Target Information
Target General Information | Top | |||||
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Target ID |
T51843
(Former ID: TTDC00001)
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Target Name |
Virus RNA-dependent RNA polymerase (Viru RdRP)
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Synonyms |
HCV NS5B; HCV p68
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Gene Name |
Viru RdRP
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | COVID-19 [ICD-11: 1D6Y] | |||||
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 |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.7.48
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Sequence |
SMSYTWTGALITPCAAEESKLPINPLSNSLLRHHSMVYSTTSRSASLRQKKVTFDRLQVL
DDHYRDVLKEMKAKASTVKARLLSIEEACKLTPPHSAKSKFGYGAKDVRSLSSRAVNHIR SVWEDLLEDTETPIDTTIMAKNEVFCVQPEKGGRKPARLIVFPDLGVRVCEKMALYDVVS TLPQAVMGPSYGFQYSPGQRVEFLVNTWKSKKCPMGFSYDTRCFDSTVTENDIRTEESIY QCCDLAPEARQAIRSLTERLYVGGPLTNSKGQNCGYRRCRASGVLTTSCGNTLTCYLKAT AACRAAKLQDCTMLVNGDDLVVICESAGTQEDAAALRAFTEAMTRYSAPPGDPPQPEYDL ELITSCSSNVSVAHDASGKRVYYLTRDPTTPLARAAWETVRHTPVNSWLGNIIMYAPTLW ARMILMTHFFSILLAQEQLEKALDCQIYGACYSIEPLDLPQIIERLHGLSAFSLHSYSPG EINRVASCLRKLGVPPLRVWRHRARSVRAKLLSQGGRAATCGKYLFNWAVKTKLKLTPIP AASQLDLSGWFVAGYNGGDIYHSLSRARPRWFMLCLLLLSVGVGIYLLPNR Click to Show/Hide
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Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | AT-527 | Drug Info | Phase 2 | Coronavirus Disease 2019 (COVID-19) | [2] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 8 Inhibitor drugs | + | ||||
1 | AT-527 | Drug Info | [3] | |||
2 | FdG | Drug Info | [1], [4], [5] | |||
3 | Guanosine-5'-Triphosphate | Drug Info | [6] | |||
4 | Pyrimidinyl acylthiourea | Drug Info | [1], [4], [5] | |||
5 | Pyrophosphate 2- | Drug Info | [7] | |||
6 | T-1105 | Drug Info | [1], [4], [5] | |||
7 | T-1106 | Drug Info | [1], [4], [5] | |||
8 | Thiadiazolo[2,3-a]pyrimidine | Drug Info | [1], [4], [5] |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: BI 201335 | Ligand Info | |||||
Structure Description | Crystal structure of HCV NS3/NS4A protease complexed with BI 201335 | PDB:3P8N | ||||
Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [8] |
PDB Sequence |
APITAYSQQT
10 RGLLGCIITS20 LTGRDKNQVD30 GEVQVLSTAT40 QSFLATCVNG50 VCWTVYHGAG 60 SKTLAGPKGP70 ITQMYTNVDQ80 DLVGWPAPPG90 ARSMTPCTCG100 SSDLYLVTRH 110 ADVIPVRRRG120 DSRGSLLSPR130 PVSYLKGSSG140 GPLLCPSGHV150 VGIFRAAVCT 160 RGVAKAVDFI170 PVESMETTMR180 AS
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Ligand Name: (2r,6s,13ar,14ar,16as)-6-{[(Cyclopentyloxy)carbonyl]amino}-14a-[(Cyclopropylsulfonyl)carbamoyl]-5,16-Dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-A][1,4]diazacyclopentadecin-2-Yl 3,4-Dihydroisoquinoline-2(1h)-Carboxylate | Ligand Info | |||||
Structure Description | NS3/NS4A protease with inhibitor | PDB:4KTC | ||||
Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [9] |
PDB Sequence |
APITAYSQQT
10 RGLLGCIITS20 LTGRDKNQVD30 GEVQVLSTAT40 QSFLATCVNG50 VCWTVYHGAG 60 SKTLAGPKGP70 ITQMYTNVDQ80 DLVGWPAPPG90 ARSMTPCTCG100 SSDLYLVTRH 110 ADVIPVRRRG120 DSRGSLLSPR130 PVSYLKGSSG140 GPLLCPSGHV150 VGIFRAAVCT 160 RGVAKAVDFI170 PVESM
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GLN41
3.404
SER42
3.939
PHE43
3.354
VAL55
4.336
HIS57
3.159
GLY58
3.410
VAL78
4.490
ASP79
3.238
GLN80
4.332
ASP81
3.682
ARG123
4.263
VAL132
3.555
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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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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-Related Models and Studies | Top | |||||
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Target Validation | ||||||
Target QSAR Model |
References | Top | |||||
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REF 1 | Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106. Antimicrob Agents Chemother. 2009 Jan;53(1):202-9. | |||||
REF 2 | ClinicalTrials.gov (NCT04709835) Study to Evaluate the Effects of AT-527 in Non-Hospitalized Adult Patients With Mild or Moderate COVID-19. U.S. National Institutes of Health. | |||||
REF 3 | AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19. Antimicrob Agents Chemother. 2021 Mar 18;65(4):e02479-20. | |||||
REF 4 | PA subunit of RNA polymerase as a promising target for anti-influenza virus agents. Antiviral Res. 2008 Jun;78(3):194-201. | |||||
REF 5 | Antiviral agents active against influenza A viruses. Nat Rev Drug Discov. 2006 Dec;5(12):1015-25. | |||||
REF 6 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 7 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
REF 8 | Combined X-ray, NMR, and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335. J Biol Chem. 2011 Apr 1;286(13):11434-43. | |||||
REF 9 | Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease. J Med Chem. 2014 Mar 13;57(5):1753-69. |
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