Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMQNTNX)

• DOT Name: Natriuretic peptides A (NPPA)
• Synonyms: Atrial natriuretic factor prohormone; proANF; Atrial natriuretic peptide prohormone; preproANP; proANP; Atriopeptigen; Cardiodilatin; CDD; preproCDD-ANF
• Gene Name: NPPA
• Related Disease:
  Lung cancer
  Stroke
  Adenocarcinoma
  Alzheimer disease
  Atherosclerosis
  Atrial fibrillation
  Breast cancer
  Cardiac failure
  Congestive heart failure
  Coronary heart disease
  Coronary ischemia
  Diabetic kidney disease
  Dilated cardiomyopathy 1A
  Essential hypertension
  Familial hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy
  Hypotension
  Liver cirrhosis
  Lung neoplasm
  Myocardial infarction
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Patent ductus arteriosus
  Prostate cancer
  Prostate neoplasm
  Pulmonary hypertension
  Atrial fibrillation, familial, 6
  Cardiovascular disease
  Melanoma
  Skin cancer
  Skin neoplasm
  Atrial standstill
  Familial atrial fibrillation
  Acute kidney injury
  Rheumatoid arthritis
  Atrial standstill 2
  Cardiomyopathy
  Glaucoma/ocular hypertension
  Myocardial ischemia
  Psoriasis
  Type-1/2 diabetes
  Dilated cardiomyopathy
• UniProt ID: ANF_HUMAN
• PDB ID: 1ANP; 1YK0; 3N57; 7BRH; 7BRJ; 7BRK
• Pfam ID: PF00212
• Sequence:
  MSSFSTTTVSFLLLLAFQLLGQTRANPMYNAVSNADLMDFKNLLDHLEEKMPLEDEVVPP
  QVLSEPNEEAGAALSPLPEVPPWTGEVSPAQRDGGALGRGPWDSSDRSALLKSKLRALLT
  APRSLRRSSCFGGRMDRIGAQSGLGCNSFRY
• Function: [Atrial natriuretic peptide]: Hormone that plays a key role in mediating cardio-renal homeostasis, and is involved in vascular remodeling and regulating energy metabolism. Acts by specifically binding and stimulating NPR1 to produce cGMP, which in turn activates effector proteins, such as PRKG1, that drive various biological responses. Regulates vasodilation, natriuresis, diuresis and aldosterone synthesis and is therefore essential for regulating blood pressure, controlling the extracellular fluid volume and maintaining the fluid-electrolyte balance. Also involved in inhibiting cardiac remodeling and cardiac hypertrophy by inducing cardiomyocyte apoptosis and attenuating the growth of cardiomyocytes and fibroblasts. Plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus, and thus prevents pregnancy-induced hypertension. In adipose tissue, acts in various cGMP- and PKG-dependent pathways to regulate lipid metabolism and energy homeostasis. This includes up-regulating lipid metabolism and mitochondrial oxygen utilization by activating the AMP-activated protein kinase (AMPK), and increasing energy expenditure by acting via MAPK11 to promote the UCP1-dependent thermogenesis of brown adipose tissue. Binds the clearance receptor NPR3 which removes the hormone from circulation ; [Long-acting natriuretic peptide]: May have a role in cardio-renal homeostasis through regulation of natriuresis, diuresis, vasodilation, and inhibiting aldosterone synthesis. In vitro, promotes the production of cGMP and induces vasodilation. May promote natriuresis, at least in part, by enhancing prostaglandin E2 synthesis resulting in the inhibition of renal Na+-K+-ATPase. However reports on the involvement of this peptide in mammal blood volume and blood pressure homeostasis are conflicting; according to a report, in vivo it is not sufficient to activate cGMP and does not inhibit collecting duct transport nor effect diuresis and natriuresis. Appears to bind to specific receptors that are distinct from the receptors bound by atrial natriuretic peptide and vessel dilator. Possibly enhances protein excretion in urine by decreasing proximal tubular protein reabsorption ; [Vessel dilator]: May have a role in cardio-renal homeostasis through regulation of natriuresis, diuresis, and vasodilation. In vitro, promotes the production of cGMP and induces vasodilation. May promote natriuresis, at least in part, by enhancing prostaglandin E2 synthesis resulting in the inhibition of renal Na+-K+-ATPase. However reports on the involvement of this peptide in mammal blood volume and blood pressure homeostasis are conflicting; according to a report it is not sufficient to activate cGMP and does not inhibit collecting duct transport nor effect diuresis and natriuresis. Appears to bind to specific receptors that are distinct from the receptors bound by the atrial natriuretic and long-acting natriuretic peptides. Possibly functions in protein excretion in urine by maintaining the integrity of the proximal tubules and enhancing protein excretion by decreasing proximal tubular protein reabsorption ; [Kaliuretic peptide]: May have a role in cardio-renal homeostasis through regulation of diuresis and inhibiting aldosterone synthesis. In vitro, promotes the production of cGMP and induces vasodilation. May promote natriuresis, at least in part, by enhancing prostaglandin E2 synthesis resulting in the inhibition of renal Na+-K+-ATPase. May have a role in potassium excretion but not sodium excretion (natriuresis). Possibly enhances protein excretion in urine by decreasing proximal tubular protein reabsorption ; [Urodilatin]: Hormone produced in the kidneys that appears to be important for maintaining cardio-renal homeostasis. Mediates vasodilation, natriuresis and diuresis primarily in the renal system, in order to maintain the extracellular fluid volume and control the fluid-electrolyte balance. Specifically binds and stimulates cGMP production by renal transmembrane receptors, likely NPR1. Urodilatin not ANP, may be the natriuretic peptide responsible for the regulation of sodium and water homeostasis in the kidney ; [Auriculin-D]: May have a role in cardio-renal homeostasis through regulation of natriuresis and vasodilation. In vivo promotes natriuresis and in vitro, vasodilates renal artery strips; [Auriculin-B]: May have a role in cardio-renal homeostasis through regulation of natriuresis and vasodilation. In vivo promotes natriuresis and in vitro, vasodilates renal artery strips; [Auriculin-A]: May have a role in cardio-renal homeostasis through regulation of regulation of natriuresis and vasodilation. In vivo promotes natriuresis. In vitro, vasodilates intestinal smooth muscle but not smooth muscle strips; [Atriopeptin-2]: May have a role in cardio-renal homeostasis through regulation of natriuresis and vasodilation. In vivo promotes natriuresis. In vitro, selectively vasodilates intestinal and vascular smooth muscle strips; [Atriopeptin-1]: May have a role in cardio-renal homeostasis through regulation of natriuresis and vasodilation. In vivo promotes natriuresis. In vitro, selectively vasodilates intestinal smooth muscle but not vascular smooth muscle strips.
• Tissue Specificity: .Detected in the kidney distal tubular cells (at protein level) . Present in urine (at protein level) .; [Atrial natriuretic peptide]: Detected in atrial and ventricular plasma samples, and in adipocytes (at protein level) . Detected in urine in one study . However, was not detected in urine in another study . In the brain, predominantly expressed in the gray matter with very weak expression in the white matter (at protein level) . Localizes to astrocyte-like structures throughout the white matter, and in the cerebral vessels detected in the leptomeningeal and parenchymal vessels, and endothelium and smooth muscle layers (at protein level) . Relatively low levels of expression in the kidneys compared to urodilatin (at protein level) .
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  HIF-1 sig.ling pathway (hsa04066)
  Vascular smooth muscle contraction (hsa04270)
  Thermogenesis (hsa04714)
  Oxytocin sig.ling pathway (hsa04921)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  African trypanosomiasis (hsa05143)
• Reactome Pathway:
  Physiological factors (R-HSA-5578768)
  Amyloid fiber formation (R-HSA-977225)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Genetic Variation	[1]
Stroke	DISX6UHX	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Therapeutic	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[9]
Coronary ischemia	DISDJJ5G	Strong	Biomarker	[10]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[11]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[12]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[13]
Familial hypertrophic cardiomyopathy	DISQ89HN	Strong	Biomarker	[14]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Altered Expression	[15]
Hypotension	DISYNSM9	Strong	Biomarker	[16]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[17]
Lung neoplasm	DISVARNB	Strong	Therapeutic	[18]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[19]
Neoplasm	DISZKGEW	Strong	Altered Expression	[20]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[21]
Obesity	DIS47Y1K	Strong	Genetic Variation	[22]
Patent ductus arteriosus	DIS9P8YS	Strong	Biomarker	[23]
Prostate cancer	DISF190Y	Strong	Therapeutic	[3]
Prostate neoplasm	DISHDKGQ	Strong	Therapeutic	[3]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[24]
Atrial fibrillation, familial, 6	DISZBKHJ	Moderate	Autosomal dominant	[25]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[26]
Melanoma	DIS1RRCY	moderate	Therapeutic	[27]
Skin cancer	DISTM18U	moderate	Therapeutic	[27]
Skin neoplasm	DIS16DDV	moderate	Therapeutic	[27]
Atrial standstill	DISFHGZA	Supportive	Autosomal dominant	[28]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[29]
Acute kidney injury	DISXZG0T	Disputed	Biomarker	[30]
Rheumatoid arthritis	DISTSB4J	Disputed	Biomarker	[31]
Atrial standstill 2	DISWNITN	Limited	Autosomal recessive	[28]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[32]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[33]
Myocardial ischemia	DISFTVXF	Limited	Genetic Variation	[34]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[35]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[36]
Dilated cardiomyopathy	DISX608J	No Known	Autosomal recessive	[37]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aldosterone	DM9S2JW	Approved	Natriuretic peptides A (NPPA) decreases the secretion of Aldosterone.	[70]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Amlodipine	DMBDAZV	Approved	Natriuretic peptides A (NPPA) increases the Cardiovascular disorder ADR of Amlodipine.	[71]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Natriuretic peptides A (NPPA).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Natriuretic peptides A (NPPA).	[64]

28 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Natriuretic peptides A (NPPA).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Natriuretic peptides A (NPPA).	[40]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Natriuretic peptides A (NPPA).	[41]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Natriuretic peptides A (NPPA).	[42]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Natriuretic peptides A (NPPA).	[43]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Natriuretic peptides A (NPPA).	[23]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Natriuretic peptides A (NPPA).	[45]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Natriuretic peptides A (NPPA).	[46]
Isoproterenol	DMK7MEY	Approved	Isoproterenol increases the expression of Natriuretic peptides A (NPPA).	[47]
Carvedilol	DMHTEAO	Approved	Carvedilol decreases the expression of Natriuretic peptides A (NPPA).	[49]
Epirubicin	DMPDW6T	Approved	Epirubicin increases the expression of Natriuretic peptides A (NPPA).	[50]
Atenolol	DMNKG1Z	Approved	Atenolol decreases the expression of Natriuretic peptides A (NPPA).	[51]
Spironolactone	DM2AQ5N	Approved	Spironolactone decreases the expression of Natriuretic peptides A (NPPA).	[52]
Furosemide	DMMQ8ZG	Approved	Furosemide decreases the expression of Natriuretic peptides A (NPPA).	[53]
Felodipine	DMOSW35	Approved	Felodipine affects the expression of Natriuretic peptides A (NPPA).	[54]
Enalapril	DMNFUZR	Approved	Enalapril decreases the expression of Natriuretic peptides A (NPPA).	[55]
Naloxone	DM3FXMA	Approved	Naloxone decreases the expression of Natriuretic peptides A (NPPA).	[56]
Labetalol	DMK8U72	Approved	Labetalol decreases the activity of Natriuretic peptides A (NPPA).	[57]
Mannitol	DMSCDY9	Approved	Mannitol increases the expression of Natriuretic peptides A (NPPA).	[58]
Alprostadil	DMWH7NQ	Approved	Alprostadil decreases the expression of Natriuretic peptides A (NPPA).	[59]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Natriuretic peptides A (NPPA).	[61]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Natriuretic peptides A (NPPA).	[62]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil increases the expression of Natriuretic peptides A (NPPA).	[63]
Omapatrilat	DMAGUY0	Terminated	Omapatrilat increases the expression of Natriuretic peptides A (NPPA).	[65]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Natriuretic peptides A (NPPA).	[66]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Natriuretic peptides A (NPPA).	[67]
Irbesartan	DMTP1DC	Investigative	Irbesartan increases the expression of Natriuretic peptides A (NPPA).	[68]
Lisinopril	DMUOK4C	Investigative	Lisinopril decreases the expression of Natriuretic peptides A (NPPA).	[69]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the secretion of Natriuretic peptides A (NPPA).	[48]
Cilazapril	DM4V6JA	Approved	Cilazapril affects the secretion of Natriuretic peptides A (NPPA).	[60]

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