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Plasmodium falciparum proteasome subunit beta type-5

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Target not currently curated in GtoImmuPdb

Malaria Pharmacology Ligand  Target has curated data in GtoMPdb

Target id: 3088

Nomenclature: Plasmodium falciparum proteasome subunit beta type-5

Family: Peptidases and proteinases (Plasmodium spp.)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 271 PF3D7_1011400 proteasome subunit beta type-5
Gene and Protein Information Comments
Our proteasome 20S subunit beta 5 summary page provides information about the homologous human target.
Previous and Unofficial Names Click here for help
PF3D7_1011400 | proteasome subunit beta type-5 | N/A | PF10_0111
Database Links Click here for help
PlasmoDB
UniProtKB

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
bortezomib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Pf Inhibition 7.3 pIC50 12
pIC50 7.3 (IC50 5.3x10-8 M) Fluorogenic peptide assay used to assess purified Pf20S proteasome activity [12]
WLL-vs Small molecule or natural product Pf Inhibition 6.1 pIC50 9
pIC50 6.1 (IC50 8x10-7 M) [9]
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
WLL-vs Small molecule or natural product Pf Parasite growth inhibition assay - - 8.2 pEC50 13
pEC50 8.2 (EC50 6x10-9 M) [13]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
analog 18 [PMID: 28696697] Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 8.5 pIC50 8
pIC50 8.5 (IC50 3.27x10-9 M) SYBR Green I assay (72h) [8]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 7.5 pIC50 10
pIC50 7.5 (IC50 3.1x10-8 M) [3H]-hypoxanthine incorporation [10]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand PfHB3 Parasite growth inhibition assay - - 7.5 pIC50 10
pIC50 7.5 (IC50 3.1x10-8 M) [3H]-hypoxanthine incorporation [10]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand PfDd2 Parasite growth inhibition assay - - 7.4 pIC50 10
pIC50 7.4 (IC50 3.7x10-8 M) [3H]-hypoxanthine incorporation [10]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand PfW2 Parasite growth inhibition assay - - 7.4 pIC50 10
pIC50 7.4 (IC50 4.3x10-8 M) [3H]-hypoxanthine incorporation [10]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
analog 18 [PMID: 28696697] Small molecule or natural product PfNF54 Parasite late stage (V) gametocyte assay - - 6.9 pIC50 8
pIC50 6.9 (IC50 1.3x10-7 M) [8]
Malaria Pharmacology Comments
The eukaryotic 26S proteasome is a highly conserved, multi-subunit protease complex that is involved in diverse cellular processes [2]. It consists of a 20S catalytic core capped at one or both ends by 19S regulatory complexes. A recent study has elucidated the structure of the P. falciparum 20S catalytic core (PDB ID: 5FMG) which is comprised of the proteolytic β1 (caspase-like), β2 (trypsin-like), and β5 (chymotrysin-like) subunits [9]. Functional studies performed in S. cerevisiae suggest that of the three subunits, β5 shows the highest involvement in protein degradation and is therefeore most attractive as a drug target [1,6].
Proteasome inhibitors have been shown to have potential as antimalarial therapies that are effective against multiple stages of the P. falciparum lifecycle [3,5] and that demonstrate synergy with artemisinin-based medicines [4], 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 [7,9,11].

References

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1. Arendt CS, Hochstrasser M. (1997) Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation. Proc Natl Acad Sci U S A, 94 (14): 7156-61. [PMID:9207060]

2. Coux O, Tanaka K, Goldberg AL. (1996) Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem, 65: 801-47. [PMID:8811196]

3. 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]

4. Dogovski C, Xie SC, Burgio G, Bridgford J, Mok S, McCaw JM, Chotivanich K, Kenny S, Gnädig N, Straimer J et al.. (2015) Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol, 13 (4): e1002132. [PMID:25901609]

5. 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]

6. Heinemeyer W, Fischer M, Krimmer T, Stachon U, Wolf DH. (1997) The active sites of the eukaryotic 20 S proteasome and their involvement in subunit precursor processing. J Biol Chem, 272 (40): 25200-9. [PMID:9312134]

7. 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 USA, 115 (29): E6863-E6870. [PMID:29967165]

8. LaMonte GM, Almaliti J, Bibo-Verdugo B, Keller L, Zou BY, Yang J, Antonova-Koch Y, Orjuela-Sanchez P, Boyle CA, Vigil E et al.. (2017) Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity. J Med Chem, 60 (15): 6721-6732. [PMID:28696697]

9. 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]

10. 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]

11. 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]

12. 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]

13. Yoo E, Stokes BH, de Jong H, Vanaerschot M, Kumar T, Lawrence N, Njoroge M, Garcia A, Van der Westhuyzen R, Momper JD et al.. (2018) Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors. J Am Chem Soc, 140 (36): 11424-11437. [PMID:30107725]

How to cite this page

Peptidases and proteinases (Plasmodium spp.): Plasmodium falciparum proteasome subunit beta type-5. Last modified on 22/08/2021. Accessed on 20/09/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3088.