Target Information
| Target General Information | Top | |||||
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| Target ID |
T31825
(Former ID: TTDI01041)
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| Target Name |
Hemoglobin subunit beta (HBB)
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| Synonyms |
LVVhemorphin7; Hemoglobin beta chain; Betaglobin; Beta-globin
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| Gene Name |
HBB
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Thalassaemia [ICD-11: 3A50] | |||||
| Function |
Involved in oxygen transport from the lung to the various peripheral tissues.
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| BioChemical Class |
Pore-forming globin
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| UniProt ID | ||||||
| Sequence |
MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPK
VKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFG KEFTPPVQAAYQKVVAGVANALAHKYH Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T40KDU | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | LentiGlobin | Drug Info | Phase 3 | Beta thalassemia | [2] | |
| 2 | OTL-300 | Drug Info | Phase 1/2 | Beta thalassemia | [3] | |
| 3 | PF-07059013 | Drug Info | Phase 1 | Sickle-cell disorder | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | LentiGlobin | Drug Info | [1] | |||
| 2 | PF-07059013 | Drug Info | [6] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Nitric oxide | Ligand Info | |||||
| Structure Description | Human hemoglobin nitric oxide adduct | PDB:4N8T | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [7] |
| PDB Sequence |
VHLTPEEKSA
10 VTALWGKVNV20 DEVGGEALGR30 LLVVYPWTQR40 FFESFGDLST50 PDAVMGNPKV 60 KAHGKKVLGA70 FSDGLAHLDN80 LKGTFATLSE90 LHCDKLHVDP100 ENFRLLGNVL 110 VCVLAHHFGK120 EFTPPVQAAY130 QKVVAGVANA140 LAHKYH
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Myo-inositol hexaphosphate | Ligand Info | |||||
| Structure Description | REFINEMENT OF A PARTIALLY OXYGENATED T STATE HAEMOGLOBIN AT 1.5 ANGSTROMS RESOLUTION | PDB:1THB | ||||
| Method | X-ray diffraction | Resolution | 1.50 Å | Mutation | No | [8] |
| PDB Sequence |
VHLTPEEKSA
10 VTALWGKVNV20 DEVGGEALGR30 LLVVYPWTQR40 FFESFGDLST50 PDAVMGNPKV 60 KAHGKKVLGA70 FSDGLAHLDN80 LKGTFATLSE90 LHCDKLHVDP100 ENFRLLGNVL 110 VCVLAHHFGK120 EFTPPVQAAY130 QKVVAGVANA140 LAHKYH
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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).
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
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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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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| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 7.47E-05 |
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| Closeness centrality | 1.89E-01 | Radiality | 1.32E+01 | Clustering coefficient | 1.67E-01 |
| Neighborhood connectivity | 1.00E+01 | Topological coefficient | 2.88E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | African trypanosomiasis | |||||
| 2 | Malaria | |||||
| Reactome | [+] 4 Reactome Pathways | + | ||||
| 1 | Erythrocytes take up carbon dioxide and release oxygen | |||||
| 2 | Erythrocytes take up oxygen and release carbon dioxide | |||||
| 3 | Scavenging of heme from plasma | |||||
| 4 | Factors involved in megakaryocyte development and platelet production | |||||
| WikiPathways | [+] 7 WikiPathways | + | ||||
| 1 | Binding and Uptake of Ligands by Scavenger Receptors | |||||
| 2 | Uptake of Carbon Dioxide and Release of Oxygen by Erythrocytes | |||||
| 3 | Uptake of Oxygen and Release of Carbon Dioxide by Erythrocytes | |||||
| 4 | Factors involved in megakaryocyte development and platelet production | |||||
| 5 | Folate Metabolism | |||||
| 6 | Vitamin B12 Metabolism | |||||
| 7 | Selenium Micronutrient Network | |||||
| References | Top | |||||
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| REF 1 | Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of beta-thalassemia and sickle cell disease. Curr Gene Ther. 2015;15(1):64-81. | |||||
| REF 2 | ClinicalTrials.gov (NCT03207009) A Study Evaluating the Efficacy and Safety of the LentiGlobin BB305 Drug Product in Subjects With Transfusion-Dependent beta-Thalassemia. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT03275051) Long-term Follow-up of Subjects Treated With OTL-300 for Transfusion Dependent Beta-thalassemia Study (TIGET-BTHAL). U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT04323124) A PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE AND MULTIPLE DOSE ESCALATION STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF PF-07059013 AND OPEN-LABEL ASSESSMENT OF FOOD AND FORMULATION ON PHARMACOKINETICS OF PF-07059013 IN HEALTHY ADULT PARTICIPANTS. U.S.National Institutes of Health. | |||||
| REF 5 | Clinical pipeline report, company report or official report of Orchard Therapeutics. | |||||
| REF 6 | PF-07059013: A non-covalent hemoglobin modulator favorably impacts disease state in a mouse model of sickle cell disease. Am J Hematol. 2021 Aug 1;96(8):E272-E275. | |||||
| REF 7 | Crystallographic characterization of the nitric oxide derivative of R-state human hemoglobin. Nitric Oxide. 2014 May 30;39:46-50. | |||||
| REF 8 | Refinement of a partially oxygenated T state human haemoglobin at 1.5 A resolution. Acta Crystallogr B. 1990 Jun 1;46 ( Pt 3):409-18. | |||||
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