Target Information
Target General Information | Top | |||||
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Target ID |
T23348
(Former ID: TTDC00108)
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Target Name |
von Willebrand factor (VWF)
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Synonyms |
vWF; F8VWF
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Gene Name |
VWF
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Thrombocytopenia [ICD-11: 3B64] | |||||
2 | Von Willebrand disease [ICD-11: 3B12] | |||||
Function |
Acts as a chaperone for coagulation factor VIII, delivering it to the site of injury, stabilizing its heterodimeric structure and protecting it from premature clearance from plasma. Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V.
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UniProt ID | ||||||
Sequence |
MIPARFAGVLLALALILPGTLCAEGTRGRSSTARCSLFGSDFVNTFDGSMYSFAGYCSYL
LAGGCQKRSFSIIGDFQNGKRVSLSVYLGEFFDIHLFVNGTVTQGDQRVSMPYASKGLYL ETEAGYYKLSGEAYGFVARIDGSGNFQVLLSDRYFNKTCGLCGNFNIFAEDDFMTQEGTL TSDPYDFANSWALSSGEQWCERASPPSSSCNISSGEMQKGLWEQCQLLKSTSVFARCHPL VDPEPFVALCEKTLCECAGGLECACPALLEYARTCAQEGMVLYGWTDHSACSPVCPAGME YRQCVSPCARTCQSLHINEMCQERCVDGCSCPEGQLLDEGLCVESTECPCVHSGKRYPPG TSLSRDCNTCICRNSQWICSNEECPGECLVTGQSHFKSFDNRYFTFSGICQYLLARDCQD HSFSIVIETVQCADDRDAVCTRSVTVRLPGLHNSLVKLKHGAGVAMDGQDVQLPLLKGDL RIQHTVTASVRLSYGEDLQMDWDGRGRLLVKLSPVYAGKTCGLCGNYNGNQGDDFLTPSG LAEPRVEDFGNAWKLHGDCQDLQKQHSDPCALNPRMTRFSEEACAVLTSPTFEACHRAVS PLPYLRNCRYDVCSCSDGRECLCGALASYAAACAGRGVRVAWREPGRCELNCPKGQVYLQ CGTPCNLTCRSLSYPDEECNEACLEGCFCPPGLYMDERGDCVPKAQCPCYYDGEIFQPED IFSDHHTMCYCEDGFMHCTMSGVPGSLLPDAVLSSPLSHRSKRSLSCRPPMVKLVCPADN LRAEGLECTKTCQNYDLECMSMGCVSGCLCPPGMVRHENRCVALERCPCFHQGKEYAPGE TVKIGCNTCVCQDRKWNCTDHVCDATCSTIGMAHYLTFDGLKYLFPGECQYVLVQDYCGS NPGTFRILVGNKGCSHPSVKCKKRVTILVEGGEIELFDGEVNVKRPMKDETHFEVVESGR YIILLLGKALSVVWDRHLSISVVLKQTYQEKVCGLCGNFDGIQNNDLTSSNLQVEEDPVD FGNSWKVSSQCADTRKVPLDSSPATCHNNIMKQTMVDSSCRILTSDVFQDCNKLVDPEPY LDVCIYDTCSCESIGDCACFCDTIAAYAHVCAQHGKVVTWRTATLCPQSCEERNLRENGY ECEWRYNSCAPACQVTCQHPEPLACPVQCVEGCHAHCPPGKILDELLQTCVDPEDCPVCE VAGRRFASGKKVTLNPSDPEHCQICHCDVVNLTCEACQEPGGLVVPPTDAPVSPTTLYVE DISEPPLHDFYCSRLLDLVFLLDGSSRLSEAEFEVLKAFVVDMMERLRISQKWVRVAVVE YHDGSHAYIGLKDRKRPSELRRIASQVKYAGSQVASTSEVLKYTLFQIFSKIDRPEASRI TLLLMASQEPQRMSRNFVRYVQGLKKKKVIVIPVGIGPHANLKQIRLIEKQAPENKAFVL SSVDELEQQRDEIVSYLCDLAPEAPPPTLPPDMAQVTVGPGLLGVSTLGPKRNSMVLDVA FVLEGSDKIGEADFNRSKEFMEEVIQRMDVGQDSIHVTVLQYSYMVTVEYPFSEAQSKGD ILQRVREIRYQGGNRTNTGLALRYLSDHSFLVSQGDREQAPNLVYMVTGNPASDEIKRLP GDIQVVPIGVGPNANVQELERIGWPNAPILIQDFETLPREAPDLVLQRCCSGEGLQIPTL SPAPDCSQPLDVILLLDGSSSFPASYFDEMKSFAKAFISKANIGPRLTQVSVLQYGSITT IDVPWNVVPEKAHLLSLVDVMQREGGPSQIGDALGFAVRYLTSEMHGARPGASKAVVILV TDVSVDSVDAAADAARSNRVTVFPIGIGDRYDAAQLRILAGPAGDSNVVKLQRIEDLPTM VTLGNSFLHKLCSGFVRICMDEDGNEKRPGDVWTLPDQCHTVTCQPDGQTLLKSHRVNCD RGLRPSCPNSQSPVKVEETCGCRWTCPCVCTGSSTRHIVTFDGQNFKLTGSCSYVLFQNK EQDLEVILHNGACSPGARQGCMKSIEVKHSALSVELHSDMEVTVNGRLVSVPYVGGNMEV NVYGAIMHEVRFNHLGHIFTFTPQNNEFQLQLSPKTFASKTYGLCGICDENGANDFMLRD GTVTTDWKTLVQEWTVQRPGQTCQPILEEQCLVPDSSHCQVLLLPLFAECHKVLAPATFY AICQQDSCHQEQVCEVIASYAHLCRTNGVCVDWRTPDFCAMSCPPSLVYNHCEHGCPRHC DGNVSSCGDHPSEGCFCPPDKVMLEGSCVPEEACTQCIGEDGVQHQFLEAWVPDHQPCQI CTCLSGRKVNCTTQPCPTAKAPTCGLCEVARLRQNADQCCPEYECVCDPVSCDLPPVPHC ERGLQPTLTNPGECRPNFTCACRKEECKRVSPPSCPPHRLPTLRKTQCCDEYECACNCVN STVSCPLGYLASTATNDCGCTTTTCLPDKVCVHRSTIYPVGQFWEEGCDVCTCTDMEDAV MGLRVAQCSQKPCEDSCRSGFTYVLHEGECCGRCLPSACEVVTGSPRGDSQSSWKSVGSQ WASPENPCLINECVRVKEEVFIQQRNVSCPQLEVPVCPSGFQLSCKTSACCPSCRCERME ACMLNGTVIGPGKTVMIDVCTTCRCMVQVGVISGFKLECRKTTCNPCPLGYKEENNTGEC CGRCLPTACTIQLRGGQIMTLKRDETLQDGCDTHFCKVNERGEYFWEKRVTGCPPFDEHK CLAEGGKIMKIPGTCCDTCEEPECNDITARLQYVKVGSCKSEVEVDIHYCQGKCASKAMY SIDINDVQDQCSCCSPTRTEPMQVALHCTNGSVVYHEVLNAMECKCSPRKCSK Click to Show/Hide
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ADReCS ID | BADD_A00503 ; BADD_A00998 ; BADD_A01930 ; BADD_A02260 ; BADD_A04520 ; BADD_A05675 ; BADD_A06187 | |||||
HIT2.0 ID | T68WYW |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
1 | Caplacizumab | Drug Info | Approved | Thrombotic thrombocytopenic purpura | [2] | |
2 | Vonvendi | Drug Info | Approved | Von willebrand disease | [3] | |
Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
1 | ALX-0081 | Drug Info | Phase 3 | Thrombotic thrombocytopenic purpura | [4] | |
2 | Recombinant von Willebrand factor/recombinant Factor VIII complex | Drug Info | Phase 3 | Von willebrand disease | [5] | |
3 | ARC1779 | Drug Info | Phase 2 | Intracranial embolism | [6] | |
4 | BT-200 | Drug Info | Phase 2 | Von willebrand disease | [7] | |
5 | DA-697b | Drug Info | Phase 1 | Thrombosis | [8] | |
6 | DTRI-031 | Drug Info | Phase 1 | Ischemic stroke | [9] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | Mitoflaxone | Drug Info | Terminated | Solid tumour/cancer | [10] | |
Mode of Action | [+] 4 Modes of Action | + | ||||
Inhibitor | [+] 6 Inhibitor drugs | + | ||||
1 | Caplacizumab | Drug Info | [2] | |||
2 | ARC1779 | Drug Info | [12] | |||
3 | DA-697b | Drug Info | [8] | |||
4 | DTRI-031 | Drug Info | [14] | |||
5 | Mitoflaxone | Drug Info | [15] | |||
6 | Auryntricarboxylic acid (ATA) | Drug Info | [15] | |||
Replacement | [+] 1 Replacement drugs | + | ||||
1 | Vonvendi | Drug Info | [3] | |||
Binder | [+] 1 Binder drugs | + | ||||
1 | ALX-0081 | Drug Info | [11] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | Recombinant von Willebrand factor/recombinant Factor VIII complex | Drug Info | [1] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Different Human System Profiles of Target | Top |
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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 Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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Tubulointerstitial nephritis antigen (TINAG) | 42.857 (15/35) | 2.00E-03 |
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.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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PI3K-Akt signaling pathway | hsa04151 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Focal adhesion | hsa04510 | Affiliated Target |
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Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
ECM-receptor interaction | hsa04512 | Affiliated Target |
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Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
Complement and coagulation cascades | hsa04610 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Platelet activation | hsa04611 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Click to Show/Hide the Information of Affiliated Human Pathways |
Degree | 16 | Degree centrality | 1.72E-03 | Betweenness centrality | 1.66E-03 |
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Closeness centrality | 2.20E-01 | Radiality | 1.39E+01 | Clustering coefficient | 1.25E-01 |
Neighborhood connectivity | 1.87E+01 | Topological coefficient | 8.89E-02 | Eccentricity | 12 |
Download | Click to Download the Full PPI Network of This Target | ||||
Target Regulators | Top | |||||
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Target-regulating Transcription Factors | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
1 | PI3K-Akt signaling pathway | |||||
2 | Focal adhesion | |||||
3 | ECM-receptor interaction | |||||
4 | Complement and coagulation cascades | |||||
5 | Platelet activation | |||||
Panther Pathway | [+] 2 Panther Pathways | + | ||||
1 | Blood coagulation | |||||
2 | Inflammation mediated by chemokine and cytokine signaling pathway | |||||
Reactome | [+] 9 Reactome Pathways | + | ||||
1 | Platelet degranulation | |||||
2 | Intrinsic Pathway of Fibrin Clot Formation | |||||
3 | Integrin cell surface interactions | |||||
4 | Integrin alphaIIb beta3 signaling | |||||
5 | GRB2:SOS provides linkage to MAPK signaling for Integrins | |||||
6 | p130Cas linkage to MAPK signaling for integrins | |||||
7 | GP1b-IX-V activation signalling | |||||
8 | MAP2K and MAPK activation | |||||
9 | Platelet Adhesion to exposed collagen | |||||
WikiPathways | [+] 7 WikiPathways | + | ||||
1 | Complement and Coagulation Cascades | |||||
2 | Focal Adhesion | |||||
3 | Blood Clotting Cascade | |||||
4 | Platelet Adhesion to exposed collagen | |||||
5 | Integrin alphaIIb beta3 signaling | |||||
6 | GP1b-IX-V activation signalling | |||||
7 | Formation of Fibrin Clot (Clotting Cascade) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | 6 Factor VIII Concentrates, Factor VIII/von Willebrand Factor Concentrates, Factor IX Concentrates, Activated Prothrombin Complex Concentrates. Transfus Med Hemother. 2009 December; 36(6): 409-418. | |||||
REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
REF 3 | Clinical pipeline report, company report or official report of Vonvendi. | |||||
REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 5 | FcRn Rescues Recombinant Factor VIII Fc Fusion Protein from a VWF Independent FVIII Clearance Pathway in Mouse Hepatocytes. PLoS One. 2015 Apr 23;10(4):e0124930. | |||||
REF 6 | ClinicalTrials.gov (NCT00742612) Effect of ARC1779 on Cerebral Microembolism in Patients Undergoing Carotid Endarterectomy. U.S. National Institutes of Health. | |||||
REF 7 | ClinicalTrials.gov (NCT04677803) A Phase 2a Multiple Dose Basket Study of the Safety, Tolerability, and Pharmacologic Activity of BT200 in Patients With Hereditary Bleeding Disorders. U.S.National Institutes of Health. | |||||
REF 8 | A new oral antiplatelet agent with potent antithrombotic properties: comparison of DZ-697b with clopidogrel a randomised phase I study. Thromb Haemost. 2010 Jan;103(1):205-12. | |||||
REF 9 | ClinicalTrials.gov (NCT05005520) A Randomized, Double-Blind, Single-Center, Placebo-Controlled Phase 1 Study to Evaluate the Safety, Tolerability, PK and PD of Intravenous DTRI-031 in Healthy Volunteers. U.S.National Institutes of Health. | |||||
REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000745) | |||||
REF 11 | Clinical pipeline report, company report or official report of Ablynx | |||||
REF 12 | Short-Acting Anti-VWF (von Willebrand Factor) Aptamer Improves the Recovery, Survival, and Hemostatic Functions of Refrigerated Platelets. Arterioscler Thromb Vasc Biol. 2019 Oct;39(10):2028-2037. | |||||
REF 13 | Clinical pipeline report, company report or official report of Guardian Theapeutics | |||||
REF 14 | Clinical pipeline report, company report or official report of Basking Biosciences | |||||
REF 15 | Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci. 2002 Jan;23(1):25-32. |
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