Plasmodium falciparum plasmepsin X

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Peptidases and proteinases (Plasmodium spp.)
Plasmodium falciparum plasmepsin X

Target id: 3071

Nomenclature: Plasmodium falciparum plasmepsin X

Abbreviated Name: PfPMX

Family: Peptidases and proteinases (Plasmodium spp.)

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Plasmodium falciparum 3D7	-	573		PMX	plasmepsin X

Previous and Unofficial Names
PMX \| Pf3D7_08_v3:415,549..419,066(-) \| PF08_0108

Database Links
Alphafold	Q8IAS0 (Pf3D7)
ChEMBL Target	CHEMBL4523390 (Pf3D7)
PlasmoDB	PF3D7_0808200 (Pf3D7)
UniProtKB	Q8IAS0 (Pf3D7)

Ligand											Sp.	Action	Value	Parameter	Reference
WM382											Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	Inhibition	10.5	pK_i	4
⤷	pK_i 10.5 (K_i 3.5x10^-11 M) [4] Description: Peptide cleavage assay using recombinant PMX

Whole Organism Assay Data Linked to This Target

Key to terms and symbols

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Ligand		Sp.	Assay description	Type	Action	Value	Parameter	Reference
WM382		Pk Plasmodium knowlesi P. knowlesi (Pk) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. This species of the parasite was originally identified as causing simian malaria but it is becoming a significant cause of zoonotic malaria and is an emerging public health issue in Southeast Asia. Pk has a 24-hour asexual replication cycle in erythrocytes and can progress quickly to severe clinical disease with fatal cases reported. ✖	Parasite growth inhibition assay	-	-	9.7	pEC₅₀	4
⤷	pEC₅₀ 9.7 (EC₅₀ 1.8x10^-10 M) SYBR Green assay [4] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 14a [WO2021155612A1]		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	Parasite growth inhibition assay	-	-	9.7	pEC₅₀	3
⤷	pEC₅₀ 9.7 (EC₅₀ 2x10^-10 M) Parasite lactate dehydrogenase (pLDH ) assay following 72 hours in culture [3]
WM382		PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖	Parasite growth inhibition assay	-	-	9.6	pEC₅₀	4
⤷	pEC₅₀ 9.6 (EC₅₀ 2.6x10^-10 M) [4] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
WM382		Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	Parasite growth inhibition assay	-	-	9.2	pEC₅₀	4
⤷	pEC₅₀ 9.2 (EC₅₀ 6x10^-10 M) Results are for R-WM382 [4] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
WM382		PfK1 Plasmodium falciparum K1 P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979. PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain. ✖	Parasite growth inhibition assay	-	-	9.2	pEC₅₀	4
⤷	pEC₅₀ 9.2 (EC₅₀ 6.5x10^-10 M) [4] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 49c [PMID: 29074775]		PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	Parasite growth inhibition assay	-	-	6.3 – 9.2	pIC₅₀	1
⤷	pIC₅₀ 9.2 (IC₅₀ 6x10^-10 M) [³H]-hypoxanthine incorporation following 72 h incubation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) pIC₅₀ <6.3 (IC₅₀ >5x10^-7 M) [³H]-hypoxanthine incorporation following 24 h incubation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
WM382		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	Standard membrane feeding assay (SMFA)	-	-	-	-	4
⤷	Oocyst count: potent inhibition of oocyst development [4] Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)

Malaria Pharmacology Comments
The P. falciparum genome encodes 10 aspartic proteases, classed together as the plasmepsin family, which are involved in diverse cellular processes [2]. P. falciparum plasmepsin X (PfPMX) has emerged as a promising target for antimalarial drug development with studies demonstrating an essential role in merozoite invasion and egress of erythrocytes [5-6].

Malaria Pharmacology Comments

The P. falciparum genome encodes 10 aspartic proteases, classed together as the plasmepsin family, which are involved in diverse cellular processes [2]. P. falciparum plasmepsin X (PfPMX) has emerged as a promising target for antimalarial drug development with studies demonstrating an essential role in merozoite invasion and egress of erythrocytes [5-6].

References

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1. Ciana CL, Siegrist R, Aissaoui H, Marx L, Racine S, Meyer S, Binkert C, de Kanter R, Fischli C, Wittlin S et al.. (2013) Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold. Bioorg Med Chem Lett, 23 (3): 658-62. [PMID:23260352]

2. Coombs GH, Goldberg DE, Klemba M, Berry C, Kay J, Mottram JC. (2001) Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol, 17 (11): 532-7. [PMID:11872398]

3. De Lera Ruiz M., Favuzza P., Guo Z., Hu B. et al.. (2021) Antimalarial agents. Patent number: WO2021155612A1. Assignee: Merck Sharp & Dohme Corp., The Walter and Eliza Hall Insitute of Medical Research, MSD R&D. Priority date: 09/02/2020. Publication date: 12/08/2021.

4. Favuzza P, de Lera Ruiz M, Thompson JK, Triglia T, Ngo A, Steel RWJ, Vavrek M, Christensen J, Healer J, Boyce C et al.. (2020) Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle. Cell Host Microbe, 27 (4): 642-658.e12. [PMID:32109369]

5. Nasamu AS, Glushakova S, Russo I, Vaupel B, Oksman A, Kim AS, Fremont DH, Tolia N, Beck JR, Meyers MJ et al.. (2017) Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science, 358 (6362): 518-522. [PMID:29074774]

6. Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, Collins CR, Blackman MJ, Kursula I, Heussler V et al.. (2017) A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science, 358 (6362): 522-528. [PMID:29074775]

How to cite this page

Peptidases and proteinases (Plasmodium spp.): Plasmodium falciparum plasmepsin X. Last modified on 31/03/2022. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3071.