Details of the Drug Combination

General Information of Drug Combination (ID: DC36BFO)

• Drug Combination Name: Emtricitabine + Lopinavir
• Indication: Acute HIV Infection; Status: Phase 1 [1]
• Component Drugs:
  Emtricitabine (DMBMUWZ): Small molecular drug
  Lopinavir (DMITQS0): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Emtricitabine

Disease Entry	ICD 11	Status	REF
Hepatitis virus infection	1E50-1E51	Approved	[2]
Human immunodeficiency virus infection	1C62	Approved	[2]
Hepatitis B virus infection	1E51.0	Phase 3	[3]

Emtricitabine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Modulator	[2]

Emtricitabine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[6]

Emtricitabine Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
E3 ubiquitin-protein ligase parkin (PRKN)	OTJBN41W	PRKN_HUMAN	Decreases Expression	[7]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[8]
Deoxycytidine kinase (DCK)	OTW8HLZC	DCK_HUMAN	Affects Binding	[9]

Indication(s) of Lopinavir

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[5]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[5]

Lopinavir Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 23S ribosomal RNA (Bact 23S rRNA)	TTLFGBV	NOUNIPROTAC	Modulator	[11]
MERS-CoV 3C-like proteinase (3CLpro)	TTWOH4Q	R1AB_CVEMC (3248-3553)	Inhibitor	[5]
SARS-CoV 3C-like protease (3CLpro)	TTPZG3C	R1AB_CVHSA (3241-3546)	Inhibitor	[5]

Lopinavir Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[12]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[13]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[15]

Lopinavir Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]

Lopinavir Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[17]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Abundance	[18]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[19]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[20]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[20]
Prelamin-A/C (LMNA)	OT3SG7ZR	LMNA_HUMAN	Increases Farnesylation	[10]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[20]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[21]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Affects Phosphorylation	[22]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[21]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[20]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[20]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[20]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[20]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Acute HIV Infection	DCKSN07	N. A.	Phase 1	[1]

References

• [1] ClinicalTrials.gov (NCT01154673) Effects of Intensive cART During Acute/Early HIV Infection
• [2] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [3] Clinical pipeline report, company report or official report of Gilead (2011).
• [4] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [5] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [6] Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters. Xenobiotica. 2017 Jan;47(1):77-85.
• [7] Chronic Nucleoside Reverse Transcriptase Inhibitors Disrupt Mitochondrial Homeostasis and Promote Premature Endothelial Senescence. Toxicol Sci. 2019 Dec 1;172(2):445-456. doi: 10.1093/toxsci/kfz203.
• [8] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [9] Nonenantioselectivity property of human deoxycytidine kinase explained by structures of the enzyme in complex with L- and D-nucleosides. J Med Chem. 2007 Jun 28;50(13):3004-14. doi: 10.1021/jm0700215. Epub 2007 May 27.
• [10] A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells. J Biol Chem. 2008 Apr 11;283(15):9797-804. doi: 10.1074/jbc.M709629200. Epub 2008 Jan 28.
• [11] Company report (JMI Laboratories)
• [12] Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother. 2007 Nov;60(5):987-93.
• [13] Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br J Pharmacol. 2010 Jul;160(5):1224-33.
• [14] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [15] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [16] Synthesis and antiviral activities of the major metabolites of the HIV protease inhibitor ABT-378 (Lopinavir). Bioorg Med Chem Lett. 2001 Jun 4;11(11):1351-3.
• [17] Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther. 2005 Feb;312(2):583-91.
• [18] Functional defect caused by the 4544G>A SNP in ABCC2: potential impact for drug cellular disposition. Pharmacogenet Genomics. 2011 Dec;21(12):884-93. doi: 10.1097/FPC.0b013e32834d672b.
• [19] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [20] Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther. 2007;12(4):489-500.
• [21] Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction. Free Radic Biol Med. 2016 May;94:218-29. doi: 10.1016/j.freeradbiomed.2016.03.003. Epub 2016 Mar 8.
• [22] Lopinavir inhibits meningioma cell proliferation by Akt independent mechanism. J Neurooncol. 2011 Feb;101(3):441-8. doi: 10.1007/s11060-010-0281-y. Epub 2010 Jul 2.