PREP

Summary

PREP (prolyl endopeptidase, HGNC:9358) is a protein-coding gene on chromosome 6q21, encoding Prolyl endopeptidase (P48147). Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.

The protein encoded by this gene is a cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides.

Source: NCBI Gene 5550 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 93 total — 2 pathogenic
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002726

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9358
Approved symbol	PREP
Name	prolyl endopeptidase
Location	6q21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000085377
Ensembl biotype	protein_coding
OMIM	600400
Entrez	5550

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000369110, ENST00000448705, ENST00000652536, ENST00000910821, ENST00000910822, ENST00000910823, ENST00000910824, ENST00000910825, ENST00000920421, ENST00000969640, ENST00000969641

RefSeq mRNA: 1 — MANE Select: NM_002726 NM_002726

CCDS: CCDS5053

Canonical transcript exons

ENST00000652536 — 15 exons

Exon	Start	End
ENSE00000421640	105377386	105377519
ENSE00000421642	105373369	105373578
ENSE00000761302	105281746	105281902
ENSE00000761324	105282451	105282582
ENSE00000761331	105285486	105285580
ENSE00000761338	105288758	105288894
ENSE00000761378	105376125	105376255
ENSE00000904122	105397853	105397927
ENSE00000974897	105368903	105369024
ENSE00000974898	105352972	105353077
ENSE00000974899	105333314	105333505
ENSE00000974900	105328829	105329026
ENSE00001448822	105402847	105403082
ENSE00002446678	105323665	105323768
ENSE00003842098	105273218	105278438

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.4639 / max 229.0095, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74876	35.4000	1823
74875	10.6812	1795
74877	0.3826	171

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.65	gold quality
gastrocnemius	UBERON:0001388	93.87	gold quality
mucosa of transverse colon	UBERON:0004991	93.43	gold quality
rectum	UBERON:0001052	93.34	gold quality
muscle of leg	UBERON:0001383	93.19	gold quality
triceps brachii	UBERON:0001509	92.59	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.46	gold quality
oocyte	CL:0000023	92.10	gold quality
muscle organ	UBERON:0001630	91.56	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.46	gold quality
gluteal muscle	UBERON:0002000	91.38	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.28	gold quality
cortical plate	UBERON:0005343	90.04	gold quality
biceps brachii	UBERON:0001507	90.03	gold quality
colonic mucosa	UBERON:0000317	90.00	gold quality
transverse colon	UBERON:0001157	89.74	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.29	gold quality
skeletal muscle tissue	UBERON:0001134	88.98	gold quality
skin of leg	UBERON:0001511	88.89	gold quality
stromal cell of endometrium	CL:0002255	88.87	gold quality
skin of abdomen	UBERON:0001416	88.78	gold quality
colonic epithelium	UBERON:0000397	88.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.91	gold quality
large intestine	UBERON:0000059	87.50	gold quality
colon	UBERON:0001155	87.49	gold quality
zone of skin	UBERON:0000014	87.33	gold quality
intestine	UBERON:0000160	87.24	gold quality
monocyte	CL:0000576	87.17	gold quality
diaphragm	UBERON:0001103	87.15	gold quality
duodenum	UBERON:0002114	87.11	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting PREP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-455-5P	98.74	67.31	795

Literature-anchored findings (GeneRIF, showing 37)

• The high activity of prolyl endopeptidase in the human cortex suggests that prolyl endopeptidase could play a role in cortical functions. Activity in humans is highest in the frontal lobe and cytosolic fractions. (PMID:11792464)
• The activities of pyroglutamyl peptidase I and prolyl endopeptidase in necrozoospermia were found to be higher in the corresponding soluble and particulate sperm fractions, respectively, with respect to those measured in normozoospermic semen (PMID:15380924)
• primary structure, recombinant expression and homology modelling of brain prolyl oligopeptidase (PMID:15838896)
• Mainly localized to perinuclear space and associated with microtubulin cytoskeleton in human neuroblastoma and glioma. Novel functions in axonal transport and/or protein secretion. PEP inhibitors may be useful in variety of related clinical conditions. (PMID:16092940)
• data demonstrate for the first time prolyl endopeptidase turnover of humanin by a limited post-cysteine as well as post-proline proteolysis resulting in the inactivation of this potentially apoptosis-related factor (PMID:16700513)
• Results describe the distribution of immunoreactive prolyl oligopeptidase in human and rat brain. (PMID:17401647)
• The results rule out a causative role of POP in the pathogenesis of CD and strongly suggest that other peptidases are needed to eliminate gliadin-derived, immunoactive and toxic peptides larger than 33-mer, which is a POP inhibitor. (PMID:17454876)
• Data reveal for the first time the presence of a new side opening in prolyl oligopeptidase that was not observed in any of the crystallographic structures described to date. (PMID:19782684)
• Cytosolic Prolyl endopeptidase activity significantly increased in clear cell renal cell carcinoma, urothelial carcinoma of the renal pelvis and head and neck squamous cell carcinoma. (PMID:20362629)
• Plasma levels of PREP activity as well as those of their endogenous inhibitor are suggested as biomarkers of inflammation and oxidative stress in multiple sclerosis (PMID:20370893)
• The constitutive expression of PREP mRNA in chronic lymphocytic leukemia was demonstrated. (PMID:20534982)
• Results indicate that there is no strong and direct interaction between POP and GAP43 at physiological conditions. (PMID:20869470)
• PREP is a regulatory target and a regulatory element in cell signalling. This is the first report of a direct influence of a cell signalling molecule, retinoic acid, on PREP expression. (PMID:21487212)
• These results indicate that POP is a part of the machinery that controls the cell cycle. (PMID:21620802)
• Molecular modeling and docking based approaches were used to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). (PMID:22132071)
• PREP may be associated with secretory processes as well as in reproduction. A more abundant expression of PREP in malignant than benign tumors suggests that PREP may be associated with expansion and metastasis of tumors. (PMID:22740343)
• analysis of the substrate preferences of two post-proline cleaving endopeptidases, prolyl oligopeptidase and fibroblast activation protein alpha (PMID:22750443)
• interaction between prolyl oligopeptidase and glyceraldehyde-3-phosphate dehydrogenase is required for cytosine arabinoside-induced glyceraldehyde-3-phosphate dehydrogenase nuclear translocation and cell death (PMID:23348613)
• first demonstration of colocalization of PREP and pathological proteins in the human brain, supporting the view that, at least in spatial terms, PREP could be associated with pathogenesis of neurodegenerative diseases (PMID:23562579)
• Oxidative stress and the levels of endogenous plasma prolyl oligopeptidase (PREP) inhibitor alpha-2-macroglobulin (alpha2M) decrease PREP activity in multiple sclerosis patients. (PMID:23643808)
• These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells. (PMID:24269815)
• The determination of PEP activity in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice. (PMID:24465166)
• Data indicate that SAXS analysis showed that presequence protease (hPreP) open states and substrate binding dynamics. (PMID:24931469)
• PREP redox inactivation is due to oxidation of cysteine residues and consequent oligomerization through intermolecular disulfide bonds. (PMID:25236746)
• PEP was significantly and positively associated with delinquent, aggressive, externalizing and internalizing behavior subscales. (PMID:26165750)
• TLR4 activation releases prolyl endopeptidase containing exosomes from airway epithelial cells. (PMID:26222144)
• This study found that circulating PREP activity was substantially reduced in all cirrhotic patients but those changes did not have evident correlation to hepatic encephalopathy. (PMID:26420028)
• These findings provide evidence for newly-discovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM. (PMID:27566163)
• Study shows that the expression of POP increases with hepatocyte steatosis suggesting an important role in hepatocytes steatosis and possibly NAFLD. (PMID:27760195)
• It was found that human PREP behaves identically to the porcine homolog, displaying a double bell-shaped pH profile and a pH-dependent solvent kinetic isotope effect of the kcat/Km, features that set it apart from the related exopeptidase dipeptidyl peptidase IV (DPP IV). (PMID:28062644)
• In mitotic phases, PREP shares its localization with tubulin in Sertoli cells, gonocytes, and spermatogonia. (PMID:30380361)
• Prolyl oligopeptidase inhibition reduces PolyQ aggregation and improves cell viability in cellular model of Huntington’s disease. (PMID:31565846)
• Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A. (PMID:31759088)
• DAAM1 and PREP are involved in human spermatogenesis. (PMID:31972124)
• Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner. (PMID:33579026)
• Prolyl oligopeptidase inhibition reduces oxidative stress via reducing NADPH oxidase activity by activating protein phosphatase 2A. (PMID:33838285)
• Preliminary Investigation on the Involvement of Cytoskeleton-Related Proteins, DAAM1 and PREP, in Human Testicular Disorders. (PMID:34360857)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prep	ENSDARG00000057151
mus_musculus	Prep	ENSMUSG00000019849
rattus_norvegicus	Prep	ENSRNOG00000051061
drosophila_melanogaster	CG5355	FBGN0032242
drosophila_melanogaster	CG2528	FBGN0032969

Paralogs (1): PREPL (ENSG00000138078)

Protein

Protein identifiers

Prolyl endopeptidase — P48147 (reviewed: P48147)

Alternative names: Post-proline cleaving enzyme

All UniProt accessions (3): P48147, A0A499FJL1, H0Y5Y0

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Post-translational modifications. The N-terminus is blocked.

Similarity. Belongs to the peptidase S9A family.

RefSeq proteins (1): NP_002717* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001375	Peptidase_S9_cat	Domain
IPR002470	Peptidase_S9A	Family
IPR002471	Pept_S9_AS	Active_site
IPR023302	Pept_S9A_N	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR051167	Prolyl_oligopep/macrocyclase	Family

Pfam: PF00326, PF02897

Enzyme classification (BRENDA):

• EC 3.4.21.26 — prolyl oligopeptidase (BRENDA: 55 organisms, 511 substrates, 729 inhibitors, 161 Km, 156 kcat entries)

Substrate kinetics (BRENDA)

92 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-LEU-4-NITROANILIDE	0.12–1.1	10
L-PHE-4-NITROANILIDE	0.063–6.2	10
BENZYLOXYCARBONYL-GLY-PRO-BETA-NAPHTHYLAMIDE	0.0054–0.14	5
CALCITONIN GENE-RELATED PEPTIDE	0.0012–0.0125	5
BENZYLOXYCARBONYL-GLY-PRO-P-NITROPHENOL	—	4
2-AMINOBENZOYL-GLY-PRO-GLN-N-(2,4-DINITROPHENYL)	0.0002–0.0022	3
BENZYLOXYCARBONYL-GLY-L-PRO-4-NITROANILIDE	0.0653–3.42	3
BENZYLOXYCARBONYL-GLY-PRO-SBZL	0.0015–0.016	3
Z-GLY-PRO-4-NITROANILIDE	0.0308–0.81	3
2-AMINOBENZOYL-ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-A	0.0004–0.0008	2
2-AMINOBENZOYL-ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-A	0.0009–0.0011	2
2-AMINOBENZOYL-GLY-PHE-SER-PRO-PHE-ARG-SER-SER-A	0.0003–0.0005	2
2-AMINOBENZOYL-GLY-PHE-SER-PRO-PHE-ARG-SER-SER-A	0.0008–0.0015	2
ABZ-GLY-L-PHE-L-ARG-L-PRO-L-PHE(NO2)-L-ARG-L-ALA	0.0008–0.0092	2
ARG-PRO-4-NITROANILIDE	0.0229–0.16	2

UniProt features (86 total): strand 44, helix 22, sequence conflict 7, turn 5, active site 3, modified residue 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
9Q5X	X-RAY DIFFRACTION	1.41
9Q5Z	X-RAY DIFFRACTION	1.41
9Q5Y	X-RAY DIFFRACTION	1.49
3DDU	X-RAY DIFFRACTION	1.56
9XZZ	X-RAY DIFFRACTION	1.58
9Q5G	X-RAY DIFFRACTION	1.63
9Q6L	X-RAY DIFFRACTION	1.66
9Q6X	X-RAY DIFFRACTION	1.66
9XYK	X-RAY DIFFRACTION	1.73
9Q6J	X-RAY DIFFRACTION	1.75
9XYL	X-RAY DIFFRACTION	1.81
9Q62	X-RAY DIFFRACTION	1.83
9Q6K	X-RAY DIFFRACTION	1.85
9Q65	X-RAY DIFFRACTION	1.89
9Q64	X-RAY DIFFRACTION	1.94
9Q66	X-RAY DIFFRACTION	2.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48147-F1	98.13	0.99

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 554 (charge relay system); 641 (charge relay system); 680 (charge relay system)

Post-translational modifications (2): 1, 157

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 164 (showing top): GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GCM_GSPT1, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_HORMONE_LEVELS, MORF_HDAC2, GOBP_PROTEIN_MATURATION, GOBP_AMIDE_METABOLIC_PROCESS, AACTTT_UNKNOWN, GFI1_01, GCM_NF2, JIANG_AGING_CEREBRAL_CORTEX_UP, MORF_AATF

GO Biological Process (2): angiotensin maturation (GO:0002003), proteolysis (GO:0006508)

GO Molecular Function (7): metallocarboxypeptidase activity (GO:0004181), serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), oligopeptidase activity (GO:0070012), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endopeptidase activity	2
regulation of angiotensin levels in blood	1
peptide hormone processing	1
protein metabolic process	1
carboxypeptidase activity	1
metalloexopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1302 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PREP	DPP8	Q6V1X1	950
PREP	PGPEP1	Q9NXJ5	948
PREP	DPP9	Q86TI2	946
PREP	DPP4	P27487	940
PREP	APEH	P13798	917
PREP	PRCP	P42785	897
PREP	TRH	P20396	842
PREP	THOP1	P52888	812
PREP	PRSS16	Q9NQE7	783
PREP	DPP7	Q9UHL4	710
PREP	NTS	P30990	688
PREP	DPP10	Q8N608	667
PREP	NLN	Q9BYT8	657
PREP	FAP	Q12884	656
PREP	MME	P08473	651

IntAct

34 interactions, top by confidence:

A	B	Type	Score
KIF3A	KIF3C	psi-mi:“MI:0914”(association)	0.730
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
PREP	GAPDH	psi-mi:“MI:0407”(direct interaction)	0.640
GAPDH	PREP	psi-mi:“MI:0915”(physical association)	0.640
GAPDH	PREP	psi-mi:“MI:0403”(colocalization)	0.640
PREP	GAPDH	psi-mi:“MI:2364”(proximity)	0.640
NSMAF	DUSP14	psi-mi:“MI:0914”(association)	0.530
MTG2	HSPD1	psi-mi:“MI:0914”(association)	0.530
LACC1	DUSP14	psi-mi:“MI:0914”(association)	0.530
LACC1	CKS2	psi-mi:“MI:0914”(association)	0.530
SUCO	RPL10	psi-mi:“MI:0914”(association)	0.350
TNFAIP3	KIF5C	psi-mi:“MI:0914”(association)	0.350
FADD	CHUK	psi-mi:“MI:0914”(association)	0.350
TANK	CNOT1	psi-mi:“MI:0914”(association)	0.350
KIF3A	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.350
SGO2	DUSP14	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
RIPPLY3	A2ML1	psi-mi:“MI:0914”(association)	0.350
PTDSS1	IGLL5	psi-mi:“MI:0914”(association)	0.350
SDC1	ARVCF	psi-mi:“MI:0914”(association)	0.350
KRTAP19-6	PREP	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (101): PREP (Affinity Capture-MS), AIP (Co-fractionation), GLO1 (Co-fractionation), HSPA4 (Co-fractionation), HSPD1 (Co-fractionation), HSPH1 (Co-fractionation), KCNAB2 (Co-fractionation), PABPC4 (Co-fractionation), PREP (Co-fractionation), PREP (Co-fractionation), PREP (Co-fractionation), PREP (Co-fractionation), PREP (Co-fractionation), PREP (Co-fractionation), PREP (Co-fractionation)

ESM2 similar proteins: A0A0K9RL25, A0A2R8QP51, A5PK39, B4G0F3, B8BKI7, B9N1F9, B9SQI7, E0CSI1, O15305, O35621, O70196, O80526, O80840, P00504, P05201, P18163, P23687, P29144, P33121, P41216, P48147, P54767, P55931, Q08DP0, Q16134, Q28BL6, Q2KIG0, Q2R483, Q3SZJ9, Q5RDD3, Q5RFI8, Q5ZMA6, Q60HD6, Q64514, Q64560, Q6UPE1, Q7SXM0, Q7TSV4, Q86TI2, Q8BVG4

Diamond homologs: A0A1Q3EPF5, A0A4S8L6U5, A5LFV8, E2JFG1, E2JFG2, H2E7Q7, H2E7Q8, O70196, P23687, P27028, P27195, P48147, P55577, P81171, P9WEN5, Q06903, Q86AS5, Q9QUR6, Q9XTA2, O07834, Q32N48, Q4J6C6, Q5RAK4, Q8C167, P24555, P55656, Q59536

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

93 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	73
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
4537358	NM_002726.5(PREP):c.1570_1573dup (p.Asn525fs)	Pathogenic
4537359	NM_002726.5(PREP):c.1839-2A>G	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4711 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:105278237:G:C	H680Q	1.000
6:105278237:G:T	H680Q	1.000
6:105278349:C:G	R643P	1.000
6:105278354:A:C	D641E	1.000
6:105278354:A:T	D641E	1.000
6:105278355:T:A	D641V	1.000
6:105278355:T:G	D641A	1.000
6:105278356:C:G	D641H	1.000
6:105281801:A:G	W595R	1.000
6:105281801:A:T	W595R	1.000
6:105288784:G:C	F476L	1.000
6:105288784:G:T	F476L	1.000
6:105288786:A:G	F476L	1.000
6:105373445:G:C	F173L	1.000
6:105373445:G:T	F173L	1.000
6:105373447:A:G	F173L	1.000
6:105373518:T:A	D149V	1.000
6:105373519:C:G	D149H	1.000
6:105278238:T:C	H680R	0.999
6:105278239:G:C	H680D	0.999
6:105278241:C:T	G679D	0.999
6:105278331:G:A	S649F	0.999
6:105278350:G:C	R643G	0.999
6:105278350:G:T	R643S	0.999
6:105278352:T:A	D642V	0.999
6:105278353:C:G	D642H	0.999
6:105278355:T:C	D641G	0.999
6:105278356:C:A	D641Y	0.999
6:105281799:C:A	W595C	0.999
6:105281799:C:G	W595C	0.999

dbSNP variants (sampled 300 via entrez): RS1000012328 (6:105309908 T>C), RS1000034223 (6:105317602 G>C), RS1000041445 (6:105300746 G>C), RS1000055118 (6:105336500 C>G,T), RS1000085570 (6:105309669 G>A), RS1000102557 (6:105351164 G>A), RS1000137657 (6:105276299 A>C), RS1000145738 (6:105369103 A>G), RS1000159046 (6:105284678 A>T), RS1000164050 (6:105360083 C>T), RS1000185890 (6:105329059 A>G,T), RS1000209511 (6:105285041 C>G), RS1000222290 (6:105315884 A>G,T), RS1000269064 (6:105366207 A>C), RS1000275270 (6:105275832 A>G)

Disease associations

OMIM: gene MIM:600400 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3202 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 93,447 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL50	QUERCETIN	3	74,559
CHEMBL67279	TALABOSTAT	3	10,259
CHEMBL267225	BOSWELLIC ACID	2	37
CHEMBL8260	BAICALEIN	2	8,592

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S9: Prolyl oligopeptidase

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
ARI-3531	Inhibition	8.89	pIC50
S 17092	Inhibition	8.8	pKi

Binding affinities (BindingDB)

23 measured of 65 human assays (68 total across all organisms); most potent 23 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-1-[(2S)-4,4-difluoro-1-[4-phenylmethoxy-3-(trifluoromethyl)benzoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	4.5 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S)-4,4-difluoro-1-(3-fluoro-4-phenylmethoxybenzoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	5 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S,4S)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4-methylpyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	13.1 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4,4-difluoropyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	48.7 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S,4R)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4-fluoropyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	60.4 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S,4R)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4-methoxypyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	63.8 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
[4-[(2S)-2-[(2S)-2-cyanopyrrolidine-1-carbonyl]-4,4-difluoropyrrolidine-1-carbonyl]-2,6-dimethoxyphenyl] benzoate	IC50	111 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S,4S)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4-methylsulfanylpyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	176 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S,4S)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4-(trifluoromethyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	176 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S)-4,4-difluoro-1-(2-phenylmethoxybenzoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	255 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S)-4,4-difluoro-1-(4-phenylmethoxybenzoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	287 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
1-[(2S)-4,4-difluoro-1-[3-methoxy-4,5-bis(phenylmethoxy)benzoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	336 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S,4S)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4-phenylpyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	339 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
[4-[(2S)-2-[(2S)-2-cyanopyrrolidine-1-carbonyl]-4,4-difluoropyrrolidine-1-carbonyl]-2,6-dimethoxyphenyl] acetate	IC50	352 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
(2S)-1-[(2S)-4,4-difluoro-1-(3-phenylmethoxybenzoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	487 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
N-[2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl]isoquinoline-4-carboxamide	IC50	610 nM	US-9346814: FAP inhibitors
(2S)-1-[(2S,4R)-1-(3,5-dimethoxy-4-phenylmethoxybenzoyl)-4-[(2-methylpropan-2-yl)oxy]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	IC50	668 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
N-[2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	IC50	860 nM	US-9346814: FAP inhibitors
[5-[(2S)-2-[(2S)-2-cyanopyrrolidine-1-carbonyl]-4,4-difluoropyrrolidine-1-carbonyl]-2,3-dimethoxyphenyl] 2,2-dimethylpropanoate	IC50	2140 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
N-[2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl]quinoline-4-carboxamide	IC50	2400 nM	US-9346814: FAP inhibitors
CHEMBL2385291	IC50	2400 nM
[5-[(2S)-2-[(2S)-2-cyanopyrrolidine-1-carbonyl]-4,4-difluoropyrrolidine-1-carbonyl]-2,3-dimethoxyphenyl] acetate	IC50	5600 nM	US-10125097: 1- [1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives
N-[2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl]isoquinoline-5-carboxamide	IC50	11700 nM	US-9346814: FAP inhibitors

ChEMBL bioactivities

537 potent at pChembl≥5 of 675 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Ki	0.02	nM	CHEMBL189620
10.64	Ki	0.023	nM	CHEMBL189620
9.80	IC50	0.16	nM	CHEMBL6058811
9.77	IC50	0.17	nM	CHEMBL5813416
9.70	IC50	0.2	nM	CHEMBL5874048
9.68	Ki	0.21	nM	CHEMBL97152
9.66	IC50	0.22	nM	CHEMBL6052358
9.59	Ki	0.26	nM	CHEMBL95698
9.55	Ki	0.28	nM	CHEMBL318284
9.49	IC50	0.325	nM	CHEMBL5941199
9.47	Ki	0.34	nM	CHEMBL318630
9.46	IC50	0.35	nM	CHEMBL5941199
9.43	IC50	0.37	nM	CHEMBL6052358
9.40	Ki	0.4	nM	Z-PRO-PROLINAL
9.38	IC50	0.42	nM	CHEMBL302654
9.35	Ki	0.45	nM	CHEMBL99305
9.35	IC50	0.45	nM	CHEMBL65284
9.34	IC50	0.46	nM	CHEMBL291393
9.30	IC50	0.5	nM	CHEMBL22766
9.29	IC50	0.51	nM	CHEMBL5949449
9.28	IC50	0.52	nM	CHEMBL63745
9.26	IC50	0.55	nM	CHEMBL294367
9.18	IC50	0.66	nM	CHEMBL5768806
9.17	IC50	0.67	nM	CHEMBL5964348
9.14	Ki	0.73	nM	CHEMBL2333024
9.14	IC50	0.73	nM	CHEMBL5820353
9.12	Ki	0.75	nM	CHEMBL3817958
9.07	IC50	0.85	nM	CHEMBL65512
9.06	IC50	0.87	nM	CHEMBL5813416
9.06	IC50	0.87	nM	CHEMBL6040206
9.04	Ki	0.92	nM	CHEMBL189620
9.03	IC50	0.935	nM	CHEMBL5914777
9.02	Ki	0.95	nM	CHEMBL189620
9.01	Ki	0.97	nM	CHEMBL289651
9.01	IC50	0.97	nM	CHEMBL5916929
9.00	Ki	1	nM	CHEMBL3817958
9.00	Ki	1	nM	Z-PRO-PROLINAL
9.00	IC50	1	nM	CHEMBL4758377
9.00	IC50	1	nM	CHEMBL4762591
9.00	IC50	1	nM	CHEMBL4746891
9.00	IC50	1	nM	CHEMBL65338
8.96	IC50	1.1	nM	CHEMBL66088
8.96	IC50	1.1	nM	Z-PRO-PROLINAL
8.92	IC50	1.2	nM	CHEMBL5874048
8.92	IC50	1.2	nM	CHEMBL62580
8.90	Ki	1.25	nM	CHEMBL318284
8.90	IC50	1.27	nM	CHEMBL6027846
8.89	IC50	1.3	nM	CHEMBL2333024
8.89	IC50	1.3	nM	CHEMBL4464623
8.85	IC50	1.4	nM	CHEMBL5914777

PubChem BioAssay actives

459 with measured affinity, of 1173 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-1-[(2S)-1-(4-phenylbutanoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	1127417: Inhibition of prolyl oligopeptidase (unknown origin)	ki	<0.0001	uM
benzyl (2S)-2-[(2S)-2-(5-phenyl-1,2-oxazole-3-carbonyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0002	uM
benzyl 2-[2-(1,2-thiazole-3-carbonyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0003	uM
benzyl (2S)-2-[(2S)-2-[5-(phenylmethoxymethyl)-1,2-oxazole-3-carbonyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0003	uM
4-phenyl-1-[(2S)-2-[(2S)-2-[5-(phenylmethoxymethyl)-1,2-oxazole-3-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]butan-1-one	160234: In vitro inhibitory activity determined against prolyl oligopeptidase (PO) in human	ki	0.0003	uM
(2S)-1-[(2S)-1-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0004	uM
(2S)-1-[(2S)-1-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0004	uM
benzyl (2S)-2-[(2S)-2-formylpyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	1539752: Inhibition of recombinant human POP assessed as affinity constant of second step of inhibition pre-incubated for 2 hrs before addition of ZGP-pNA substrate and measured every 30 secs for first 60 mins followed by every 2 mins for next 5 hrs by dilution assay	ki	0.0004	uM
benzyl (2S)-2-[(2S)-2-(5-trimethylsilyl-1,2-oxazole-3-carbonyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0004	uM
(2S)-1-[(2S)-1-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0005	uM
(2S)-1-[(4R)-3-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0005	uM
(2S)-1-[(4R)-3-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0006	uM
[(2R)-1-[(2S)-3-methyl-2-(pyridine-3-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid	736680: Competitive inhibition of human PREP using Suc-GP-AMC as substrate by Lineweaver-Burk plot analysis	ki	0.0007	uM
(4R)-3-[(4R)-3-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]-1,3-thiazolidine-4-carbonyl]-1,3-thiazolidine-4-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0008	uM
(2S)-1-[(3aS,4R,7aR)-2-benzyl-3-oxo-3a,4,5,7a-tetrahydro-1H-isoindole-4-carbonyl]pyrrolidine-2-carbonitrile	1307737: Inhibition of human POP by tight binding based Morrison equation analysis	ki	0.0008	uM
(2S)-1-[(4R)-3-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0010	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(3,4-dichlorophenyl)sulfanylmethyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0010	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(2,4-dichlorophenyl)methyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0010	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(2-iodophenyl)methyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0010	uM
4-phenyl-1-[(2S)-2-(pyrrolidine-1-carbonyl)pyrrolidin-1-yl]butan-1-one	1127417: Inhibition of prolyl oligopeptidase (unknown origin)	ki	0.0010	uM
(2S)-1-[(4R)-3-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0011	uM
(2S)-1-[(2S)-1-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0012	uM
[(2R)-1-[(2S)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid	1539747: Inhibition of POP (unknown origin)	ic50	0.0013	uM
[(2S,3aS,7aS)-2-(1,3-thiazolidine-3-carbonyl)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-[(1R,2R)-2-phenylcyclopropyl]methanone	1307744: Inhibition of human POP using Z-Gly-Pro-7-AMC substrate	ki	0.0015	uM
[(2R)-1-(4-oxo-4-phenylbutanoyl)pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0017	uM
[(2R)-1-[2-(naphthalene-1-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736684: Inhibition of human PREP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0018	uM
[(2R)-1-[2-(pyridine-3-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736684: Inhibition of human PREP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0018	uM
(3S)-8-acetyl-6-(2-phenylethoxy)-3-(pyrrolidine-1-carbonyl)-2,3-dihydro-1H-indolizin-5-one	341663: Inhibition of human recombinant POP expressed in sEscherichia coli	ic50	0.0020	uM
[(2R)-1-[2-[(2,5-dichlorobenzoyl)amino]acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0022	uM
[(2R)-1-[2-(cyclopentanecarbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0023	uM
2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]-1-[(4R)-4-(1,3-thiazolidine-3-carbonyl)-1,3-thiazolidin-3-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0023	uM
[(2R)-1-[2-(cyclohexanecarbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0027	uM
[(2R)-1-[2-(3-oxo-1H-isoindol-2-yl)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0028	uM
benzyl N-[(2S)-1-[(2S)-2-cyanopyrrolidin-1-yl]-1-oxopropan-2-yl]carbamate	470837: Inhibition of prolyl oligopeptidase in human LN229 cell extracts assessed as blockade of Z-Gly-Pro-AMC substrate hydrolysis by fluorimetric assay	ic50	0.0030	uM
(3S)-8-acetyl-6-[2-(4-fluorophenyl)ethoxy]-3-(pyrrolidine-1-carbonyl)-2,3-dihydro-1H-indolizin-5-one	341663: Inhibition of human recombinant POP expressed in sEscherichia coli	ic50	0.0030	uM
2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]-1-[(2R)-2-(1,3-thiazolidine-3-carbonyl)pyrrolidin-1-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0034	uM
(2S)-1-(2-benzyl-3-oxo-1H-isoindole-4-carbonyl)pyrrolidine-2-carbaldehyde	1539752: Inhibition of recombinant human POP assessed as affinity constant of second step of inhibition pre-incubated for 2 hrs before addition of ZGP-pNA substrate and measured every 30 secs for first 60 mins followed by every 2 mins for next 5 hrs by dilution assay	ki	0.0035	uM
1-[(4R)-4-(pyrrolidine-1-carbonyl)-1,3-thiazolidin-3-yl]-2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0040	uM
(3S)-8-(benzenesulfonyl)-6-[(3,5-difluorophenyl)methoxy]-3-(pyrrolidine-1-carbonyl)-2,3-dihydro-1H-indolizin-5-one	341663: Inhibition of human recombinant POP expressed in sEscherichia coli	ic50	0.0040	uM
1-[(2S)-2-(cyclopentanecarbonyl)pyrrolidin-1-yl]-5-[(2S)-2-[(2S)-2-(2-hydroxyacetyl)pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-3,3-dimethylpentane-1,5-dione	2082814: Inhibition of recombinant human PREP proteolytic activity transfected in PREP knockout HEK293 cells using Suc-Gly-Pro-AMC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence based microplate reader analysis	ic50	0.0040	uM
[(2R)-1-[2-[(2,6-dichlorobenzoyl)amino]acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0044	uM
[(2R)-1-[2-(2-methylpropanoylamino)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0045	uM
[(3S)-3-(pyrrolidine-1-carbonyl)-2-azabicyclo[2.2.2]octan-2-yl]-[(1R,2S)-2-thiophen-2-ylcyclopropyl]methanone	161115: Inhibitory activity was evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0048	uM
1-[(2S,3aS,7aS)-2-(pyrrolidine-1-carbonyl)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-6,6,6-trifluoro-5-phenylhexan-1-one	161116: Inhibitory activity evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0050	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(4-methoxyphenyl)methyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0050	uM
[(2R)-1-[2-(pyridine-4-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736684: Inhibition of human PREP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0050	uM
1-[(2R)-2-(pyrrolidine-1-carbonyl)pyrrolidin-1-yl]-2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0054	uM
tert-butyl (3R)-3-(pyrrolidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate	161116: Inhibitory activity evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0055	uM
(2S)-2-[[(2S)-1-[(3R)-2-[(2S)-2-[[2-[[2-[[(2S,4R)-1-[(2S)-1-[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]-2,3-dihydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid	161116: Inhibitory activity evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0055	uM
N-[3-methoxy-4-[(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]pyrrolidine-1-carbonyl]phenyl]acetamide	1520002: Inhibition of recombinant human N-terminal His-tagged POP (2 to 710 residues) expressed in SF21 cells using Z-Gly-Pro-AMC as substrate incubated for 5 to 10 mins followed by substrate addition and measured for 30 mins by fluorescence based assay	ki	0.0060	uM

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
sulindac sulfide	increases expression	1
N-benzyloxycarbonylprolylprolinal	decreases activity	1
di-n-butylphosphoric acid	affects expression	1
sciadopitysin	decreases activity	1
CGP 52608	affects binding, increases reaction	1
JTP 4819	decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol AF	increases expression	1
Acetaminophen	affects response to substance	1
Aspirin	decreases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Dactinomycin	affects cotreatment, increases secretion	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases expression	1

ChEMBL screening assays

197 unique, capped per target: 195 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1010602	Binding	Inhibition of POP	(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor. — Bioorg Med Chem Lett
CHEMBL5723281	Functional	Affinity Biochemical interaction: (inhibition of bovine prolyl endopeptidase in cleaving chromogenic substrate) EUB0002698a PREP	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3EU	Abcam HEK293T PREP KO	Transformed cell line	Female
CVCL_TG56	HAP1 PREP (-) 1	Cancer cell line	Male
CVCL_XR83	HAP1 PREP (-) 2	Cancer cell line	Male
CVCL_XR84	HAP1 PREP (-) 3	Cancer cell line	Male
CVCL_XR85	HAP1 PREP (-) 4	Cancer cell line	Male
CVCL_XR86	HAP1 PREP (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.