Details of the Drug Combination

General Information of Drug Combination (ID: DCPG5FB)

• Drug Combination Name: Artesunate + Mefloquine
• Indication: Plasmodium Falciparum Malaria; Status: Phase 1 [1]
• Component Drugs:
  Artesunate (DMR27C8): Small molecular drug
  Mefloquine (DMWT905): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Artesunate

Disease Entry	ICD 11	Status	REF
Infection of P. falciparum	1F40	Approved	[2]
Malaria	1F40-1F45	Approved	[3]
Plasmodium falciparum malaria	1F40	Approved	[2]

Artesunate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A)	TTZVSJ2	NOUNIPROTAC	Inhibitor	[3]

Artesunate Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[11]

Artesunate Interacts with 57 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Increases Expression	[8]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Decreases Expression	[8]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Expression	[8]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[8]
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Increases Phosphorylation	[12]
Ubiquitin-like protein ATG12 (ATG12)	OTJRO09Y	ATG12_HUMAN	Increases Expression	[13]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Affects Localization	[14]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Phosphorylation	[12]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Increases Expression	[13]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Decreases Expression	[13]
Ferritin heavy chain (FTH1)	OT6IFS0O	FRIH_HUMAN	Decreases Expression	[13]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[14]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[14]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[13]
Replication protein A 32 kDa subunit (RPA2)	OTZ54WAF	RFA2_HUMAN	Increases Phosphorylation	[12]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[12]
Desmin (DES)	OTI09KBW	DESM_HUMAN	Decreases Expression	[13]
Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4)	OTRAFFX2	GPX4_HUMAN	Decreases Activity	[13]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[9]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Affects Expression	[14]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[14]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[13]
Nuclear receptor coactivator 4 (NCOA4)	OTRVU0UA	NCOA4_HUMAN	Decreases Expression	[13]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Affects Localization	[16]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[9]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[13]
DNA dC->dU-editing enzyme APOBEC-3C (APOBEC3C)	OTPL0AI1	ABC3C_HUMAN	Increases Expression	[12]
Ubiquitin-like-conjugating enzyme ATG3 (ATG3)	OT28VBVK	ATG3_HUMAN	Increases Expression	[13]
Small ribosomal subunit protein uS8 (RPS15A)	OT0BUA12	RS15A_HUMAN	Decreases Response To Substance	[10]
Mitochondrial thiamine pyrophosphate carrier (SLC25A19)	OT157TY3	TPC_HUMAN	Decreases Response To Substance	[10]
Atypical kinase COQ8A, mitochondrial (COQ8A)	OT1ETSA2	COQ8A_HUMAN	Decreases Response To Substance	[10]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Decreases Response To Substance	[10]
Large ribosomal subunit protein uL30 (RPL7)	OT4WCQBE	RL7_HUMAN	Decreases Response To Substance	[10]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Decreases Response To Substance	[17]
Integrin beta-1 (ITGB1)	OT6G1IAR	ITB1_HUMAN	Increases Response To Substance	[10]
CAP-Gly domain-containing linker protein 4 (CLIP4)	OT75KVQK	CLIP4_HUMAN	Increases Response To Substance	[10]
Glutathione S-transferase theta-2 (GSTT2)	OTANW3TJ	GST2_HUMAN	Affects Response To Substance	[17]
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2 (BST1)	OTAV5SE7	BST1_HUMAN	Increases Response To Substance	[10]
Small ribosomal subunit protein eS12 (RPS12)	OTBRQ8MS	RS12_HUMAN	Decreases Response To Substance	[10]
Dopamine beta-hydroxylase (DBH)	OTC6I2SP	DOPO_HUMAN	Increases Response To Substance	[10]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Decreases Response To Substance	[17]
Nck-associated protein 1 (NCKAP1)	OTEZQXXJ	NCKP1_HUMAN	Increases Response To Substance	[10]
Small ribosomal subunit protein eS32 (RPL41)	OTFW5IFO	RS32_HUMAN	Decreases Response To Substance	[10]
Translationally-controlled tumor protein (TPT1)	OTHMTRJU	TCTP_HUMAN	Affects Response To Substance	[18]
Nascent polypeptide-associated complex subunit alpha (NACA)	OTLP1KR3	NACA_HUMAN	Decreases Response To Substance	[10]
Glutathione S-transferase Mu 4 (GSTM4)	OTOTF8DU	GSTM4_HUMAN	Affects Response To Substance	[17]
Maleylacetoacetate isomerase (GSTZ1)	OTQ43JCE	MAAI_HUMAN	Affects Response To Substance	[17]
Large ribosomal subunit protein eL6 (RPL6)	OTRU71O4	RL6_HUMAN	Decreases Response To Substance	[10]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Response To Substance	[10]
Frizzled-7 (FZD7)	OTTK3F6E	FZD7_HUMAN	Increases Response To Substance	[10]
Serine/arginine-rich splicing factor 2 (SRSF2)	OTVDHO6U	SRSF2_HUMAN	Decreases Response To Substance	[10]
T-complex protein 1 subunit beta (CCT2)	OTW1VV4E	TCPB_HUMAN	Decreases Response To Substance	[10]
Glutathione S-transferase 3, mitochondrial (MGST3)	OTYK80JA	MGST3_HUMAN	Affects Response To Substance	[17]
Filamin-A (FLNA)	OTYZ9JXM	FLNA_HUMAN	Increases Response To Substance	[10]

Indication(s) of Mefloquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[6]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[6]
Progressive multifocal leukoencephalopathy	8A45.02	Investigative	[7]

Mefloquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium 80S ribosome (Malaria 80S)	TTT28H3	NOUNIPROTAC	Binder	[19]

Mefloquine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[20]

Mefloquine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[21]

References

• [1] ClinicalTrials.gov (NCT01659281) Efficacy of Artesunate-Mefloquine Combination Therapy in Trat Province, Thailand
• [2] Artesunate FDA Label
• [3] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [4] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 019578
• [5] ClinicalTrials.gov (NCT04347031) An Open Randomized Study of the Effectiveness of Mefloquine for the Treatment of Patients With COVID19. U.S. National Institutes of Health.
• [6] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [7] Mefloquine FDA Label
• [8] Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol. 2009 Jul;35(1):149-58.
• [9] Artesunate induces autophagy dependent apoptosis through upregulating ROS and activating AMPK-mTOR-ULK1 axis in human bladder cancer cells. Chem Biol Interact. 2020 Nov 1;331:109273. doi: 10.1016/j.cbi.2020.109273. Epub 2020 Sep 28.
• [10] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.
• [11] Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42.
• [12] Induction of APOBEC3C Facilitates the Genotoxic Stress-Mediated Cytotoxicity of Artesunate. Chem Res Toxicol. 2019 Dec 16;32(12):2526-2537. doi: 10.1021/acs.chemrestox.9b00358. Epub 2019 Nov 11.
• [13] Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. 2019 Jan;109:2043-2053. doi: 10.1016/j.biopha.2018.11.030. Epub 2018 Nov 26.
• [14] Artesunate induces apoptosis through caspase-dependent and -independent mitochondrial pathways in human myelodysplastic syndrome SKM-1 cells. Chem Biol Interact. 2014 Aug 5;219:28-36. doi: 10.1016/j.cbi.2014.03.011. Epub 2014 Apr 3.
• [15] AMG900 as novel inhibitor of the translationally controlled tumor protein. Chem Biol Interact. 2021 Jan 25;334:109349. doi: 10.1016/j.cbi.2020.109349. Epub 2020 Nov 28.
• [16] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [17] Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate. In Vivo. 2005 Jan-Feb;19(1):225-32.
• [18] Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Drug Resist Updat. 2005 Feb-Apr;8(1-2):85-97. doi: 10.1016/j.drup.2005.04.003.
• [19] An ultrastructural study of the effects of mefloquine on malaria parasites. Am J Trop Med Hyg. 1987 Jan;36(1):9-14.
• [20] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [21] Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000 Oct;52(10):1265-9.