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Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)

Stage ID:5
Name:Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Associated with:6 targets
13 ligands
Description
Any lifecycle stage of Plasmodium that is spent in the invertebrate vector (female Anopheles mosquitos) and can include:
  • gametocyte, the sexually committed form of the parasite that is ingested by the vector during a blood meal. The process of ingestion induces the production of gametes and release from the host erythrocyte into the mosquito midgut.
  • gamete, the male gametocyte divides to give many flagellated microgametes, whereas the female gametocyte differentiates to a macrogamete.
  • zygote, diploid stage formed by fusion of a male and female gamete. Meiosis occurs in the zygote which then develops into the ookinete.
  • ookinete, the motile form of the parasite that develops from the zygote. The ookinete penetrates through the epithelial cells lining the midgut of the mosquito where it differentiates into an oocyst.
  • oocyst, a thick-walled structure that forms under the mosquito's outer gut lining. The oocyst undergos asexual replication, called sporogony, which culminates in the production of several thousand sporozoites. Upon maturation the oocyst ruptures and releases the sporozoites into the hemocoel of the mosquito.
  • sporozoite, a motile form of the parasite that is responsible for the initial infection of the host. Following release from the oocyst, sporozoites migrate to the salivary glands of the vector with a few injected into the host during the mosquito's blood meal.
Blocking development of the parasite during this stage prevents transmission from mosquito to human.

Interactions

Interactions
Key to terms and symbols Click column headers to sort
Target Ligand Sp. Action Value Parameter Reference
Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase cipargamin PfNF54 - - - 10
Oocyst count: significantly reduced count observed with the addition of cipargamin when compared to control feeds [10]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
Plasmodium falciparum phosphatidylinositol 4-kinase MMV048 Pf - 6.9 pIC50 9
pIC50 6.9 (IC50 1.11x10-7 M) Indirect SMFA [9]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
Plasmodium falciparum phosphatidylinositol 4-kinase UCT943 Pf - 7.0 – 7.1 pIC50 3
pIC50 7.1 (IC50 8x10-8 M) Reports on the functional viability of male and female mature stage V gametocytes [3]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite dual gamete formation assay (DGFA)
pIC50 7.0 (IC50 9.6x10-8 M)
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
Plasmodium falciparum elongation factor 2 M5717 PfNF54 - 8.0 – 8.9 pEC50 2
pEC50 8.9 (EC50 1.2x10-9 M) Female gamete formation [2]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite gamete formation assay
pEC50 8.7 (EC50 1.8x10-9 M) Male gamete formation [2]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite gamete formation assay
pEC50 8.7 (EC50 1.8x10-9 M) Indirect SMFA [2]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
pEC50 8.0 (EC50 1x10-8 M) Direct SMFA [2]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
Plasmodium falciparum cGMP-dependent protein kinase MMV030084 PfNF54 - 6.8 pIC50 11
pIC50 6.8 (IC50 1.41x10-7 M) Dual Gamete Formation Assay (DGFA): male gamete exflagellation was inhibited in the presence of MMV030084, but not when the compound was washed out prior to gamete formation. Activity against female gametes was not clearly identified [11]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite exflagellation assay
Plasmodium falciparum lysine--tRNA ligase compound 5 [PMID: 30894487] PfNF54 - <6.0 pEC50 1
pEC50 <6.0 (EC50 >1x10-6 M) [1]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite gamete formation assay
Plasmodium falciparum plasmepsin X WM382 Pf - - - 5
Oocyst count: potent inhibition of oocyst development [5]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
Unknown MOA OSM-S-38 Pf3D7 - 8.4 pIC50 12
pIC50 8.4 (IC50 4x10-9 M) [12]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite late stage (IV–V) gametocyte assay
Unknown MOA ganaplacide PfNF54 - - - 6
Oocyst count: >90% reduction of oocyst numbers at a concentration of 500 nM [6]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
Unknown MOA artefenomel Pf - - - 4
>60% inhibition of exflagellation following 24hour exposure of mature gametocytes to 10µM artefenomel [4]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite exflagellation assay
Unknown MOA ACT-451840 Pf - 7.5 pIC50 7
pIC50 7.5 (IC50 3x10-8 M) Indirect mode: dose-dependent inhibition of oocyst development in the mosquito was observed. Direct mode: no activity at concentrations up to 1 μM [7]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)
Unknown MOA GSK369796 Pf - - - 4
Total inhibition of exflagellation following 24hour exposure of mature gametocytes to 10µM GSK369796 [4]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Parasite exflagellation assay
Unknown MOA E209 Pf - 7.8 pIC50 8
pIC50 7.8 (IC50 1.45x10-8 M) determined by the reduction in oocyst mean intensity. A corresponding ~60 and 90% transmission blocking activity (defined as the percentage of mosquitoes with no observed oocysts) was determined at 100nM and 1µM, respectively [8]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
Description: Standard membrane feeding assay (SMFA)

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. Baragaña B, Hallyburton I, Lee MC, Norcross NR, Grimaldi R, Otto TD, Proto WR, Blagborough AM, Meister S, Wirjanata G et al.. (2015) A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature, 522 (7556): 315-20. [PMID:26085270]

3. 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]

4. Delves M, Plouffe D, Scheurer C, Meister S, Wittlin S, Winzeler EA, Sinden RE, Leroy D. (2012) The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites. PLoS Med, 9 (2): e1001169. [PMID:22363211]

5. 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]

6. 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]

7. 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]

8. O'Neill PM, Amewu RK, Charman SA, Sabbani S, Gnädig NF, Straimer J, Fidock DA, Shore ER, Roberts NL, Wong MH et al.. (2017) A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nat Commun, 8: 15159. [PMID:28537265]

9. 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]

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]

11. Vanaerschot M, Murithi JM, Pasaje CFA, Ghidelli-Disse S, Dwomoh L, Bird M, Spottiswoode N, Mittal N, Arendse LB, Owen ES et al.. (2020) Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity. Cell Chem Biol, 27 (7): 806-816.e8. [PMID:32359426]

12. Williamson AE, Ylioja PM, Robertson MN, Antonova-Koch Y, Avery V, Baell JB, Batchu H, Batra S, Burrows JN, Bhattacharyya S et al.. (2016) Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles. ACS Cent Sci, 2 (10): 687-701. [PMID:27800551]