Target Information

Target General Information

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Target ID

T04321 (Former ID: TTDI02092)

Target Name

Staphylococcus Alpha-hemolysin (Stap-coc hly)

Synonyms

hla; Alpha-toxin; Alpha-hemolysin; Alpha-HL

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Gene Name

Stap-coc hly

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Phlegmy cough [ICD-11: SA80-SA8Z]

Medical/surgical procedure injury [ICD-11: PK80-PK81]

Function

Alpha-toxin binds to the membrane of eukaryotic cells (particularly red blood cells, RBC) forming pores, resulting in hemolysis, with the release of low-molecular weight molecules leading to eventual osmotic RBC lysis. Human RBCs bind much less alpha-toxin than do rabbit RBCs. Heptamer oligomerization and pore formation is required for lytic activity.

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BioChemical Class

Alpha-hemolysin channel-forming toxin

UniProt ID

HLA_STAAU

Sequence

MKTRIVSSVTTTLLLGSILMNPVAGAADSDINIKTGTTDIGSNTTVKTGDLVTYDKENGM
HKKVFYSFIDDKNHNKKLLVIRTKGTIAGQYRVYSEEGANKSGLAWPSAFKVQLQLPDNE
VAQISDYYPRNSIDTKEYMSTLTYGFNGNVTGDDTGKIGGLIGANVSIGHTLKYVQPDFK
TILESPTDKKVGWKVIFNNMVNQNWGPYDRDSWNPVYGNQLFMKTRNGSMKAADNFLDPN
KASSLLSSGFSPDFATVITMDRKASKQQTNIDVIYERVRDDYQLHWTSTNWKGTNTKDKW
TDRSSERYKIDWEKEEMTN

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

AR-301

Drug Info

Phase 3

Ventilator-associated pneumonia

[2]

Cyrtominetin

Drug Info

Phase 3

Phlegmy cough

[1]

MEDI4893

Drug Info

Phase 2b

Ventilator-associated pneumonia

[3]

ASN100

Drug Info

Phase 2

Ventilator-associated pneumonia

[4]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

AR-301

Drug Info

[5]

Modulator

[+] 2 Modulator drugs

Cyrtominetin

Drug Info

[1]

ASN100

Drug Info

[7]

Drug Binding Sites of Target

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Ligand Name: O-(Tetradecyloxyphosphonyl)choline

Ligand Info

Structure Description

Structure-based discovery of a novel small-molecule inhibitor of methicillin-resistant S. aureus

PDB:6U49

Method

X-ray diffraction

Resolution

2.35 Å

Mutation

[8]

PDB Sequence

ADSDINIKTG

¹⁰

TTDIGSNTTV

²⁰

KTGDLVTYDK

³⁰

ENGMHKKVFY

⁴⁰

SFIDDKNHNK

⁵⁰

KLLVIRTKGT

⁶⁰

IAGQYRVYSE

⁷⁰

EGANKSGLAW

⁸⁰

PSAFKVQLQL

⁹⁰

PDNEVAQISD

¹⁰⁰

YYPRNSIDTK

¹¹⁰

EYMSTLTYGF

¹²⁰

NGNVTGDDTG

¹³⁰

KIGGLIGANV

¹⁴⁰

SIGHTLKYVQ

¹⁵⁰

PDFKTILESP

¹⁶⁰

TDKKVGWKVI

¹⁷⁰

FNNMVNQNWG

¹⁸⁰

PYDRDSWNPV

¹⁹⁰

YGNQLFMKTR

²⁰⁰

NGSMKAADNF

²¹⁰

LDPNKASSLL

²²⁰

SSGFSPDFAT

²³⁰

VITMDRKASK

²⁴⁰

QQTNIDVIYE

²⁵⁰

RVRDDYQLHW

²⁶⁰

TSTNWKGTNT

²⁷⁰

KDKWTDRSSE

²⁸⁰

RYKIDWEKEE

²⁹⁰

MTN

Residue

Distance (Å)

TYR112

3.843

SER114

3.320

ILE142

4.008

GLY143

3.710

HIS144

2.775

ASN176

3.457

GLN177

3.528

TRP179

3.284

GLY180

2.840

Residue

Distance (Å)

PRO181

3.312

TYR182

2.694

SER186

4.591

GLN194

3.476

MET197

3.361

LYS198

3.941

THR199

4.213

ARG200

3.695

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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 Similarity Proteins

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 Similarity Proteins

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

Target Affiliated Biological Pathways

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Reactome

[+] 1 Reactome Pathways

The NLRP3 inflammasome

WikiPathways

[+] 1 WikiPathways

Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways

References

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REF 1

Molecular insight into the inhibition mechanism of cyrtominetin to alpha-hemolysin by molecular dynamics simulation. Eur J Med Chem. 2013 Apr;62:320-8.

REF 2

ClinicalTrials.gov (NCT03816956) Adjunctive Therapy to Antibiotics in the Treatment of S. Aureus Ventilator-Associated Pneumonia With AR-301 (AR-301-002). U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT02296320) Study of the Efficacy and Safety of MEDI4893

REF 4

ClinicalTrials.gov (NCT02940626) Prevention of S. Aureus Pneumonia Study in Heavily Colonized, Mechanically Ventilated Subjects

REF 5

Clinical pipeline report, company report or official report of Aridis Pharmaceuticals.

REF 6

Mechanisms of neutralization of a human anti-alpha-toxin antibody. J Biol Chem. 2014 Oct 24;289(43):29874-80.

REF 7

Antibacterial antibodies gain traction. Nat Rev Drug Discov. 2015 Nov;14(11):737-8.

REF 8

Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence. J Biol Chem. 2020 May 1;295(18):5944-5959.

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