Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5LF3C)

• DTT Name: Solute carrier family 15 member 1 (SLC15A1)
• Synonyms: PEPT1; Oligopeptide transporter, small intestine isoform; Intestinal H(+)/peptide cotransporter
• Gene Name: SLC15A1
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Proton-dependent oligopeptide transporter
• UniProt ID: S15A1_HUMAN
• TTD ID: T91180
• Sequence:
  MGMSKSHSFFGYPLSIFFIVVNEFCERFSYYGMRAILILYFTNFISWDDNLSTAIYHTFV
  ALCYLTPILGALIADSWLGKFKTIVSLSIVYTIGQAVTSVSSINDLTDHNHDGTPDSLPV
  HVVLSLIGLALIALGTGGIKPCVSAFGGDQFEEGQEKQRNRFFSIFYLAINAGSLLSTII
  TPMLRVQQCGIHSKQACYPLAFGVPAALMAVALIVFVLGSGMYKKFKPQGNIMGKVAKCI
  GFAIKNRFRHRSKAFPKREHWLDWAKEKYDERLISQIKMVTRVMFLYIPLPMFWALFDQQ
  GSRWTLQATTMSGKIGALEIQPDQMQTVNAILIVIMVPIFDAVLYPLIAKCGFNFTSLKK
  MAVGMVLASMAFVVAAIVQVEIDKTLPVFPKGNEVQIKVLNIGNNTMNISLPGEMVTLGP
  MSQTNAFMTFDVNKLTRINISSPGSPVTAVTDDFKQGQRHTLLVWAPNHYQVVKDGLNQK
  PEKGENGIRFVNTFNELITITMSGKVYANISSYNASTYQFFPSGIKGFTISSTEIPPQCQ
  PNFNTFYLEFGSAYTYIVQRKNDSCPEVKVFEDISANTVNMALQIPQYFLLTCGEVVFSV
  TGLEFSYSQAPSNMKSVLQAGWLLTVAVGNIIVLIVAGAGQFSKQWAEYILFAALLLVVC
  VIFAIMARFYTYINPAEIEAQFDEDEKKNRLEKSNPYFMSGANSQKQM
• Function: May constitute a major route for the absorption of protein digestion end-products. Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway: Proton/oligopeptide cotransporters (R-HSA-427975)

Molecular Interaction Atlas (MIA) of This DTT

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-AMBA	DMYNASR	Discovery agent	N.A.	Investigative	[2]
Lys[Z(NO2)]-Pro	DMJX4GA	Discovery agent	N.A.	Investigative	[1]
[11C]GlySar	DM5Q08F	Discovery agent	N.A.	Investigative	[3]
[14C]GlySar	DMGLQ72	Discovery agent	N.A.	Investigative	[3]
[3H]GlySar	DMFEYLS	Discovery agent	N.A.	Investigative	[3]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Peptide transporter 1 (SLC15A1) DTP Info
• Gene Name: SLC15A1

52 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminolevulinic acid hci	DMS4BLQ	Acne vulgaris	ED80	Approved	[4]
Amoxicillin	DMUYNEI	Acute otitis media	AB00	Approved	[5]
Ampicillin	DMHWE7P	Acute epiglottitis		Approved	[6]
Benazepril	DMH1M9B	Hypertension	BA00-BA04	Approved	[7]
Bestatin	DM8L9D4	Acute myeloid leukaemia	2A60	Approved	[8]
Captopril	DM458UM	Chronic heart failure	BD1Z	Approved	[9]
Cefaclor	DMJXDGC	Bacterial infection	1A00-1C4Z	Approved	[10]
Cefadroxil	DMMC345	Bacterial infection	1A00-1C4Z	Approved	[11]
Cefamandole	DMNEXZF	Bacteremia	1A73	Approved	[12]
Cefazolin	DMPDYFR	Bacteremia	1A73	Approved	[13]
Cefdinir	DMJ7A0H	Bacterial infection	1A00-1C4Z	Approved	[14]
Cefixime	DMY60I8	Acute gonococcal cervicitis		Approved	[15]
Cefmetazole	DM42W1B	Bacterial infection	1A00-1C4Z	Approved	[12]
Cefoxitin	DMY8NC4	Acute gonococcal cervicitis		Approved	[13]
Cefpodoxime	DMJUNY5	Acute gonococcal cervicitis		Approved	[13]
Cefradine	DMUNSWV	Acute otitis media	AB00	Approved	[16]
Cefsulodin	DMQXLF3	Pseudomonas infection	1B92	Approved	[12]
Ceftibuten	DMWV2AG	Acute otitis media	AB00	Approved	[17]
Ceftriaxone	DMCEW64	Acute gonococcal cervicitis		Approved	[12]
Cefuroxime axetil	DM4CHN0	N. A.	N. A.	Approved	[12]
Cephalexin	DMD5JU8	Acute otitis media	AB00	Approved	[18]
Cephaloglycin	DMYZITL	Bacterial infection	1A00-1C4Z	Approved	[19]
Cyclacillin	DMHSJB4	Bacterial infection	1A00-1C4Z	Approved	[20]
Dexamethasone	DMMWZET	Acute adrenal insufficiency		Approved	[21]
Dicloxacillin	DM8EU0Z	Bacterial infection	1A00-1C4Z	Approved	[20]
Enalapril	DMNFUZR	Congestive heart failure	BD10	Approved	[22]
Enalaprilat	DMFYAM1	Congestive heart failure	BD10	Approved	[23]
Eprosartan	DM07K2I	Hypertension	BA00-BA04	Approved	[11]
Flucloxacillin	DMNUWST	Bacterial infection	1A00-1C4Z	Approved	[13]
Fosinopril	DM9NJ52	Chronic heart failure	BD1Z	Approved	[7]
Furosemide	DMMQ8ZG	Congestive heart failure	BD10	Approved	[21]
Irbesartan	DMTP1DC	Diabetic kidney disease	GB61.Z	Approved	[11]
Lisdexamfetamine	DM6W8V5	Attention deficit hyperactivity disorder	6A05.Z	Approved	[24]
Lisinopril	DMUOK4C	Chronic heart failure	BD1Z	Approved	[21]
Losartan	DM72JXH	Diabetic kidney disease	GB61.Z	Approved	[11]
Metoprolol	DMOJ0V6	Acute coronary syndrome	BA41	Approved	[21]
Midodrine	DME2PY5	Orthostatic hypotension	BA21	Approved	[20]
Moexipril	DM26E4B	Hypertension	BA00-BA04	Approved	[7]
Oseltamivir	DMGO72P	Influenza	1E30-1E32	Approved	[25]
Perindopril	DMOPZDT	Hypertension	BA00-BA04	Approved	[7]
Piperacillin	DMTBKF3	Acute gonococcal cervicitis		Approved	[13]
Ramipril	DM2R68E	Acute heart failure	BD10-BD13	Approved	[7]
Ribavirin	DMEYLH9	Hepatitis C virus infection	1E51.1	Approved	[26]
Spirapril	DM5XLTY	Hypertension	BA00-BA04	Approved	[7]
Sulfasalazine	DMICA9H	Irritable bowel syndrome	DD91.0	Approved	[21]
Sulpiride	DMF54ZG	Schizophrenia	6A20	Approved	[27]
Temocapril	DM1A79H	N. A.	N. A.	Approved	[28]
Temocaprilate	DMNX2QI	N. A.	N. A.	Approved	[23]
Trandolapril	DM4L6EU	Chronic heart failure	BD1Z	Approved	[7]
Valaciclovir	DMHKS94	Genital herpes	1A94	Approved	[29]
Valganciclovir	DMS2IUH	Virus infection	1A24-1D9Z	Approved	[30]
Valsartan	DMREUQ6	Chronic heart failure	BD1Z	Approved	[11]

1 Clinical Trial Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Benzylpenicillin	DMS9503	Actinomycosis		Phase 3	[31]

2 Discontinued Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cephaloridine	DM4Y95F	Gram-positive bacterial infection	1B74-1G40	Withdrawn from market	[12]
Ceronapril	DMFBNI6	Major depressive disorder	6A70.3	Discontinued in Phase 2	[19]

2 Preclinical Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Metampicillin	DMQW5MH	N. A.	N. A.	Preclinical	[20]
QSP	DMASVOD	N. A.	N. A.	Preclinical	[32]

2 Investigative Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
carnosine	DMFYCB4	Discovery agent	N.A.	Investigative	[33]
NAAG	DMFGOW0	Discovery agent	N.A.	Investigative	[34]

References

• [1] A novel inhibitor of the mammalian peptide transporter PEPT1. Biochemistry. 2001 Apr 10;40(14):4454-8.
• [2] Activation of vagal afferents in the rat duodenum by protein digests requires PepT1. J Nutr. 2005 Jun;135(6):1491-5.
• [3] 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. (Target id: 984).
• [4] Transport of the photodynamic therapy agent 5-aminolevulinic acid by distinct H+-coupled nutrient carriers coexpressed in the small intestine. J Pharmacol Exp Ther. 2010 Jan;332(1):220-8.
• [5] Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Drug Metab Dispos. 2006 Apr;34(4):547-55.
• [6] Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR. Res Microbiol. 2017 Jun;168(5):443-449.
• [7] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [8] Dipeptide transporters in apical and basolateral membranes of the human intestinal cell line Caco-2. Am J Physiol. 1993 Aug;265(2 Pt 1):G289-94.
• [9] Membrane transporters in drug development. Nat Rev Drug Discov. 2010 Mar;9(3):215-36.
• [10] Protein hydrolysate-induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter PepT1. Am J Physiol Gastrointest Liver Physiol. 2011 May;300(5):G895-902.
• [11] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [12] Intestinal transport of beta-lactam antibiotics: analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayers and the transepithelial flux. Pharm Res. 1999 Jan;16(1):55-61.
• [13] Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of the mammalian H+/peptide cotransporter PEPT1. J Med Chem. 2005 Jun 30;48(13):4410-9.
• [14] Transporter-mediated drug delivery: recent progress and experimental approaches. Drug Discov Today. 2004 Aug 15;9(16):712-20.
• [15] Flavonoids with epidermal growth factor-receptor tyrosine kinase inhibitory activity stimulate PEPT1-mediated cefixime uptake into human intestinal epithelial cells. J Pharmacol Exp Ther. 2001 Oct;299(1):351-7.
• [16] Recognition of beta-lactam antibiotics by rat peptide transporters, PEPT1 and PEPT2, in LLC-PK1 cells. Am J Physiol. 1997 Nov;273(5 Pt 2):F706-11.
• [17] Increased protein level of PEPT1 intestinal H+-peptide cotransporter upregulates absorption of glycylsarcosine and ceftibuten in 5/6 nephrectomized rats. Am J Physiol Gastrointest Liver Physiol. 2005 Apr;288(4):G664-70.
• [18] Direct evidence for efficient transport and minimal metabolism of L-cephalexin by oligopeptide transporter 1 in budded baculovirus fraction. Biol Pharm Bull. 2009 Aug;32(8):1459-61.
• [19] Pharmaceutical and pharmacological importance of peptide transporters. J Pharm Pharmacol. 2008 May;60(5):543-85.
• [20] Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives. J Pharmacol Exp Ther. 2006 Jul;318(1):455-60.
• [21] Peptide transporter substrate identification during permeability screening in drug discovery: comparison of transfected MDCK-hPepT1 cells to Caco-2 cells. Arch Pharm Res. 2007 Apr;30(4):507-18.
• [22] The intestinal H+/peptide symporter PEPT1: structure-affinity relationships. Eur J Pharm Sci. 2004 Jan;21(1):53-60.
• [23] Transporter-mediated Drug Interactions. Drug Metab Pharmacokinet. 2002;17(4):253-74.
• [24] Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010 Jun 24;6:317-27.
• [25] Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos. 2009 Aug;37(8):1676-81.
• [26] Transport of levovirin prodrugs in the human intestinal Caco-2 cell line. J Pharm Sci. 2006 Jun;95(6):1318-25.
• [27] Studies on intestinal absorption of sulpiride (2): transepithelial transport of sulpiride across the human intestinal cell line Caco-2. Biol Pharm Bull. 2002 Oct;25(10):1345-50.
• [28] The role of transporters in drug interactions. Eur J Pharm Sci. 2006 Apr;27(5):501-17.
• [29] Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun. 1998 May 19;246(2):470-5.
• [30] Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci. 2000 Jun;89(6):781-9.
• [31] Drug transport in corneal epithelium and blood-retina barrier: emerging role of transporters in ocular pharmacokinetics. Adv Drug Deliv Rev. 2006 Nov 15;58(11):1136-63.
• [32] Tripeptides of RS1 (RSC1A1) inhibit a monosaccharide-dependent exocytotic pathway of Na+-D-glucose cotransporter SGLT1 with high affinity. J Biol Chem. 2007 Sep 28;282(39):28501-13.
• [33] Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs. Amino Acids. 2012 Jul;43(1):111-26.
• [34] Molecular interactions between dipeptides, drugs and the human intestinal H+ -oligopeptide cotransporter hPEPT1. J Physiol. 2006 Jul 1;574(Pt 1):149-66.