Targeting the Plasmodium falciparum proteome and organelles for potential antimalarial drug candidates

Abugri, James; Ayariga, Joseph A.; Sunwiale, Samuel Sunyazi; Opare-Asamoah, Kwame; Gyamfi, Julien Agyemang; Adu‐Frimpong, Michael; Agongo, Godfred; Dongdem, Julius Tieroyaare; Abugri, Daniel A.; Dinko, Bismarck

doi:10.1016/j.heliyon.2022.e10390

Cited by 7 publications

(7 citation statements)

References 159 publications

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“…Among the four most upregulated proteins, plasmepsin X (PMX) was detected [ 257 ]. Similarly, plasmepsin V (PMV) is essential for gametogenesis, as gametocyte generation and transmission to mosquitoes were shown to be blocked by PMV inhibiting [ 258 , 259 ].…”

Section: Protein Ptms In Plasmodium Parasite Growt...mentioning

confidence: 99%

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Schwarzer,

Skorokhod

2024

IJMS

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Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of Plasmodium spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.

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Section: Protein Ptms In Plasmodium Parasite Growt...mentioning

confidence: 99%

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Schwarzer,

Skorokhod

2024

IJMS

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“…When the erythrocytes burst, the emerging merozoites are free to invade other cells and this cycle then repeats itself. When an infected human is bitten by another mosquito, gametocytes are engulfed into the gut of the insect, and develop into female gametes, or undergo gamogony and produce male gametes (5). Gametes forming a zygotic cell are the only diploid stage.…”

Section: General Characterization Of Plasmodium Sppmentioning

confidence: 99%

“…After several generations of asexual division, the sporozoites emerge to produce more merozoites. The development of a diploid zygote then leads to fertilization and the establishment of infective diploid sporozoites (5).…”

Section: Introductionmentioning

confidence: 99%

Review of Lipid Metabolic Pathways and Calcium Signaling in the Apicomplexan Families and their Importance in Drug Discovery

Ayariga¹,

Ibrahim²,

Syamala³

et al. 2023

Preprint

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Calcium signaling and lipid metabolism are crucial in the infection processes of Apicomplexans parasites. Thus, enzymes involved in these processes can be drug targets against Apicomplexans. For example, in malaria infection, in-depth research into lipid metabolic pathways is crucial in understanding the parasite's infection cycle, particularly during its erythrocytic infection cycle, which has been demonstrated to be a critical stage during the disease progression. Most enzymes that play critical roles in lipid synthesis and calcium signaling have been extensively studied; nonetheless, a vast knowledge gap still exists, especially on specific enzymes and their roles in the transmission and progression of the Apicomplexan parasites. Many types of infections caused by Apicomplexans are life-threatening and hard to treat. These intracellular parasites proliferate within parasitophorous vacuoles in their host cells. As the parasites multiply, they need to meet their high demand for nutrients such as amino acids and lipids. They can acquire nutrients through scavenging and biosynthesis. This review summarizes a few interesting, unique pathways in selected Apicomplexa and how such unique pathways can be targets for drugs.

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“…Merozoite invasion of erythrocytes, sporozoite invasion of hepatocytes, trophozoite growth, hemoglobin metabolism, essential compound biosynthesis, gametocytogenesis, etc. are some of the pathways that have been considered in the development of new antimalarial agents [3]. Malaria liver stage chemoprophylaxis refers to medications that act on the parasite when it invades the hepatocytes to destroy the parasite early in the infectious phase, providing a sustainable approach as this deviates from the norm of most chemotherapeutic targeting the asexual blood stage [4].…”

Section: Introductionmentioning

confidence: 99%

Design of Potential Inhibitors of Pf5-ALAS in Liver Stage Plasmodium falciparum: A Sustainable Chemotherapeutic Approach to Address Antimalarial Resistance

Elebiju,

Oduselu,

Ogunnupebi

et al. 2024

IOP Conf. Ser.: Earth Environ. Sci.

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Plasmodium falciparum delta-aminolevulinate synthase (Pf5-ALAS) is the first enzyme in the heme biosynthetic pathway, and it is a liver stage specific enzyme in the developmental stages of Plasmodium falciparum. 8-amino quinoline derivatives have been reported to be active against liver stage parasite and hence was used as a template in the design of 12 derivatives as sustainable chemotherapeutics that were screened in this study designed as potential inhibitors of Pf5-ALAS. The target was modelled due to the unavailability of its experimentally validated 3-dimensional (3D) structure. The binding energy of all 12 designed compounds ranged from -7.9 to -9.1 Kcal/mol which all performed better than primaquine a known inhibitor of liver stage malaria. All twelve designed compounds had comparatively good pharmacokinetic profiles and did not present a toxicity risk, according to in silico ADMET prediction. The position and presence of a functional group that introduces a synergistic impact and subsequently raises the binding energy are highlighted in the qualitative structural assessment of the top three hits. This might pave way to highly economical new antimalarial therapeutic for sustainability health and wellbeing in sub-Saharan Africa and beyond.

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Targeting the Plasmodium falciparum proteome and organelles for potential antimalarial drug candidates

Cited by 7 publications

References 159 publications

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Review of Lipid Metabolic Pathways and Calcium Signaling in the Apicomplexan Families and their Importance in Drug Discovery

Design of Potential Inhibitors of Pf5-ALAS in Liver Stage Plasmodium falciparum: A Sustainable Chemotherapeutic Approach to Address Antimalarial Resistance

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