Target Information

Target General Information

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Target ID

T14558 (Former ID: TTDS00130)

Target Name

Tryptase alpha/beta-1 (Tryptase)

Synonyms

Tryptase-1; Tryptase alpha-1; Tryptase I; TPSB1; TPS2; TPS1

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Gene Name

TPSAB1

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Fungal infection [ICD-11: 1F29-1F2F]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

May play a role in innate immunity. Isoform 2 cleaves large substrates, such as fibronectin, more efficiently than isoform 1, but seems less efficient toward small substrates. Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type.

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BioChemical Class

Peptidase

UniProt ID

TRYB1_HUMAN

EC Number

EC 3.4.21.59

Sequence

MLNLLLLALPVLASRAYAAPAPGQALQRVGIVGGQEAPRSKWPWQVSLRVHGPYWMHFCG
GSLIHPQWVLTAAHCVGPDVKDLAALRVQLREQHLYYQDQLLPVSRIIVHPQFYTAQIGA
DIALLELEEPVNVSSHVHTVTLPPASETFPPGMPCWVTGWGDVDNDERLPPPFPLKQVKV
PIMENHICDAKYHLGAYTGDDVRIVRDDMLCAGNTRRDSCQGDSGGPLVCKVNGTWLQAG
VVSWGEGCAQPNRPGIYTRVTYYLDWIHHYVPKKP

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3D Structure

Click to Show 3D Structure of This Target

PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Lactoferrin

Drug Info

Approved

Solid tumour/cancer

[2]

Pentamidine

Drug Info

Approved

Fungal infection

[3]

Discontinued Drug(s)

[+] 5 Discontinued Drugs

APC-2059

Drug Info

Discontinued in Phase 2

Inflammatory bowel disease

[4]

APC-366

Drug Info

Discontinued in Phase 2

Asthma

[5]

BABIM

Drug Info

Terminated

Asthma

[6]

BAY-17-1998

Drug Info

Terminated

Asthma

[7]

BAY-44-3428

Drug Info

Terminated

Asthma

[8]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 11 Inhibitor drugs

Lactoferrin

Drug Info

[1]

Pentamidine

Drug Info

[1], [9]

APC-2059

Drug Info

[10]

APC-366

Drug Info

[1]

BABIM

Drug Info

[1]

BAY-44-3428

Drug Info

[12]

AMG-126737

Drug Info

[13]

BMS-262084

Drug Info

[14]

Grassystatin a

Drug Info

[15]

Lactoferrin

Drug Info

[1]

MOL 6131

Drug Info

[13]

Modulator

[+] 1 Modulator drugs

BAY-17-1998

Drug Info

[11]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: (3'-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}[1,1'-biphenyl]-3-yl){4-[3-(aminomethyl)phenyl]piperidin-1-yl}[3,4-di(hydroxy-kappaO)phenyl]methanonato(2-)hydroxyborate(1-)

Ligand Info

Structure Description

Human beta-tryptase co-crystal structure with 5-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-2-(3'-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-[1,1'-biphenyl]-3-yl)-2-hydroxy-2H-1,3,2-benzodioxaborol-2-uide

PDB:6P0P

Method

X-ray diffraction

Resolution

2.55 Å

Mutation

[16]

PDB Sequence

IVGGQEAPRS

⁴⁰

KWPWQVSLRV

⁵⁰

HGPYWMHFCG

⁶⁰

GSLIHPQWVL

⁷⁰

TAAHCVGPDV

⁸⁰

KDLAALRVQL

⁹⁰

REQHLYYQDQ

¹⁰⁰

LLPVSRIIVH

¹¹⁰

PQFYTAQIGA

¹²⁰

DIALLELEEP

¹³⁰

VKVSSHVHTV

¹⁴⁰

TLPPASETFP

¹⁵⁰

PGMPCWVTGW

¹⁶⁰

GDVDNDERLP

¹⁷⁰

PPFPLKQVKV

¹⁸⁰

PIMENHICDA

¹⁹⁰

KYHLGAYTGD

²⁰⁰

DVRIVRDDML

²¹⁰

CAGNTRRDSC

²²⁰

QGDSGGPLVC

²³⁰

KVNGTWLQAG

²⁴⁰

VVSWGEGCAQ

²⁵⁰

PNRPGIYTRV

²⁶⁰

TYYLDWIHHY

²⁷⁰

VPK

Residue

Distance (Å)

THR115

4.794

GLN117

3.874

ASP218

2.951

SER219

2.849

CYS220

3.760

GLN221

3.514

SER224

3.478

VAL242

3.800

SER243

4.445

Residue

Distance (Å)

TRP244

3.424

GLY245

3.276

GLU246

3.896

GLY247

2.918

CYS248

3.595

ALA249

4.626

GLY255

3.848

ILE256

4.545

Ligand Name: (R,R)-2,3-butanediol

Ligand Info

Structure Description

Crystal Structure of the Recombinant Human Alpha I Tryptase Mutant K192Q/D216G in Complex with Leupeptin

PDB:2F9N

Method

X-ray diffraction

Resolution

1.60 Å

Mutation

Yes

[17]

PDB Sequence

IVGGQEAPRS

²⁵

KWPWQVSLRV

³⁵

RDRYWMHFCG

⁴³

GSLIHPQWVL

⁵³

TAAHCVGPDV

^60C

KDLATLRVQL

⁶⁸

REQHLYYQDQ

⁸¹

LLPVSRIIVH

⁹¹

PQFYIIQTGA

¹⁰¹

DIALLELEEP

¹¹¹

VNISSRVHTV

¹²¹

MLPPASETFP

¹³¹

PGMPCWVTGW

¹⁴¹

GDVDNDEPLP

¹⁵²

PPFPLKQVKV

¹⁶⁰

PIMENHICDA

¹⁷⁰

KYHLGAYTGD

^173G

DVRIIRDDML

¹⁸¹

CAGNSQRDSC

¹⁹¹

QGDSGGPLVC

²⁰¹

KVNGTWLQAG

²¹¹

VVSWGEGCAQ

^221A

PNRPGIYTRV

²³¹

TYYLDWIHHY

²⁴¹

VPK

Residue

Distance (Å)

LEU173A

3.413

GLY173B

3.966

GLU217

4.153

GLN221A

2.975

Residue

Distance (Å)

PRO222

2.776

ASN223

2.911

ARG224

3.583

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Click to View More Binding Site Information of This Target with Different Ligands

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.

Chemical Structure based Activity Landscape of Target

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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

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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Reactome

[+] 1 Reactome Pathways

Activation of Matrix Metalloproteinases

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Inhibitors of tryptase for the treatment of mast cell-mediated diseases. Curr Pharm Des. 1998 Oct;4(5):381-96.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 3

Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.

REF 4

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010270)

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003595)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010022)

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007862)

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010843)

REF 9

Bis(5-amidino-2-benzimidazolyl)methane and related amidines are potent, reversible inhibitors of mast cell tryptases. J Pharmacol Exp Ther. 1993 Feb;264(2):676-82.

REF 10

Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study. Aliment Pharmacol Ther. 2002 Mar;16(3):407-13.

REF 11

Bayer AG to Develop Arris Asthma Compound; Arris to Receive Milestone Payment. 1996 Business Wire

REF 12

Bayer AG to Develop Arris Asthma Compound; Arris to Receive Milestone Payment. 1996 Business Wire

REF 13

Tryptase inhibition blocks airway inflammation in a mouse asthma model. J Immunol. 2002 Feb 15;168(4):1992-2000.

REF 14

Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors. Bioorg Med Chem Lett. 2002 Nov 4;12(21):3229-33.

REF 15

Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. J Med Chem. 2009 Sep 24;52(18):5732-47.

REF 16

Novel, Self-Assembling Dimeric Inhibitors of Human Beta Tryptase. J Med Chem. 2020 Mar 26;63(6):3004-3027.

REF 17

X-ray structures of free and leupeptin-complexed human alphaI-tryptase mutants: indication for an alpha-->beta-tryptase transition. J Mol Biol. 2006 Mar 17;357(1):195-209.

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