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Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)

Stage ID:1
Name:Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Associated with:3 targets
5 ligands
Description
The collective lifecycle stage that occurs in the liver of the host organism and can include:
  • sporozoite, the motile form of the parasite that is responsible for the initial infection of the host. Sporozoites from the salivary glands of the vector (female Anopheles mosquitos) are injected into the host during the mosquito's blood meal, before migrating to the host liver and entering hepatic cells. The number of sporozoites introduced during a blood meal is low (<100) and the process of hepatocyte infection is rapid (<1 hour).
  • hepatic schizont, the multinucleate form of the parasite that develops in hepatic cells from the sporozoite by asexual reproduction (schizogony) with incomplete cytokineses. This form of the parasite is also found in host erythrocytes (see erythrocytic schizont).
  • hepatic merozoite, completion of cytokinesis produces several thousand merozoites from a single schizont, leading to rupture of the infected hepatocyte and release of merozoites into the bloodstream. These merozoites do not re-enter hepatocytes but invade erythrocytes instead and this begins the asexual blood stage (see Plasmodium asexual blood stage). Merozoites are non-motile but have an apical complex that facilitates entry into host cells. This form of the parasite is also found in host erythrocytes (see erythrocytic merozoite).
Further development of the Plasmodium infection can be prevented by blocking the parasite lifecycle during an early point of the liver stage. Antimalarial drugs that have liver stage activity have the potential to hit new targets that are not present or essential during the asexual blood stage. It has also been suggested that resistance to these compounds may develop more slowly due to the much smaller number of parasites present during this initial stage of the disease.

Interactions

Interactions
Key to terms and symbols Click column headers to sort
Target Ligand Sp. Action Affinity Parameter Reference
Plasmodium falciparum N-Myristoyltransferase Compound 34c [PMID 24641010] Pb - 6.4 pEC50 4
pEC50 6.4 (EC50 3.72x10-7 M) Luciferase bioluminescence assay to measure viability of exoerythrocytic forms (EEF) [4]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Description: Parasite liver stage assay
Plasmodium falciparum phosphatidylinositol 4-kinase MMV048 Pc - 7.2 pIC50 3
pIC50 7.2 (IC50 6.4x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [3]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Description: Parasite liver stage assay
Plasmodium falciparum phosphatidylinositol 4-kinase UCT943 Pc - >8.0 pIC50 2
pIC50 >8.0 (IC50 <1x10-8 M) P. cynomolgi assay to assess inhibition of liver stage development (prophylactic activity) [2]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Description: Parasite liver stage assay
Plasmodium falciparum phosphatidylinositol 4-kinase UCT943 Pb - 9.0 pIC50 2
pIC50 9.0 (IC50 9.2x10-10 M) Luciferase bioluminescence assay to measure sporozoite invasion (prophylactic activity) [2]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Description: Parasite liver stage assay
Plasmodium falciparum elongation factor 2 M5717 Pb - 8.8 pEC50 1
pEC50 8.8 (EC50 1.65x10-9 M) P. berghei Luciferase liver stage assay [1]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Description: Parasite liver stage assay
Unknown MOA OSM-S-38 Pb - 7.7 pIC50 5
pIC50 7.7 (IC50 1.9x10-8 M) [5]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Description: Parasite liver stage assay

References

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1. 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]

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. 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]

4. Rackham MD, Brannigan JA, Rangachari K, Meister S, Wilkinson AJ, Holder AA, Leatherbarrow RJ, Tate EW. (2014) Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP). J. Med. Chem., 57 (6): 2773-88. [PMID:24641010]

5. 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]