Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Prolyl endopeptidase (PREP)
• Synonyms: Post-proline cleaving enzyme; PREP; PE
• Gene Name: PREP
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: PPCE_HUMAN
• TTD ID: T86161
• EC Number: EC 3.4.21.26
• Sequence:
  MLSLQYPDVYRDETAVQDYHGHKICDPYAWLEDPDSEQTKAFVEAQNKITVPFLEQCPIR
  GLYKERMTELYDYPKYSCHFKKGKRYFYFYNTGLQNQRVLYVQDSLEGEARVFLDPNILS
  DDGTVALRGYAFSEDGEYFAYGLSASGSDWVTIKFMKVDGAKELPDVLERVKFSCMAWTH
  DGKGMFYNSYPQQDGKSDGTETSTNLHQKLYYHVLGTDQSEDILCAEFPDEPKWMGGAEL
  SDDGRYVLLSIREGCDPVNRLWYCDLQQESSGIAGILKWVKLIDNFEGEYDYVTNEGTVF
  TFKTNRQSPNYRVINIDFRDPEESKWKVLVPEHEKDVLEWIACVRSNFLVLCYLHDVKNI
  LQLHDLTTGALLKTFPLDVGSIVGYSGQKKDTEIFYQFTSFLSPGIIYHCDLTKEELEPR
  VFREVTVKGIDASDYQTVQIFYPSKDGTKIPMFIVHKKGIKLDGSHPAFLYGYGGFNISI
  TPNYSVSRLIFVRHMGGILAVANIRGGGEYGETWHKGGILANKQNCFDDFQCAAEYLIKE
  GYTSPKRLTINGGSNGGLLVAACANQRPDLFGCVIAQVGVMDMLKFHKYTIGHAWTTDYG
  CSDSKQHFEWLVKYSPLHNVKLPEADDIQYPSMLLLTADHDDRVVPLHSLKFIATLQYIV
  GRSRKQSNPLLIHVDTKAGHGAGKPTAKVIEEVSDMFAFIARCLNVDWIP
• Function: Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.
• KEGG Pathway: Renin-angiotensin system (hsa04614)

Molecular Interaction Atlas (MIA) of This DTT

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALV-003	DMXSFA0	Coeliac disease	DA95	Phase 2	[2]
BAICALEIN	DM4C7E6	Influenza virus infection	1E30-1E32	Phase 2	[3]
ONO-1603	DMKIZAL	Cognitive impairment	6D71	Phase 2	[1]
S-17092-1	DMYR1K8	Cognitive impairment	6D71	Phase 1	[4]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
JTP-4819	DMI0UJS	Cognitive impairment	6D71	Discontinued in Phase 2	[5]
Z-321	DMLO2QY	Parkinson disease	8A00.0	Discontinued in Phase 1	[6]
BAICALIN	DMY1TLZ	Human immunodeficiency virus infection	1C62	Terminated	[7]
Y-29794	DMLAVES	N. A.	N. A.	Terminated	[7]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-Hydroxy-1-Thio-Glycerol	DMIOTQ8	Discovery agent	N.A.	Investigative	[8]
ARI-3531	DMEO82V	Discovery agent	N.A.	Investigative	[9]
Double Oxidized Cysteine	DM6TU84	Discovery agent	N.A.	Investigative	[8]
Monothioglycerol	DMENSOZ	Discovery agent	N.A.	Investigative	[8]
Z-Pro-Prolinal	DM43O2U	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	4.07E-27	0.3	0.92
Parkinson's disease	8A00.0	Substantia nigra tissue	5.70E-01	-0.09	-0.33

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Prolyl endopeptidase (PREP) DME Info
• Gene Name: PREP

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Gonadorelin	DMAQ469	Amenorrhea	GA20.0	Approved	[11]

1 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BRADYKININ	DM4R6UV	N. A.	N. A.	Phase 1	[12]

References

• [1] ONO-1603, a potential antidementia drug, shows neuroprotective effects and increases m3-muscarinic receptor mRNA levels in differentiating rat cerebellar granule neurons. Neurosci Lett. 1996 Aug 23;214(2-3):151-4.
• [2] The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol. 2010 Mar;134(3):289-95.
• [3] Baicalin, a prodrug able to reach the CNS, is a prolyl oligopeptidase inhibitor. Bioorg Med Chem. 2008 Aug 1;16(15):7516-24.
• [4] Effect of S 17092, a novel prolyl endopeptidase inhibitor, on substance P and alpha-melanocyte-stimulating hormone breakdown in the rat brain. J Neurochem. 2003 Mar;84(5):919-29.
• [5] A novel prolyl endopeptidase inhibitor, JTP-4819, with potential for treating Alzheimer's disease. Behav Brain Res. 1997 Feb;83(1-2):147-51.
• [6] Z-321, a prolyl endopeptidase inhibitor, augments the potentiation of synaptic transmission in rat hippocampal slices. Behav Brain Res. 1997 Feb;83(1-2):213-6.
• [7] Inhibitors of prolyl oligopeptidases for the therapy of human diseases: defining diseases and inhibitors. J Med Chem. 2010 May 13;53(9):3423-38.
• [8] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [9] Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase. J Med Chem. 2013 May 9;56(9):3467-77.
• [10] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [11] Ion-exchange chromatography: basic principles and application to the partial purification of soluble mammalian prolyl oligopeptidase. Methods Mol Biol. 2011;681:215-28.
• [12] Bradykinin release and inactivation in brain of rats submitted to an experimental model of Alzheimer's disease. Peptides. 2006 Dec;27(12):3363-9.