Details of the Drug Combination

General Information of Drug Combination (ID: DCFPEZJ)

• Drug Combination Name: Benazepril + Hydroxychloroquine
• Indication: Alport Syndrome, X-Linked; Status: Phase 2 [1]
• Component Drugs:
  Benazepril (DMH1M9B): Small molecular drug
  Hydroxychloroquine (DMSIVND): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Benazepril

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]
Malignant essential hypertension	BA00	Approved	[3]

Benazepril Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[7]

Benazepril Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[8]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[8]

Benazepril Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Methylenetetrahydrofolate reductase (MTHFR)	DEOXTPZ	MTHR_HUMAN	Metabolism	[9]

Benazepril Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Methylenetetrahydrofolate reductase (MTHFR)	OTUBJSR7	MTHR_HUMAN	Affects Response To Substance	[10]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Decreases Expression	[11]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[12]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[13]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[13]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[11]
Protein AMBP (AMBP)	OTLU8GU8	AMBP_HUMAN	Decreases Expression	[14]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[11]
Methionine synthase (MTR)	OTF2K2TA	METH_HUMAN	Affects Response To Substance	[9]
Cytochrome P450 11B2, mitochondrial (CYP11B2)	OTIOLWYN	C11B2_HUMAN	Affects Response To Substance	[15]
Lysosomal Pro-X carboxypeptidase (PRCP)	OTIUY91L	PCP_HUMAN	Affects Response To Substance	[16]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Response To Substance	[17]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Response To Substance	[18]

Indication(s) of Hydroxychloroquine

Disease Entry	ICD 11	Status	REF
Chronic renal failure	GB61.Z	Approved	[4]
Malaria	1F40-1F45	Approved	[5]
Plasmodium falciparum malaria	1F40	Approved	[4]
Plasmodium malariae malaria	N.A.	Approved	[4]
Plasmodium ovale malaria	N.A.	Approved	[4]
Systemic lupus erythematosus	4A40.0	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Colon cancer	2B90.Z	Investigative	[4]

Hydroxychloroquine Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN pH-dependent viral fusion/replication (pH-DVF/R)	TTD16BI	N.A.	Inhibitor	[19]
HUMAN glycosylation of host receptor (GHR)	TTZGK1R	N.A.	Inhibitor	[19]
Toll-like receptor 7 (TLR7)	TTRJ1K4	TLR7_HUMAN	Antagonist	[20]
HUMAN toll-like receptor 7/9 signalling pathway (TLR7/9 pathway)	TT3A1EZ	N.A.	Inhibitor	[21]

Hydroxychloroquine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[22]

Hydroxychloroquine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[23]

Hydroxychloroquine Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[24]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3)	OTPGHZB9	IFIT3_HUMAN	Increases Expression	[25]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[26]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[25]
Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1)	OT4TMERS	NFAC1_HUMAN	Affects Expression	[27]
Claudin-1 (CLDN1)	OT27KV99	CLD1_HUMAN	Increases Expression	[28]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[25]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Increases Expression	[25]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Affects Expression	[29]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Affects Expression	[29]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[25]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Affects Localization	[30]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[31]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[32]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[32]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Degradation	[25]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[27]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[26]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Expression	[25]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Activity	[30]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Increases Expression	[25]
Nuclear factor of activated T-cells, cytoplasmic 2 (NFATC2)	OTK5T6HZ	NFAC2_HUMAN	Affects Localization	[27]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[33]
Interferon regulatory factor 3 (IRF3)	OT81U8ME	IRF3_HUMAN	Increases Phosphorylation	[25]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Increases Expression	[28]
Mitochondrial antiviral-signaling protein (MAVS)	OTTQ0J64	MAVS_HUMAN	Increases Expression	[25]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)	OTCA9WCM	RSAD2_HUMAN	Increases Expression	[25]
Interferon-induced helicase C domain-containing protein 1 (IFIH1)	OTZA2AHA	IFIH1_HUMAN	Increases Expression	[25]
Toll-like receptor 9 (TLR9)	OTFZ45HX	TLR9_HUMAN	Decreases Expression	[34]
7-dehydrocholesterol reductase (DHCR7)	OTLILBUI	DHCR7_HUMAN	Affects Expression	[29]

References

• [1] ClinicalTrials.gov (NCT04937907) Study of Hydroxychloroquine in Patients With X-linked Alport Syndrome in China (CHXLAS)
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6374).
• [3] Amlodipine FDA Label
• [4] Hydroxychloroquine FDA Label
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7198).
• [6] ClinicalTrials.gov (NCT04341727) Hydroxychloroquine,Hydroxychloroquine,Azithromycin in the Treatment of SARS CoV-2 Infection (WU352). U.S. National Institutes of Health.
• [7] Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman Pinschers. J Vet Intern Med. 2009 Sep-Oct;23(5):977-83.
• [8] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [9] Effects of MTHFR and MS gene polymorphisms on baseline blood pressure and Benazepril effectiveness in Chinese hypertensive patients. J Hum Hypertens. 2011 Mar;25(3):172-7.
• [10] A common haplotype on methylenetetrahydrofolate reductase gene modifies the effect of angiotensin-converting enzyme inhibitor on blood pressure in essential hypertension patients--a family-based association study. Clin Exp Hypertens. 2005 Aug;27(6):509-21.
• [11] Expression of toll-like receptor 4, tumor necrosis factor- alpha, matrix metalloproteinase-9 and effects of benazepril in patients with acute coronary syndromes. Clin Med Insights Cardiol. 2010 Oct 11;4:89-93. doi: 10.4137/CMC.S5659.
• [12] Sympathomoderating influence of benazepril in essential hypertension. J Hypertens. 1992 Apr;10(4):373-8. doi: 10.1097/00004872-199204000-00009.
• [13] Transforming growth factor-beta1 is associated with kidney damage in patients with essential hypertension: renoprotective effect of ACE inhibitor and/or angiotensin II receptor blocker. Nephrol Dial Transplant. 2008 Sep;23(9):2841-6. doi: 10.1093/ndt/gfn159. Epub 2008 Apr 5.
• [14] Low-dose dual blockade of the renin-angiotensin system improves tubular status in non-diabetic proteinuric patients. Scand J Urol Nephrol. 2005;39(6):511-7. doi: 10.1080/00365590510031264.
• [15] Associations between CYP11B2 gene polymorphisms and the response to angiotensin-converting enzyme inhibitors. Clin Pharmacol Ther. 2006 Jun;79(6):581-9. doi: 10.1016/j.clpt.2006.02.007.
• [16] E112D polymorphism in the prolylcarboxypeptidase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients. Chin Med J (Engl). 2009 Oct 20;122(20):2461-5.
• [17] Beta2 adrenergic receptor gene Arg16Gly polymorphism is associated with therapeutic efficacy of benazepril on essential hypertension in Chinese. Clin Exp Hypertens. 2004 Aug;26(6):581-92. doi: 10.1081/ceh-200031839.
• [18] Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. J Hum Hypertens. 2016 Dec;30(12):766-771. doi: 10.1038/jhh.2016.24. Epub 2016 Apr 28.
• [19] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
• [20] TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm Allergy Drug Targets. 2007 Dec;6(4):223-35.
• [21] Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):155-166.
• [22] MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013 Sep-Oct;31(5):779-87.
• [23] Hydroxychloroquine: a physiologically-based pharmacokinetic model in the context of cancer-related autophagy modulation. J Pharmacol Exp Ther. 2018 Jun;365(3):447-459.
• [24] Somer M, Kallio J, Pesonen U, Pyykko K, Huupponen R, Scheinin M "Influence of hydroxychloroquine on the bioavailability of oral metoprolol." Br J Clin Pharmacol 49 (2000): 549-54. [PMID: 10848718]
• [25] Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery. J Interferon Cytokine Res. 2015 Mar;35(3):143-56. doi: 10.1089/jir.2014.0038. Epub 2014 Oct 16.
• [26] Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes. Clin Exp Immunol. 2006 Jun;144(3):503-11. doi: 10.1111/j.1365-2249.2006.03070.x.
• [27] Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017 Aug 9;19(1):183. doi: 10.1186/s13075-017-1393-y.
• [28] Chloroquine and Hydroxychloroquine Increase Retinal Pigment Epithelial Layer Permeability. J Biochem Mol Toxicol. 2015 Jul;29(7):299-304. doi: 10.1002/jbt.21696. Epub 2015 Mar 9.
• [29] Hydroxychloroquine decreases human MSC-derived osteoblast differentiation and mineralization in vitro. J Cell Mol Med. 2018 Feb;22(2):873-882. doi: 10.1111/jcmm.13373. Epub 2017 Oct 3.
• [30] Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003 Jun 19;22(25):3927-36. doi: 10.1038/sj.onc.1206622.
• [31] Attenuation of chloroquine and hydroxychloroquine on the invasive potential of bladder cancer through targeting matrix metalloproteinase 2 expression. Environ Toxicol. 2021 Nov;36(11):2138-2145. doi: 10.1002/tox.23328. Epub 2021 Jul 19.
• [32] Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia. 2004 Jul;47(1):9-20. doi: 10.1002/glia.20017.
• [33] d-galactose induces premature senescence of lens epithelial cells by disturbing autophagy flux and mitochondrial functions. Toxicol Lett. 2018 Jun 1;289:99-106. doi: 10.1016/j.toxlet.2018.02.001. Epub 2018 Feb 6.
• [34] Antagonist-mediated down-regulation of Toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus. Arthritis Res Ther. 2012 Apr 18;14(2):R80. doi: 10.1186/ar3803.