Plasmodium falciparum proteasome subunit beta type-5 | Antimalarial targets | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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Plasmodium falciparum proteasome subunit beta type-5

Target id: 3088

Nomenclature: Plasmodium falciparum proteasome subunit beta type-5

Family: Antimalarial targets

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 271 PF3D7_1011400 proteasome subunit beta type-5
Database Links
PlasmoDB
UniProtKB

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
bortezomib Pf Inhibition 7.3 pIC50 7
pIC50 7.3 (IC50 5.3x10-8 M) Fluorogenic peptide assay used to assess purified Pf20S proteasome activity [7]
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
bortezomib Pf3D7 Parasite growth inhibition assay - - 7.5 pIC50 5
pIC50 7.5 (IC50 3.1x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib PfHB3 Parasite growth inhibition assay - - 7.5 pIC50 5
pIC50 7.5 (IC50 3.1x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib PfDd2 Parasite growth inhibition assay - - 7.4 pIC50 5
pIC50 7.4 (IC50 3.7x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib PfW2 Parasite growth inhibition assay - - 7.4 pIC50 5
pIC50 7.4 (IC50 4.3x10-8 M) [3H]-hypoxanthine incorporation [5]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Malaria Pharmacology Comments
The eukaryotic 26S proteasome is a multi-subunit protease complex that is involved in diverse cellular processes. It consists of a 20S catalytic core capped at one or both ends by 19S regulatory complexes, with a recent study elucidating the structure of the P. falciparum 20S core (PDB ID: 5FMG,[4]). Proteasome inhibitors have been shown to have potential as antimalarial therapies that are effective against multiple stages of the P. falciparum lifecycle [1-2], but have been precluded from clinical development because of low species selectivity. Next-generation proteasome inhibitors that target the β2 and β5 subunits of the P. falciparum 20S core have been developed and these exhibit improved selectivity for the malaria parasite [3-4,6].

References

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1. Czesny B, Goshu S, Cook JL, Williamson KC. (2009) The proteasome inhibitor epoxomicin has potent Plasmodium falciparum gametocytocidal activity. Antimicrob. Agents Chemother., 53 (10): 4080-5. [PMID:19651911]

2. Gantt SM, Myung JM, Briones MR, Li WD, Corey EJ, Omura S, Nussenzweig V, Sinnis P. (1998) Proteasome inhibitors block development of Plasmodium spp. Antimicrob. Agents Chemother., 42 (10): 2731-8. [PMID:9756786]

3. Kirkman LA, Zhan W, Visone J, Dziedziech A, Singh PK, Fan H, Tong X, Bruzual I, Hara R, Kawasaki M et al.. (2018) Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance. Proc. Natl. Acad. Sci. U.S.A., 115 (29): E6863-E6870. [PMID:29967165]

4. Li H, O'Donoghue AJ, van der Linden WA, Xie SC, Yoo E, Foe IT, Tilley L, Craik CS, da Fonseca PC, Bogyo M. (2016) Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature, 530 (7589): 233-6. [PMID:26863983]

5. Reynolds JM, El Bissati K, Brandenburg J, Günzl A, Mamoun CB. (2007) Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B. BMC Clin Pharmacol, 7: 13. [PMID:17956613]

6. Stokes BH, Yoo E, Murithi JM, Luth MR, Afanasyev P, da Fonseca PCA, Winzeler EA, Ng CL, Bogyo M, Fidock DA. (2019) Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents. PLoS Pathog., 15 (6): e1007722. [PMID:31170268]

7. Xie SC, Gillett DL, Spillman NJ, Tsu C, Luth MR, Ottilie S, Duffy S, Gould AE, Hales P, Seager BA et al.. (2018) Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome. J. Med. Chem., 61 (22): 10053-10066. [PMID:30373366]

How to cite this page

Antimalarial targets: Plasmodium falciparum proteasome subunit beta type-5. Last modified on 23/09/2020. Accessed on 25/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3088.