymerase that plays an essential role in the virus replication.
BioChemical Class
Peptidase
Target Validation
T40492
UniProt ID
P26664 (1027-1657)
EC Number
EC 3.4.21.98
Sequence
APITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTAAQTFLATCINGVCWTVYHGAG
TRTIASPKGPVIQMYTNVDQDLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRG
DSRGSLLSPRPISYLKGSSGGPLLCPAGHAVGIFRAAVCTRGVAKAVDFIPVENLETTMR
SPVFTDNSSPPVVPQSFQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGA
YMSKAHGIDPNIRTGVRTITTGSPITYSTYGKFLADGGCSGGAYDIIICDECHSTDATSI
LGIGTVLDQAETAGARLVVLATATPPGSVTVPHPNIEEVALSTTGEIPFYGKAIPLEVIK
GGRHLIFCHSKKKCDELAAKLVALGINAVAYYRGLDVSVIPTSGDVVVVATDALMTGYTG
DFDSVIDCNTCVTQTVDFSLDPTFTIETITLPQDAVSRTQRRGRTGRGKPGIYRFVAPGE
RPSGMFDSSVLCECYDAGCAWYELTPAETTVRLRAYMNTPGLPVCQDHLEFWEGVFTGLT
HIDAHFLSQTKQSGENLPYLVAYQATVCARAQAPPPSWDQMWKCLIRLKPTLHGPTPLLY
RLGAVQNEITLTHPVTKYIMTCMSADLEVVT
Structure
1RTL; 2A4G; 2GVF; 3EYD; 3HKW; 3KN2; 3QGH; 3QGI; 3RC4; 3RC5
Drugs and Mode of Action
Drug(s) Ombitasvir/paritaprevir/ritonavir Drug Info Approved Unspecified [1]
BILN-2061 Drug Info Phase 2 Hepatitis virus infection [2]
GS-9451 Drug Info Phase 2 Chronic HCV infection [3]
GS-9857 Drug Info Phase 2 HCV infection [4]
ACH-2684 Drug Info Phase 1 HCV infection [5]
VBY-376 Drug Info Phase 1 HCV infection [6]
BMS-605339 Drug Info Terminated HCV infection [7]
Inhibitor 2,4,6-Trihydroxy-3-nitro-N-tridecyl-benzamide Drug Info [8]
Ac-Glu-Cha-Cys Drug Info [9]
AcAsp-D-Gla-Leu-Ile-Cha-Cys Drug Info [8]
AcAsp-D-Glu-Leu-Glu-Cha-Cys Drug Info [9]
AcAsp-Gla-Leu-Ile-Cha-Cys Drug Info [9]
AcAsp-Glu-Cha-Val-Prb-Cpg Drug Info [8]
AcAsp-Glu-Cha-Val-Prb-Cys Drug Info [8]
AcAsp-Glu-Dif-Glu-Cha-Cys Drug Info [8]
AcAsp-Glu-Dif-Glu-Cha-Fab Drug Info [8]
AcAsp-Glu-Dif-Ile-Cha-Cys Drug Info [9]
AcAsp-Glu-Dif-Ile-Cha-Cys-Iqc-Nle-Thr-TyrNH2 Drug Info [8]
AcAsp-Glu-Dif-Ile-Cha-Cys-Pro-Cha-Asp-ValNH2 Drug Info [8]
AcAsp-Glu-Dif-Ile-Cha-Cys-Pro-Nle-Asp-ValNH2 Drug Info [8]
AcAsp-Glu-Dif-Lys-Cha-Cys Drug Info [9]
AcAsp-Glu-Leu-Glu-Cha-Cys Drug Info [9]
AcAsp-Glu-Met-Glu-Cha-Cys Drug Info [9]
AcAsp-Glu-Met-Glu-Glu-Cys Drug Info [8]
AcAsp-Glu-Met-Glu-Nal-Cyse Drug Info [9]
AcDif-Glu-Cha-Cys Drug Info [9]
AcDif-Ile-Cha-Cys Drug Info [9]
AcGlu-Asp-Val-Val-Leu-Cys-Iqc-Nle-Thr-TyrNH2 Drug Info [8]
AcGlu-Dif-Glu-Cha-Cys Drug Info [9]
AcGlu-Dif-Ile-Cha-Cys Drug Info [9]
Asp-D-Glu-Leu-Glu-Cha-Cys Drug Info [9]
Azapeptide Drug Info [10]
Azapeptide derivative Drug Info [11]
BILN-2061 Drug Info [12]
BMS-605339 Drug Info [13]
Boc-Ile-Leu-L-(difluoro)aminobutyric aid Drug Info [8]
Cbz-Ile-Leu-L-(difluoro)aminobutyric acid Drug Info [8]
GNF-PF-3464 Drug Info [14]
GS-9857 Drug Info [15]
PATULIN Drug Info [8]
Peptide Boronic Acid analogue Drug Info [16]
Ribavirin-TP Drug Info [17]
SCH-68631 Drug Info [8]
VBY-376 Drug Info [18]
Modulator ACH-2684 Drug Info [19]
GS-9451 Drug Info [20]
Ombitasvir/paritaprevir/ritonavir Drug Info
References
REF 1Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 2ClinicalTrials.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 3ClinicalTrials.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 4ClinicalTrials.gov (NCT02202980) Efficacy and Safety of Oral Regimens for the Treatment of Chronic HCV Infection. U.S. National Institutes of Health.
REF 5Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034265)
REF 6ClinicalTrials.gov (NCT00557583) Evaluation of Safety and Pharmacokinetics of Single Doses of VBY-376 in Healthy Adults. U.S. National Institutes of Health.
REF 7Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030836)
REF 8J Med Chem. 2005 Jan 13;48(1):1-20.Control of hepatitis C: a medicinal chemistry perspective.
REF 9Bioorg Med Chem Lett. 2001 Jan 22;11(2):203-6.Inhibition of hepatitis C virus NS3 protease activity by product-based peptides is dependent on helicase domain.
REF 10Bioorg Med Chem Lett. 2002 Apr 8;12(7):1005-8.Azapeptides as inhibitors of the hepatitis C virus NS3 serine protease.
REF 11J Med Chem. 2004 Jul 15;47(15):3788-99.Novel azapeptide inhibitors of hepatitis C virus serine protease.
REF 12Antiviral 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 13Discovery 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 14Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6. Epub 2010 Oct 21.In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2).
REF 15Clinical pipeline report, company report or official report of Gilead.
REF 16Bioorg Med Chem Lett. 2002 Nov 4;12(21):3199-202.P1 Phenethyl peptide boronic acid inhibitors of HCV NS3 protease.
REF 17ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy. Acta Biochim Pol. 2000;47(1):173-80.
REF 18Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel. Viruses. 2010 August; 2(8): 1752-1765.
REF 19Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 20Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients. Antimicrob Agents Chemother. 2012 October; 56(10): 5289-5295.

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