Target Information

Target General Information

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Target ID

T56625 (Former ID: TTDR01033)

Target Name

Tripeptidyl-peptidase II (TPP2)

Synonyms

Tripeptidyl aminopeptidase; TPP2; TPP-II; TPP II; CCK-inactivating peptidase tripeptidyl peptidase

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Gene Name

TPP2

Target Type

Discontinued target

[1]

Disease

[+] 1 Target-related Diseases

Obesity [ICD-11: 5B80-5B81]

Function

Component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. May be able to complement the 26S proteasome function to some extent under conditions in which the latter is inhibited. Stimulates adipogenesis.

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BioChemical Class

Peptidase

UniProt ID

TPP2_HUMAN

EC Number

EC 3.4.14.10

Sequence

MATAATEEPFPFHGLLPKKETGAASFLCRYPEYDGRGVLIAVLDTGVDPGAPGMQVTTDG
KPKIVDIIDTTGSGDVNTATEVEPKDGEIVGLSGRVLKIPASWTNPSGKYHIGIKNGYDF
YPKALKERIQKERKEKIWDPVHRVALAEACRKQEEFDVANNGSSQANKLIKEELQSQVEL
LNSFEKKYSDPGPVYDCLVWHDGEVWRACIDSNEDGDLSKSTVLRNYKEAQEYGSFGTAE
MLNYSVNIYDDGNLLSIVTSGGAHGTHVASIAAGHFPEEPERNGVAPGAQILSIKIGDTR
LSTMETGTGLIRAMIEVINHKCDLVNYSYGEATHWPNSGRICEVINEAVWKHNIIYVSSA
GNNGPCLSTVGCPGGTTSSVIGVGAYVSPDMMVAEYSLREKLPANQYTWSSRGPSADGAL
GVSISAPGGAIASVPNWTLRGTQLMNGTSMSSPNACGGIALILSGLKANNIDYTVHSVRR
ALENTAVKADNIEVFAQGHGIIQVDKAYDYLVQNTSFANKLGFTVTVGNNRGIYLRDPVQ
VAAPSDHGVGIEPVFPENTENSEKISLQLHLALTSNSSWVQCPSHLELMNQCRHINIRVD
PRGLREGLHYTEVCGYDIASPNAGPLFRVPITAVIAAKVNESSHYDLAFTDVHFKPGQIR
RHFIEVPEGATWAEVTVCSCSSEVSAKFVLHAVQLVKQRAYRSHEFYKFCSLPEKGTLTE
AFPVLGGKAIEFCIARWWASLSDVNIDYTISFHGIVCTAPQLNIHASEGINRFDVQSSLK
YEDLAPCITLKNWVQTLRPVSAKTKPLGSRDVLPNNRQLYEMVLTYNFHQPKSGEVTPSC
PLLCELLYESEFDSQLWIIFDQNKRQMGSGDAYPHQYSLKLEKGDYTIRLQIRHEQISDL
ERLKDLPFIVSHRLSNTLSLDIHENHSFALLGKKKSSNLTLPPKYNQPFFVTSLPDDKIP
KGAGPGCYLAGSLTLSKTELGKKADVIPVHYYLIPPPTKTKNGSKDKEKDSEKEKDLKEE
FTEALRDLKIQWMTKLDSSDIYNELKETYPNYLPLYVARLHQLDAEKERMKRLNEIVDAA
NAVISHIDQTALAVYIAMKTDPRPDAATIKNDMDKQKSTLVDALCRKGCALADHLLHTQA
QDGAISTDAEGKEEEGESPLDSLAETFWETTKWTDLFDNKVLTFAYKHALVNKMYGRGLK
FATKLVEEKPTKENWKNCIQLMKLLGWTHCASFTENWLPIMYPPDYCVF

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3D Structure

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AlphaFold

HIT2.0 ID

T44BA7

Drugs and Modes of Action

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Discontinued Drug(s)

[+] 1 Discontinued Drugs

UCL-2000; butabindide

Drug Info

Discontinued in Phase 1

Obesity

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 19 Inhibitor drugs

UCL-2000; butabindide

Drug Info

[1]

(2S)-aminobutyryl-(R)-pipecolinic acid amide

Drug Info

[3]

(2S)-aminobutyryl-L-prolinamide

Drug Info

[3]

(2S)-aminobutyryl-L-proline (R)-sec-butylamide

Drug Info

[3]

(2S)-aminobutyryl-L-proline isobutylamide

Drug Info

[3]

(2S)-aminobutyryl-L-proline n-butylamide

Drug Info

[3]

(2S)-aminobutyryl-L-proline n-pentylamide

Drug Info

[3]

(2S)-aminobutyryl-L-proline n-propylamide

Drug Info

[3]

(2S)-aminobutyryl-L-proline-(2S)-methylbutylamide

Drug Info

[3]

Alpha-methylalanyl-L-proline butylamide

Drug Info

[3]

example 8 [WO1999033801A1]

Drug Info

[4]

L-isoleucyl-L-prolinamide

Drug Info

[3]

L-leucyl-L-prolinamide

Drug Info

[3]

L-norleucyl-L-prolinamide

Drug Info

[3]

L-norvalyl-L-prolinamide

Drug Info

[3]

L-valyl-L-prolinamide

Drug Info

[3]

L-valyl-L-proline benzylamide

Drug Info

[3]

L-valyl-L-proline hexylamide

Drug Info

[3]

peptide 4

Drug Info

[5]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Similarity Proteins Human Tissue Distribution

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Similarity Proteins

Human Tissue Distribution

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Affiliated Biological Pathways

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Reactome

[+] 1 Reactome Pathways

Antigen processing: Ubiquitination & Proteasome degradation

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.

REF 2

Clinical pipeline report, company report or official report of University College London.

REF 3

Inhibitors of tripeptidyl peptidase II. 3. Derivation of butabindide by successive structure optimizations leading to a potential general approach ... J Med Chem. 2005 Nov 17;48(23):7333-42.

REF 4

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: 2423).

REF 5

Use of lantibiotic synthetases for the preparation of bioactive constrained peptides. Bioorg Med Chem Lett. 2008 May 15;18(10):3025-8.

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