Antimalarial Drug Resistance and Novel Targets for Antimalarial Drug Discovery

Figures & data

Table 1 Summary of Some Antimalarial Drugs, Mechanism of Action, Site of Action, and Mechanism of Resistance

Antimalarial Drug	Mechanism of Action	Site of Action	Mechanism of Resistance
Antifolates ((pyrimethamine (PYR) and cycloguanil (CYC))	Inhibition of dihydrofolate reductase (DHFR)	Cytosol	Mutations in dihydrofolate reductase (DHFR)
Antifolates (sulfadoxine (SDX))	Inhibition dihydropteroate synthetase (DHPS)	Cytosol	Dihydropteroate synthetase (DHPS)
Naphthoquinones (Atovaquone (ATQ))	Inhibits mitochondrial electron transport	Mitochondria	A single point mutation in the cytochrome b subunit (CYTb) of the bc1 complex
Antibiotics (Clindamycin (CLD) and Doxycycline (DOX))	Inhibit protein translation inside the apicoplast	Inside the apicoplast	A point mutation in the apicoplast encoded 23S rRNA (CLD)
Artemisinin (ART)	Alkylation of proteins and lipids	ER, vesicular structures	Mutation in K13
4- aminoquinolines (CQ, AQ, PPQ, Mannich base pyronaridine (PND))	They bind reactive heme and interfere with its detoxification through incorporation into chemically inert hemozoin.	Digestive vacuole	Point mutations in the transporters PfCRT and PfMDR1, increased expression of the hemoglobinases plasmepsin 2 and 3 (PM2/PM3, in the digestive vacuole), and might in some instances involve mutant PfCRT

Table 2 Role of Kinase in the Plasmodium Parasite Life Cycle

Type	Role in the Parasite Life Cycle	Reference
Serine/threonine-protein kinase, casein kinase 2α (PfCK2α)	Crucial for asexual blood-stage parasites	[^Citation79]
Calcium-dependent protein kinase 1 (PfCDPK1)	Essential for parasite survival	[^Citation79]
Mitogen-activated protein kinase 2 (PfMAP-2)	Essential for completion of the asexual cycle	[^Citation80]
cGMP dependent protein kinase (PfPKA)	Essential for parasite growth and survival	[^Citation81]
Orphan protein kinase PfPK7	Significant for asexual stage development in humans and oocyst production in mosquitoes	[^Citation82]

Figure 1 Targets of proteases and amino peptidase, malaria parasite detoxification mechanism.

Abbreviation: PDT, possible drug targets.

Table 3 Mechanism of Action of Protease Inhibitors

Name of Drug	Mechanism of Action on Cultured Parasite
Leupeptin	Causes the food vacuole to swell and fill with dark-staining material, blocks the processing of hemoglobin, Inhibits lysis of erythrocyte membranes
Anti-pain	Inhibits lysis of erythrocyte membranes
E-64	Causes the food vacuole to swell and fill with dark-staining material, inhibits lysis of parasitophorous vacuole, Blocks the processing of hemoglobin
Chymostatin (serine protease inhibitor)	Inhibits erythrocyte invasion

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