Details of the Drug Combination

General Information of Drug Combination (ID: DCLHAK6)

• Drug Combination Name: Ribavirin + Interferon beta-1b
• Indication: Coronavirus Disease 2019 (COVID-19); Status: Phase 2 [1]
• Component Drugs:
  Ribavirin (DMEYLH9): Small molecular drug
  Interferon beta-1b (DMCN61Z): N.A.

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	[5]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[6]

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	[10]
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	[6]
SARS-CoV RNA-directed RNA polymerase (RdRp)	TTKXI53	R1AB_CVHSA (4370-5301)	Inhibitor	[6]

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	[11]
Concentrative nucleoside transporter 2 (SLC28A2)	DT82KPY	S28A2_HUMAN	Substrate	[12]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)	DT4YL5R	S28A3_HUMAN	Substrate	[13]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[14]

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	[15]
Cytosolic 5'-nucleotidase II (NT5C2)	DE1DOKJ	5NTC_HUMAN	Metabolism	[16]

Ribavirin Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[17]
Eukaryotic translation initiation factor 4E (EIF4E)	OTDAWNLA	IF4E_HUMAN	Decreases Expression	[9]
Myosin-6 (MYH6)	OT3YNCH1	MYH6_HUMAN	Decreases Expression	[18]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[18]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Expression	[19]
Alpha-actinin-2 (ACTN2)	OT9FOLD7	ACTN2_HUMAN	Decreases Expression	[18]
Transcription factor GATA-4 (GATA4)	OTQHWAZG	GATA4_HUMAN	Decreases Expression	[18]
Troponin T, cardiac muscle (TNNT2)	OT80NN7R	TNNT2_HUMAN	Decreases Expression	[18]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Decreases Response To Substance	[20]
Protein arginine N-methyltransferase 2 (PRMT2)	OT63JZCI	ANM2_HUMAN	Decreases Expression	[9]
Insulin gene enhancer protein ISL-1 (ISL1)	OTVNVKAX	ISL1_HUMAN	Decreases Expression	[18]
Protein arginine N-methyltransferase 6 (PRMT6)	OT5V3XIN	ANM6_HUMAN	Affects Expression	[9]
Protein arginine N-methyltransferase 8 (PRMT8)	OT3MRK62	ANM8_HUMAN	Decreases Expression	[9]
Equilibrative nucleoside transporter 3 (SLC29A3)	OTGLX8XU	S29A3_HUMAN	Affects Transport	[21]
Equilibrative nucleoside transporter 1 (SLC29A1)	OTLOOZZS	S29A1_HUMAN	Increases Uptake	[22]
Inosine triphosphate pyrophosphatase (ITPA)	OTQ47WVR	ITPA_HUMAN	Increases Response To Substance	[23]

Indication(s) of Interferon beta-1b

Disease Entry	ICD 11	Status	REF
Multiple sclerosis	8A40	Approved	[7]

Interferon beta-1b Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Interferon alpha/beta receptor 2 (IFNAR2)	TTMQB37	INAR2_HUMAN	Binder	[24]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Coronavirus Disease 2019 (COVID-19)	DC4PUE0	N. A.	Phase 2	[1]

References

• [1] ClinicalTrials.gov (NCT04276688) Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment
• [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] SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 2016 Aug;14(8):523-34.
• [6] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [7] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [8] 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.
• [9] 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.
• [10] Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother. 2006 Jan;57(1):8-13.
• [11] Transport of levovirin prodrugs in the human intestinal Caco-2 cell line. J Pharm Sci. 2006 Jun;95(6):1318-25.
• [12] 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.
• [13] 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.
• [14] Effects of dipyridamole coadministration on the pharmacokinetics of ribavirin in healthy volunteers. Drug Metab Pharmacokinet. 2013;28(5):406-10.
• [15] Functional analysis of purine nucleoside phosphorylase as a key enzyme in ribavirin metabolism. Drug Metab Pharmacokinet. 2014;29(2):211-4.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Characterization of ribavirin uptake systems in human hepatocytes. J Hepatol. 2010 Apr;52(4):486-92.
• [23] 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.
• [24] Interferon-beta(1b) Treatment in Neuromyelitis Optica. Eur Neurol. 2009 Jul 7;62(3):167-170.