Target Information
Target General Information | Top | |||||
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Target ID |
T34997
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Target Name |
Hepatitis C virus Serine protease NS4A (HCV NS4A)
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Synonyms |
HCV p8
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Gene Name |
HCV NS4A
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Target Type |
Clinical trial 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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UniProt ID | ||||||
Sequence |
STWVLVGGVLAALAAYCLSTGCVVIVGRVVLSGKPAIIPDREVLYREFDEMEECSQHLPY
IEQGMMLAEQFKQKALGLLQTASRQAEVIAPAVQTNWQKLETFWAKHMWNFISGIQYLAG LSTLPGNPAIASLMAFTAAVTSPLTTSQTLLFNILGGWVAAQLAAPGAATAFVGAGLAGA AIGSVGLGKVLIDILAGYGAGVAGALVAFKIMSGEVPSTEDLVNLLPAILSPGALVVGVV CAAILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTAILSSLTVTQLL RRLHQWISSECTTPC Click to Show/Hide
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Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
1 | TG-2349 | Drug Info | Phase 2 | Hepatitis C virus infection | [2] | |
2 | MK-6325 | Drug Info | Phase 1 | Hepatitis C virus infection | [3] | |
3 | PHX-1766 | Drug Info | Phase 1 | Hepatitis C virus infection | [4] | |
Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
1 | GS-9132 | Drug Info | Discontinued in Phase 1/2 | Hepatitis C virus infection | [5] | |
2 | IDX-320 | Drug Info | Discontinued in Phase 1/2 | Hepatitis C virus infection | [6] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Modulator | [+] 5 Modulator drugs | + | ||||
1 | TG-2349 | Drug Info | [1] | |||
2 | MK-6325 | Drug Info | [7] | |||
3 | PHX-1766 | Drug Info | [8] | |||
4 | GS-9132 | Drug Info | [1] | |||
5 | IDX-320 | Drug Info | [9] |
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 |
References | Top | |||||
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REF 1 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034971) | |||||
REF 3 | ClinicalTrials.gov (NCT01329913) Safety, Pharmacokinetics, and Pharmacodynamics of MK-6325 in Hepatitis C Virus (HCV) Infections (MK-6325-003). U.S. National Institutes of Health. | |||||
REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029167) | |||||
REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022995) | |||||
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 800031987) | |||||
REF 7 | Synthesis of bis-macrocyclic HCV protease inhibitor MK-6325 via intramolecular sp -sp Suzuki-Miyaura coupling and ring closing metathesis. Org Lett. 2015 Mar 20;17(6):1533-6. | |||||
REF 8 | Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design. Antivir Ther. 2012;17(2):365-75. | |||||
REF 9 | Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.Antivir Ther.2012;17(4):633-42. |
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