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Plasmodium sexual blood stage (gametocyte)

Stage ID:4
Name:Plasmodium sexual blood stage (gametocyte)
Associated with:5 targets
10 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
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Target Ligand Sp. Action Value Parameter Reference
Plasmodium falciparum phenylalanine--tRNA ligase alpha subunit BRD3444 Pf3D7 - 6.2 pEC50 4
pEC50 6.2 (EC50 6.63x10-7 M) [4]
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 - - - 10
Giemsa-stained blood film counts: dose-dependent, inhibition of stage V gametocyte development [10]
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 [10]
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 9
pEC50 7.4 (EC50 3.9x10-8 M) inhibition of gamete formation from mature Stage V male gametocytes [9]
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 [9]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite dual gamete formation assay (DGFA)
Plasmodium falciparum phosphatidylinositol 4-kinase MMV048 PfNF54 - 6.6 – 6.8 pIC50 8
pIC50 6.8 (IC50 1.4x10-7 M) Parasite late stage (IV-V) gametocyte assay using luciferase reporter line [8]
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 [8]
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 [8]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte viability assay
Plasmodium falciparum phosphatidylinositol 4-kinase 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 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 cytochrome b ELQ-300 PfNF54 - - - 7
Giemsa-stained blood film counts: treated gametocytes did not develop past stage III, even at 0.1 μM, the lowest dose tested [7]
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 7
pIC50 7.1 (IC50 7.19x10-8 M) High-content fluorescence-based image analysis of gametocyte viability throughout a period of 72 hours [7]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite late stage (IV–V) gametocyte assay
Unknown MOA ganaplacide PfNF54 - - - 5
Giemsa-stained blood film counts: potent inhibiton of gametocyte maturation at concentrations as low as 50 nM [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Description: Parasite gametocyte maturation assay
Unknown MOA ACT-451840 PfNF54 - 8.2 pIC50 6
pIC50 8.2 (IC50 5.89x10-9 M) male gamete formation from the gametocyte stage [6]
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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1. Baragaña B, Forte B, Choi R, Nakazawa Hewitt S, Bueren-Calabuig JA, Pisco JP, Peet C, Dranow DM, Robinson DA, Jansen C et al.. (2019) Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proc Natl Acad Sci USA, 116 (14): 7015-7020. [PMID:30894487]

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. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]