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Table 2 List of potential antimalarial targets

From: Malaria therapeutics: are we close enough?

Sl. no

Drug target

Functions in parasite

Refs.

1

Acetyl CoA synthetase

It provides acetyl moieties for several metabolic and regulatory cellular pathways, which help in parasite growth

[42]

2

Adenylyl cyclase-β

It helps in cyclic adenosine monophosphate (cAMP) synthesis, an essential element of the parasite life cycle

[43]

3

Aminoacyl-tRNA synthetase

It helps in the protein synthesis (translation) process by adding an aminoacyl group to the 3’ end of tRNA

[44]

4

Aminopeptidase

It is a protease enzyme essential in cell maintenance, cell growth, peptide catabolism (during the asexual erythrocytic replication cycle), protein maturation, antigen presentation on immune cells, and hormone regulation

[15]

5

Anion-exchange protein-1

Involved in erythrocyte invasion (adhesion of infected erythrocytes to endothelial cells) and acid-base homeostasis regulation

[15]

6

Apical membrane antigen-1

Transmembrane protein. It helps parasites invade host erythrocytes

[15]

7

Aspartate aminotransferase

It is one of the key enzymes in energy metabolism and de novo biosynthesis of pyrimidines

[45]

8

Aspartate transcarbamoylase

It is essential in catalyzing the second step in de novo pyrimidine biosynthesis

[46]

9

ATP synthase

Involved in the ATP generation during aerobic glycolysis at the blood stage of the parasite’s life cycle

[47]

10

Calcium-dependent protein kinase-I

Significant role in activating translation of repressed mRNA during the sexual stage. It regulates parasite mobility. It helps in microneme secretion during erythrocyte invasion

[48]

11

Carbamoyl phosphate synthetase-II

It helps in the de novo pyrimidine biosynthesis process by catalyzing the formation of carbamoyl phosphate, glutamine, and ATP

[49]

12

Carbonic anhydrasU + 0065

Metalloenzyme. An essential metabolic enzyme catalyzes carbon dioxide's reversible conversion to bicarbonate in pyrimidines de novo synthesis

[15, 50]

13

Casein kinase 2α

Involved in the critical cellular process; cell differentiation, proliferation, stress response, DNA damage, apoptosis, and circadian rhythm

[51]

14

cGMP-dependent protein kinase

Key regulator of cGMP signaling in the malaria parasite. It is required in the parasite life cycle's sexual and asexual stages

[52]

15

Choline transporter

The first enzyme of the Kennedy pathway. involved in the biosynthesis of phospholipid and phosphatidyl-choline

[53]

16

Choline phosphate cytidylyl transferase

It catalyzes the rate-limiting step of the Kennedy pathway and is crucial for the survival of the murine parasite

[54]

17

Cysteine protease

Key role in hemoglobin degradation and erythrocyte cytoskeletal proteins hydrolysis

[15, 55]

18

Cytochrome bc1

Essential for pyrimidine biosynthesis

[47]

19

Cytochrome c oxidase (Complex IV)

Involved in Plasmodium mitochondrial electron transport chain

[56]

20

Dihydrofolate reductase

Involved in the pyrimidine synthesis in Plasmodium by de novo pathway

[57]

21

Dihydroorotate dehydrogenase

Involved in the de novo pyrimidine synthesis, the primary energy source and essential for parasite survival

[47]

22

Dihydropteroate synthase

Significant role in folate metabolism

[58]

23

Dipeptidyl aminopeptidase

Present in food vacuole and cleaves dipeptides from amino termini of proteins/oligopeptides

[59]

24

DNA methyltransferases

Involved in the epigenetic mechanism

[60]

25

DXP reductoisomerase

An essential enzyme of the DXP/MEP pathway that triggers isoprenoid formation (required for the production of cholesterol, dolichols, and ubiquinones)

[61]

26

Falcipain

Endopeptidase. It involves host hemoglobin hydrolysis, erythrocyte invasion, and erythrocyte rupture

[62]

27

Farnesyltransferase

Involved in the blood stage of the parasite life cycle

[63]

28

Fumarate hydratase

A vital component of the tricarboxylic acid cycle of the Plasmodium parasite (helps in the interconversion of fumarate to malate)

[47]

29

Gamma-glutamylcysteine synthetase

An essential enzyme of glutathione biosynthesis

[15]

30

Geranylgeranyl pyrophosphate synthase

Key branchpoint enzyme in isoprenoid biosynthesis

[43]

31

Glutathione reductase

A flavoenzyme regenerates glutathione (an essential enzyme antioxidant defense against cell damage)

[64]

32

Glutathione S-transferase

Involved in cellular detoxification

[65]

33

Glycerol 3-phosphate dehydrogenase

Key glycolytic homotetrameric enzyme. Involved in vesicular transport and apical organelle biogenesis

[66, 67]

34

Heat shock protein 90

The most abundant chaperone in cells is responsible for cell cycle regulation and signal transduction

[68]

35

Hemozoin

A crystallized heme dimer. Sequestration of heme into hemozoin formation is an essential process for parasite development

[69]

36

Hexose transporter

Glucose uptake is mediated by the hexose transporter enzyme

[70]

37

Histone acetyltransferase

Involved in the acetylation of histone tails that causes localized chromatin relaxation and transcriptional activation of nearby genes

[71]

38

Histone acetyltransferase GCN5

Key role in the epigenetic mechanism. It controls erythrocyte invasion and virulence in the Plasmodium parasite

[72]

39

Histone deacetylase

It catalyzes the deacetylation of acetylated histones leading to transcriptional repression

[71]

40

Hypoxanthine guanine phosphoribosyl transferase

Helps in DNA/RNA synthesis via de novo synthesis

[73]

41

Lactate dehydrogenase

The critical enzyme of energy production. It catalyzes the interconversion of pyruvate to lactate in the glycolysis process

[74]

42

Malate dehydrogenase

It involves NADH and citrate production to support the TCA cycle, ETC

[75]

43

Malatequinone oxidoreductase

Membrane protein. Involved in three essential pathways (ETC, TCA, and fumarate cycle)

[76]

44

Merozoite surface protein-1

Essential for the attachment of merozoites to host receptor. Role in RBC invasion

[15]

45

Methionine aminopeptidase 1b

Metalloproteases. Involved in protein maturation and activation by catalyzing the removal of the N-terminal initiator methionine during protein synthesis

[77]

46

Mitogen-activated protein kinase 2

It plays a vital role in critical cellular processes and signal transduction

[78]

47

N-myristoyl transferase

The key enzyme of post-translational modifications

[79]

48

NADH dehydrogenase type II

It is an essential enzyme of the Plasmodium mitochondrial electron transport chain system

[80]

49

Niemann-Pick Type C1

Present on the parasite’s plasma membrane—essential protein for the intraerythrocytic growth of Plasmodium falciparum

[81]

50

Ornithine decarboxylase

Involvement in polyamines biosynthesis (key component of transcription, translation, and several cellular processes)

[82]

51

Orotatephospho-ribosyl transferase

Crucial enzyme for the de novo pyrimidine synthesis pathway

[83]

52

Orotidine 5′-monophosphate decarboxylase

The key enzyme for the de novo pyrimidine synthesis pathway

[84]

53

Orphan protein kinase PfPK7

An essential enzyme in the melatonin transduction pathway

[85]

54

Pantothenic acid

Essential vitamin and precursor of coenzyme A

[86]

55

Phosphocholine cytidylyltransferase

Essential enzyme for the biosynthesis of phosphatidylcholine

[54]

56

Phosphodiesterase β

The key enzyme for developing the asexual blood stage of the malaria parasite

[87]

57

Phosphoinositide lipid kinases

Lipid phosphoinositides are signaling molecules involved in cellular functions (e.g. cell growth, cell division, and membrane trafficking)

[88]

58

Phosphatidylinositol 3-phosphate

An essential enzyme in vesicular trafficking processes and intraerythrocytic development

[89]

59

Phosphoribosyl transferase

Key purine salvage enzyme

[90]

60

Plasmepsin

Plasmepsin is responsible for hemoglobin digestion, cytoskeleton protein processing, oocyst development, parasite virulence modulation, and host-targeted protein export

[91]

61

Reactive oxygen species

It plays a significant role in the regulatory mediators in signaling processes (e.g. lipid peroxidation, cell signaling, ETC, and hemoglobin digestion)

[92]

62

Rhoptry-associated protein

Involve in the invasion of RBC by merozoites

[93]

63

S-adenosylhomo-cysteine hydrolase

It is required for the metabolic pathway (sulfur-containing amino acids) and biological methylation process

[94]

64

Serine repeat antigen-5

The key enzyme for parasite development at the blood stage

[95]

65

Serine/threonine-protein kinase

Involved in cellular processes such as differentiation, proliferation, cell cycle progression, apoptosis, and DNA damage

[96]

66

Signal peptide peptidase

Membrane-bound endopeptidases. Help in parasite protein maturation and transport

[97]

67

Subtilisin-like protease-1

Role in merozoite invasion and mediates the proteolytic maturation

[98]

68

Succinate dehydrogenase Complex II

Essential enzyme for the TCA, ETC pathway

[99]

69

SUMOylation

A post-translational modification enzyme in the parasite life cycle

[100]

70

Surface anion channel

Parasite-induced ion channel on host erythrocyte membrane mediates nutrients update, various bulky organic solutes, and supports intracellular parasite growth

[101]

71

Thioredoxin reductase

Homo dimeric protein. It maintains redox equilibrium in the glutathione system

[102]

72

Thymidylate synthase

Involved in folate de novo synthesis

[103]

73

Topoisomerase

Role in DNA transcription, replication, repair, and cell division

[104]

74

V-Type H + ATPase

Regulate intracellular pH and plasma membrane potential. It is associated with chloride channels

[105]