Details of the Drug Combination

General Information of Drug Combination (ID: DCOUT2D)

• Drug Combination Name: Ribavirin + Interferon Alfa-2b
• Indication: Middle East Respiratory Syndrome (MERS); Status: Investigative [1]
• Component Drugs:
  Ribavirin (DMEYLH9): Small molecular drug
  Interferon Alfa-2b (DMWCQP4): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ribavirin

Disease Entry	ICD 11	Status	REF
Hepatitis C virus infection	1E51.1	Approved	[2]
Respiratory syncytial virus infection	1C80	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[1]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[5]

Ribavirin Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN inosine-5'-monophosphate dehydrogenase 1 (IMPDH1)	TT3GRLK	IMDH1_HUMAN	Inhibitor	[4]
Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1)	TTL7C8Q	IMDH1_HUMAN	Inhibitor	[8]
HUMAN inosine-5'-monophosphate dehydrogenase 2 (IMPDH2)	TTTU6X1	IMDH2_HUMAN	Inhibitor	[4]
MERS-CoV RNA-directed RNA polymerase (RdRp)	TTOA6YT	R1AB_CVEMC (4378-5310)	Inhibitor	[5]
SARS-CoV RNA-directed RNA polymerase (RdRp)	TTKXI53	R1AB_CVHSA (4370-5301)	Inhibitor	[5]

Ribavirin Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[9]
Concentrative nucleoside transporter 2 (SLC28A2)	DT82KPY	S28A2_HUMAN	Substrate	[10]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)	DT4YL5R	S28A3_HUMAN	Substrate	[11]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[12]

Ribavirin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Purine nucleoside phosphorylase (PNP)	DE2WSAL	PNPH_HUMAN	Metabolism	[13]
Cytosolic 5'-nucleotidase II (NT5C2)	DE1DOKJ	5NTC_HUMAN	Metabolism	[14]

Ribavirin Interacts with 43 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Protein arginine N-methyltransferase 5 (PRMT5)	OTF6IGJS	ANM5_HUMAN	Decreases Expression	[15]
Protein arginine N-methyltransferase 3 (PRMT3)	OTH2KILE	ANM3_HUMAN	Decreases Expression	[7]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[16]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[17]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Decreases Expression	[18]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[19]
Erythropoietin (EPO)	OTZ90CN4	EPO_HUMAN	Increases Expression	[20]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[21]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[17]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[17]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Decreases Expression	[22]
Eukaryotic translation initiation factor 4E (EIF4E)	OTDAWNLA	IF4E_HUMAN	Decreases Expression	[7]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[15]
Myosin-6 (MYH6)	OT3YNCH1	MYH6_HUMAN	Decreases Expression	[21]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[21]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[15]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Expression	[17]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[16]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Expression	[15]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Expression	[23]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[16]
Alpha-actinin-2 (ACTN2)	OT9FOLD7	ACTN2_HUMAN	Decreases Expression	[21]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[24]
Transcription factor GATA-4 (GATA4)	OTQHWAZG	GATA4_HUMAN	Decreases Expression	[21]
Troponin T, cardiac muscle (TNNT2)	OT80NN7R	TNNT2_HUMAN	Decreases Expression	[21]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Decreases Response To Substance	[25]
Protein arginine N-methyltransferase 2 (PRMT2)	OT63JZCI	ANM2_HUMAN	Decreases Expression	[7]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Increases Expression	[17]
Insulin gene enhancer protein ISL-1 (ISL1)	OTVNVKAX	ISL1_HUMAN	Decreases Expression	[21]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[16]
Histone-arginine methyltransferase CARM1 (CARM1)	OT0IPRVR	CARM1_HUMAN	Decreases Expression	[7]
Protein arginine N-methyltransferase 6 (PRMT6)	OT5V3XIN	ANM6_HUMAN	Affects Expression	[7]
Protein arginine N-methyltransferase 1 (PRMT1)	OTN8GTXW	ANM1_HUMAN	Affects Expression	[7]
Protein arginine N-methyltransferase 8 (PRMT8)	OT3MRK62	ANM8_HUMAN	Decreases Expression	[7]
Protein arginine N-methyltransferase 7 (PRMT7)	OTE73PO1	ANM7_HUMAN	Decreases Expression	[15]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases ADR	[26]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Increases ADR	[26]
Equilibrative nucleoside transporter 3 (SLC29A3)	OTGLX8XU	S29A3_HUMAN	Affects Transport	[27]
Haptoglobin (HP)	OTGUGAF9	HPT_HUMAN	Increases ADR	[26]
Equilibrative nucleoside transporter 1 (SLC29A1)	OTLOOZZS	S29A1_HUMAN	Increases Uptake	[28]
Interferon lambda-3 (IFNL3)	OTPIMGAU	IFNL3_HUMAN	Decreases Response	[29]
Inosine triphosphate pyrophosphatase (ITPA)	OTQ47WVR	ITPA_HUMAN	Increases Response To Substance	[30]

Indication(s) of Interferon Alfa-2b

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[2]

Interferon Alfa-2b Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Interferon-alpha 2 (IFNA2)	TTSIUJ9	IFNA2_HUMAN	Modulator	[32]

Interferon Alfa-2b Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
2'-5'-oligoadenylate synthase 1 (OAS1)	OT8ZLOCY	OAS1_HUMAN	Increases Expression	[31]
Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2)	OT8DXMS3	E2AK2_HUMAN	Increases Expression	[31]
Tyrosine-protein kinase JAK1 (JAK1)	OT0X3D17	JAK1_HUMAN	Increases Expression	[31]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Phosphorylation	[31]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Increases Expression	[31]
Signal transducer and activator of transcription 2 (STAT2)	OTO9G2RZ	STAT2_HUMAN	Increases Phosphorylation	[31]

References

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• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Ribavirin FDA Label
• [4] Proteomics of SARS-CoV-2-infected Host Cells Reveals Therapy Targets. Nature. 2020 May 14. doi: 10.1038/s41586-020-2332-7.
• [5] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [6] Glutathione peroxidase, thioredoxin, and membrane protein changes in erythrocytes predict ribavirin-induced anemia. Clin Pharmacol Ther. 2005 Oct;78(4):422-32. doi: 10.1016/j.clpt.2005.07.002.
• [7] Ribavirin inhibits the growth and ascites formation of hepatocellular carcinoma through downregulation of type I CARM1 and type II PRMT5. Toxicol Appl Pharmacol. 2022 Jan 15;435:115829. doi: 10.1016/j.taap.2021.115829. Epub 2021 Dec 14.
• [8] Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother. 2006 Jan;57(1):8-13.
• [9] Transport of levovirin prodrugs in the human intestinal Caco-2 cell line. J Pharm Sci. 2006 Jun;95(6):1318-25.
• [10] Identification and functional analysis of variants in the human concentrative nucleoside transporter 2, hCNT2 (SLC28A2) in Chinese, Malays and Indians. Pharmacogenet Genomics. 2007 Sep;17(9):783-6.
• [11] Kinetic study of anti-viral ribavirin uptake mediated by hCNT3 and hENT1 in Xenopus laevis oocytes. Biophys Chem. 2010 Mar;147(1-2):59-65.
• [12] Effects of dipyridamole coadministration on the pharmacokinetics of ribavirin in healthy volunteers. Drug Metab Pharmacokinet. 2013;28(5):406-10.
• [13] Functional analysis of purine nucleoside phosphorylase as a key enzyme in ribavirin metabolism. Drug Metab Pharmacokinet. 2014;29(2):211-4.
• [14] Phosphorylation of ribavirin and viramidine by adenosine kinase and cytosolic 5'-nucleotidase II: Implications for ribavirin metabolism in erythrocytes. Antimicrob Agents Chemother. 2005 Jun;49(6):2164-71.
• [15] Ribavirin inhibits colorectal cancer growth by downregulating PRMT5 expression and H3R8me2s and H4R3me2s accumulation. Toxicol Appl Pharmacol. 2021 Mar 15;415:115450. doi: 10.1016/j.taap.2021.115450. Epub 2021 Feb 9.
• [16] Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin-induced eIF4E activation. J Biochem Mol Toxicol. 2018 Jan;32(1). doi: 10.1002/jbt.22007. Epub 2017 Nov 7.
• [17] Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J Hepatol. 1999 Mar;30(3):376-82. doi: 10.1016/s0168-8278(99)80093-2.
• [18] Direct evidence for immunomodulatory properties of ribavirin on T-cell reactivity to hepatitis C virus. Antiviral Res. 2007 Jul;75(1):36-42. doi: 10.1016/j.antiviral.2006.11.008. Epub 2006 Dec 13.
• [19] Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.
• [20] Normal erythropoietin response in chronic hepatitis C patients with ribavirin-induced anaemia. Antivir Ther. 2003 Feb;8(1):57-63.
• [21] Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity. Toxicology. 2020 Apr 15;435:152422. doi: 10.1016/j.tox.2020.152422. Epub 2020 Feb 26.
• [22] Correlation of sICAM-1 and sVCAM-1 level with biochemical, histological and viral findings in chronic hepatitis C after interferon-alpha + ribavirin therapy. Rom J Gastroenterol. 2003 Jun;12(2):91-5.
• [23] Serotonin transporter mRNA expression is decreased by lamivudine and ribavirin and increased by interferon in immune cells. Scand J Immunol. 2006 Feb;63(2):106-15. doi: 10.1111/j.1365-3083.2005.01715.x.
• [24] Ribavirin and alpha interferon enhance death receptor-mediated apoptosis and caspase activation in human hepatoma cells. Antimicrob Agents Chemother. 2003 Jun;47(6):1912-21. doi: 10.1128/AAC.47.6.1912-1921.2003.
• [25] Two distinct phases of virus-induced nuclear factor kappa B regulation enhance tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in virus-infected cells. J Biol Chem. 2003 May 16;278(20):18092-100. doi: 10.1074/jbc.M300265200. Epub 2003 Mar 13.
• [26] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [27] Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G910-22. doi: 10.1152/ajpgi.90672.2008. Epub 2009 Jan 22.
• [28] Characterization of ribavirin uptake systems in human hepatocytes. J Hepatol. 2010 Apr;52(4):486-92.
• [29] Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon--based regimens. Clin Pharmacol Ther. 2014 Feb;95(2):141-6. doi: 10.1038/clpt.2013.203. Epub 2013 Oct 4.
• [30] ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy--a genome-wide study of Japanese HCV virus patients. Gastroenterology. 2010 Oct;139(4):1190-7. doi: 10.1053/j.gastro.2010.06.071. Epub 2010 Jul 14.
• [31] 6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the anti-proliferative effect of interferon / by promoting activation of the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma cells. Toxicol Appl Pharmacol. 2017 Dec 1;336:31-39. doi: 10.1016/j.taap.2017.10.004. Epub 2017 Oct 12.
• [32] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.