Novel Therapeutics for Malaria
Abstract
:1. Malaria
1.1. Parasite Life Cycle and Clinical Manifestations
1.2. Diagnostic Modalities
2. Antimalarial Drugs
2.1. Current Treatments
Class | Category | Drugs | Side Effects | Mechanism of Action | Ref. |
---|---|---|---|---|---|
Quinoline | Cinchona alkaloid | Quinine, quinidine | Hypoglycemia, cinchonism (tinnitus, hearing loss, visual disturbances, headache, dysphoria, nausea, vomiting), hypotension | Toxic accumulation of heme inside the infected red blood cell and inhibition of glycolytic enzymes | [14,26] |
4-AQ | Chloroquine | Pruritis, nausea, vomiting, diarrhea, keratopathy, retinopathy (with prolonged use) | [14,27,28] | ||
Amodiaquine | Hepatitis, myelotoxicity, agranulocytosis | [29,30] | |||
Piperaquine | Headache, dizziness, nausea, abdominal pain | [31] | |||
8-AQ | Primaquine, tafenoquine | Hemolytic anemia in G6PD deficiency | Inhibit pyrimidine synthesis and disrupt mitochondrial electron transport chain by producing oxidative metabolites | [32] | |
Quinoline-menthol | Mefloquine | Dizziness, anorexia, vomiting | Toxic accumulation of heme inside the infected red blood cell | [33,34] | |
Aryl amino-alcohol | Lumefantrine, halofantrine | Nausea, vomiting, diarrhea, pruritis, rash, cardiac toxicity (with halofantrine) | [35] | ||
Benzonaphthyridine derivative | Pyronaridine | Headache, vomiting, abdominal pain, bradycardia, hypoglycemia | [36] | ||
Naphthoquinones | Hydroxynaphthoquinone | Atovaquone | Nausea, vomiting, diarrhea, headache, fever, transient liver enzyme elevation | Inhibit the electron transport system at the cytochrome bc1 complex | [17] |
Antifolate | Diaminopyrimidine | Pyrimethamine | Bone marrow suppression, glossitis, stomatitis, exfoliative dermatitis, hair loss | Interfere with DNA synthesis by inhibiting DHFR, parasite mitochondrial toxicity seen with proguanil | [20,37] |
Biguanide | Proguanil | ||||
Sulfonamides | Sulfadoxine | Fever, arthralgia, bone marrow suppression, SJS, hemolytic anemia in G6PD | Interfere with DNA synthesis by inhibiting DHPS enzyme | [38,39] | |
Artemisinin | Sesquiterpene lactone endoperoxides | Artemether, artesunate, dihydroartemisinin | Nausea, vomiting, diarrhea | Protein alkylation and DNA damage by free radical generation | [21,40] |
Trioxolanes | Trioxolane peroxide | Arterolane | Headache, nausea, vomiting | Inhibit heme detoxification and PfATP6 | [41] |
Antimicrobials | Lincosamide | Clindamycin | Rash, DRESS, SJS, diarrhea, C. difficile | Interfere with protein translation | [42] |
Tetracycline | Doxycycline, tetracycline | Nausea, vomiting, diarrhea, epigastric pain | [43] | ||
Macrolide | Azithromycin | Nausea, vomiting, diarrhea | [44] |
2.2. Plasmodium Drug Resistance
2.3. Novel Therapies
2.3.1. Triple Combination Therapy
2.3.2. Phosphatidylinositol 4-Kinase (PI4K) Inhibitors
2.3.3. Plasmodium falciparum P-Type Na+ ATPase (PfATP4) Inhibitors
2.3.4. Dihydroorotate Dehydrogenase (DHODH) Inhibitors
2.3.5. Dihydrofolate Reductase (DHFR) and Thymidylate Synthase (TS) Inhibitors
2.3.6. Isoprenoid Biosynthesis Inhibitors
2.3.7. Choline Transport Inhibitors
2.3.8. P. falciparum Translational Elongation Factor 2 Inhibitors
2.3.9. Triaminopyrimidine
2.3.10. Adhesive Polysaccharide Inhibitors
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Species | Signs and Symptoms | Laboratory Findings |
---|---|---|
P. falciparum | Prostration | Acidosis (lactate > 5 mmol/L or plasma bicarbonate < 15 mEq/L or base deficit of >8 mEq/L) |
Convulsions (>2 within 24 h) | Anemia: Hgb < 7 g/dL or hematocrit < 20% in adults (≤5 g/dL or hematocrit ≤ 15% in children < 12 years of age) with a parasite count > 10,000/microliter | |
Coma (Glasgow coma scale < 11) | Hypoglycemia < 40 mg/dL | |
Abnormal bleeding | Jaundice or bilirubin > 3 mg/dl and parasite count >100,000/microliter | |
Circulatory shock | Creatinine > 3 mg/dL or blood urea nitrogen > 56 mg/dL) | |
Pulmonary edema, radiologically confirmed or oxygen saturation < 92% on room air with a respiratory rate > 30/minutes | Hyperparasitemia: P. falciparum parasitemia > 10% | |
P. vivax, P. ovale, and P. malariae | Defined as per P. falciparum but excluding parasite density thresholds | |
P. knowlesi | Defined as per P. falciparum except parasite density of >100,000/microliter or jaundice and parasite density > 20,000/microliter |
Target | Function | Significance | Drugs in Development | Reference |
---|---|---|---|---|
Malaria Proteases | Degradation of hemoglobin and proteins and aid in cell penetration | Development of the parasite, immune evasion, and activation of inflammation | Not available | [56,57] |
Malaria transporters (PSAC, PVM, PfHT, and lactate transporters) | Diffusion of nutrients to infected erythrocyte | Promote growth of the parasite | Preclinical stage (Pentafluoro-3-hydroxy-pent-2-en-1-ones) | [58,59,60,61,62] |
V-Type H+ ATPase Channels | Regulate hydrogen ion transportation | Maintain pH for survival of the parasite | Not available | [63] |
Aquaporin-3 (AQP3) | Facilitate water and glycerol movement in and out of cells | Parasite survival and replication | Pre-clinical stage (auphen) | [64,65] |
Farnesyltransferase | Catalyzing the transfer of farnesyl group from farnesyl pyrophosphate to the C-terminus of proteins containing the CaaX motif | DNA replication, cell division, binding of intracellular proteins to membranes, and protein to protein interaction | Pre-clinical stage (R115777) | [65,66,67] |
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Alaithan, H.; Kumar, N.; Islam, M.Z.; Liappis, A.P.; Nava, V.E. Novel Therapeutics for Malaria. Pharmaceutics 2023, 15, 1800. https://doi.org/10.3390/pharmaceutics15071800
Alaithan H, Kumar N, Islam MZ, Liappis AP, Nava VE. Novel Therapeutics for Malaria. Pharmaceutics. 2023; 15(7):1800. https://doi.org/10.3390/pharmaceutics15071800
Chicago/Turabian StyleAlaithan, Haitham, Nirbhay Kumar, Mohammad Z. Islam, Angelike P. Liappis, and Victor E. Nava. 2023. "Novel Therapeutics for Malaria" Pharmaceutics 15, no. 7: 1800. https://doi.org/10.3390/pharmaceutics15071800