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Plasmodium sexual blood stage (gametocyte)

Stage ID:4
Name:Plasmodium sexual blood stage (gametocyte)
Associated with:8 targets
16 ligands
Description
The lifecycle stage during which a small percentage of merozoites commit to a cycle of sexual reproduction and differentiate into male or female gametocytes. It is this form of the parasite that is ingested in the vector's blood meal, leading to transmission back to the mosquito from the human host. The sexual blood stage can be further subdivided into stages I-V within the human host, with mature stage V gametocytes infective to the mosquito.

Blocking development of the parasite during this stage prevents transmission from human to mosquito.

Interactions

Interactions
Key to terms and symbols Click column headers to sort
Target Ligand Sp. Action Value Parameter Reference
Plasmodium falciparum phenylalanine--tRNA ligase alpha subunit BRD3444 Pf3D7 - 6.2 pEC50 6
pEC50 6.2 (EC50 6.63x10-7 M) [6]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite late stage (IV–V) gametocyte assay
Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase cipargamin PfNF54 - - - 16
Giemsa-stained blood film counts: dose-dependent, inhibition of stage V gametocyte development [16]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite late stage (III–V) gametocyte assay
Giemsa-stained blood film counts: dose-dependent, significant inhibition of stage II gametocyte development [16]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite early stage (I–II) gametocyte assay
Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PA21A092 PfNF54 - 7.1 – 7.4 pEC50 15
pEC50 7.4 (EC50 3.9x10-8 M) inhibition of gamete formation from mature Stage V male gametocytes [15]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite dual gamete formation assay (DGFA)
pEC50 7.1 (EC50 7.4x10-8 M) inhibition of gamete formation from mature Stage V female gametocytes [15]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite dual gamete formation assay (DGFA)
Plasmodium falciparum phosphatidylinositol 4-kinase beta MMV048 PfNF54 - 6.6 – 6.8 pIC50 11
pIC50 6.8 (IC50 1.4x10-7 M) Parasite late stage (IV-V) gametocyte assay using luciferase reporter line [11]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
pIC50 6.7 (IC50 2.14x10-7 M) Parasite early stage (I-III) gametocyte assay using luciferase reporter line [11]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
pIC50 6.6 (IC50 2.85x10-7 M) Parasite late stage (IV-V) gametocyte assay: parasitic lactate dehydrogenase (pLDH) assay [11]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Plasmodium falciparum phosphatidylinositol 4-kinase beta UCT943 Pf - 6.9 – 7.2 pIC50 2
pIC50 7.2 (IC50 6.6x10-8 M) Parasite late stage (IV-V) gametocyte assay using luciferase reporter line [2]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
pIC50 6.9 (IC50 1.34x10-7 M) Parasite early stage (I-III) gametocyte assay using luciferase reporter line [2]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Plasmodium falciparum phosphatidylinositol 4-kinase beta NCATS-SM3710 Pf - 8.2 pEC50 7
pEC50 8.2 (EC50 5.77x10-9 M) Viability measured using MitoProbe DiIC1(5) staining and flow cytometry [7]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite late stage (IV–V) gametocyte assay
Plasmodium falciparum lysine--tRNA ligase compound 5 [PMID: 30894487] PfNF54 - 5.0 pEC50 1
pEC50 5.0 (EC50 9.9x10-6 M) Saponin-lysis Sexual Stage Assay (SaLSSA) [1]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite stage V gametocyte assay
Plasmodium falciparum histone deacetylase 1 panobinostat Pf3D7 - 6.0 pIC50 14
pIC50 6.0 (IC50 9.35x10-7 M) AlamarBlue viability assay [14]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Plasmodium falciparum histone deacetylase 1 panobinostat PfDd2 - 6.8 pIC50 14
pIC50 6.8 (IC50 1.48x10-7 M) AlamarBlue viability assay [14]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Plasmodium falciparum histone deacetylase 1 panobinostat PfHB3 - 6.9 pIC50 14
pIC50 6.9 (IC50 1.18x10-7 M) AlamarBlue viability assay [14]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Plasmodium falciparum histone deacetylase 1 FNDR-20123 Pf - 6.7 pIC50 12
pIC50 6.7 (IC50 1.9x10-7 M) Activity against male gametocytes. IC50 values of 190 nM for male and  > 5 µM for female gametocytes [12]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite dual gamete formation assay (DGFA)
Plasmodium falciparum histone deacetylase 1 JX21108 PfNF54 - 7.4 – 8.2 pEC50 4
pEC50 8.2 (EC50 5.9x10-9 M) Parasite late stage (IV) gametocyte assay using luciferase reporter line [4]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
pEC50 7.4 (EC50 3.88x10-8 M) Parasite early stage (II) gametocyte assay using luciferase reporter line [4]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Plasmodium falciparum cytochrome b ELQ-300 PfNF54 - - - 10
Giemsa-stained blood film counts: treated gametocytes did not develop past stage III, even at 0.1 μM, the lowest dose tested [10]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite early stage (I–III) gametocyte assay
Plasmodium falciparum cytochrome b ELQ-300 PfNF54 - 7.1 pIC50 10
pIC50 7.1 (IC50 7.19x10-8 M) High-content fluorescence-based image analysis of gametocyte viability throughout a period of 72 hours [10]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite late stage (IV–V) gametocyte assay
Plasmodium falciparum plasmepsin V WEHI-842 PfNF54 - 7.4 pEC50 5
pEC50 7.4 (EC50 4x10-8 M) Giemsa-stained blood film counts: no stage II-V gametocytes were observed [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte assay
Plasmodium falciparum acetyl-CoA synthetase MMV693183 PfNF54 - 8.1 pIC50 13
pIC50 8.1 (IC50 8x10-9 M) [13]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Unknown MOA ganaplacide PfNF54 - - - 8
Giemsa-stained blood film counts: potent inhibiton of gametocyte maturation at concentrations as low as 50 nM [8]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte maturation assay
Unknown MOA ACT-451840 PfNF54 - 8.2 pIC50 9
pIC50 8.2 (IC50 5.89x10-9 M) male gamete formation from the gametocyte stage [9]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite dual gamete formation assay (DGFA)
Conditions: ACT-451840 had no effect on the functional viability of female gametocytes up to a concentration of 20 μM.
Unknown MOA compound 24 [PMID: 32959656] Pf3D7 - 6.3 – 6.4 pEC50 3
pEC50 6.4 (EC50 3.936x10-7 M) [3]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite late stage (IV–V) gametocyte assay
pEC50 6.3 (EC50 4.715x10-7 M) [3]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite early stage (II–III) gametocyte assay

References

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2. Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab GS, Le Manach C, Paquet T, Cabrera DG, Nchinda AT et al.. (2018) UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria. Antimicrob Agents Chemother, 62 (9). [PMID:29941635]

3. Huang G, Murillo Solano C, Melendez J, Shaw J, Collins J, Banks R, Arshadi AK, Boonhok R, Min H, Miao J et al.. (2020) Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines. J Med Chem, 63 (20): 11756-11785. [PMID:32959656]

4. Huang Z, Li R, Tang T, Ling D, Wang M, Xu D, Sun M, Zheng L, Zhu F, Min H et al.. (2020) A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1. Cell Discov, 6 (1): 93. [PMID:33311461]

5. Jennison C, Lucantoni L, O'Neill MT, McConville R, Erickson SM, Cowman AF, Sleebs BE, Avery VM, Boddey JA. (2019) Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes. Cell Rep, 29 (12): 3796-3806.e4. [PMID:31851913]

6. Kato N, Comer E, Sakata-Kato T, Sharma A, Sharma M, Maetani M, Bastien J, Brancucci NM, Bittker JA, Corey V et al.. (2016) Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature, 538 (7625): 344-349. [PMID:27602946]

7. Krishnan K, Ziniel P, Li H, Huang X, Hupalo D, Gombakomba N, Guerrero SM, Dotrang T, Lu X, Caridha D et al.. (2020) Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIIIβ). ACS Pharmacol Transl Sci, 3 (5): 948-964. [PMID:33073193]

8. Kuhen KL, Chatterjee AK, Rottmann M, Gagaring K, Borboa R, Buenviaje J, Chen Z, Francek C, Wu T, Nagle A et al.. (2014) KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. Antimicrob Agents Chemother, 58 (9): 5060-7. [PMID:24913172]

9. Le Bihan A, de Kanter R, Angulo-Barturen I, Binkert C, Boss C, Brun R, Brunner R, Buchmann S, Burrows J, Dechering KJ et al.. (2016) Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling. PLoS Med, 13 (10): e1002138. [PMID:27701420]

10. Nilsen A, LaCrue AN, White KL, Forquer IP, Cross RM, Marfurt J, Mather MW, Delves MJ, Shackleford DM, Saenz FE et al.. (2013) Quinolone-3-diarylethers: a new class of antimalarial drug. Sci Transl Med, 5 (177): 177ra37. [PMID:23515079]

11. Paquet T, Le Manach C, Cabrera DG, Younis Y, Henrich PP, Abraham TS, Lee MCS, Basak R, Ghidelli-Disse S, Lafuente-Monasterio MJ et al.. (2017) Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med, 9 (387). [PMID:28446690]

12. Potluri V, Shandil RK, Gavara R, Sambasivam G, Campo B, Wittlin S, Narayanan S. (2020) Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria. Malar J, 19 (1): 365. [PMID:33046062]

13. Schalkwijk J, Hermkens PHH, Dechering KJ, Bonnert RV. (2020) Pantothenamide analogues. Patent number: WO2020141155A1. Assignee: Medicines for Malaria Venture (MMV). Priority date: 31/12/2018. Publication date: 09/07/2020.

14. Sun W, Tanaka TQ, Magle CT, Huang W, Southall N, Huang R, Dehdashti SJ, McKew JC, Williamson KC, Zheng W. (2014) Chemical signatures and new drug targets for gametocytocidal drug development. Sci Rep, 4: 3743. [PMID:24434750]

15. Vaidya AB, Morrisey JM, Zhang Z, Das S, Daly TM, Otto TD, Spillman NJ, Wyvratt M, Siegl P, Marfurt J et al.. (2014) Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nat Commun, 5: 5521. [PMID:25422853]

16. van Pelt-Koops JC, Pett HE, Graumans W, van der Vegte-Bolmer M, van Gemert GJ, Rottmann M, Yeung BK, Diagana TT, Sauerwein RW. (2012) The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. Antimicrob Agents Chemother, 56 (7): 3544-8. [PMID:22508309]