Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development
Abstract
:1. Introduction
2. The Transmission-Blocking Screening Landscape
2.1. Gametocytocidal Assays
2.2. Dual Gamete Formation Assay (DGFA)
2.3. SMFA
2.4. Sporogonic Development Assays Using P. berghei
3. Transmission-Blocking Antimalarial Drugs
3.1. Transmission Blockers in Clinical Development
3.2. Epigenetic Transmission-Blocking Drugs
3.3. Antiplasmodial Transmission-Blocking Compounds Inhibiting Plasmodium Kinases
3.4. Aminoacyl-tRNA Synthetase Inhibitors
3.5. Pfs16 Inhibitors
3.6. Acetyl Coenzyme a Synthesis Inhibitors
3.7. Transmission-Blocking Compounds Altering Microtubule Assembly, Plasmepsins IX and X, and Pf20S Proteasome
3.8. Drug Repurposing as an Approach to Developing Transmission-Blocking Compounds
3.9. Multistage Active Drugs with Unknown Targets
3.10. Innovative Approaches: Atovaquone-Coated Surfaces to Block Parasite Transmission
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
ABSs | Asexual blood stages |
Ac-COA | Acetyl coenzyme A |
ACS | Acyl-CoA synthetase |
AMS | Adenosine-5′-sulfamate |
aaRSs | Aminoacyl-tRNA synthetases |
ATP | Adenosine triphosphate |
BCKDH | Branched-chain keto-dehydrogenase |
CETSA | Cellular thermal shift assay |
CYP | Cytochrome P450 |
DGFA | Dual gamete formation assay |
DMSO | Dimethyl sulfoxide |
DNMT | DNA methyltransferase |
EC50 | 50% effective concentration |
ED90 | 90% effective dose |
EIA | Exflagellation inhibition assay |
EM | Electron microscopy |
ETC | Electron transport chain |
FGAA | Female gamete activation assay |
G6PD | Glucose-6-phosphate dehydrogenase |
GAPDH | Glyceraldehyde-3-phosphate dehydrogenase |
GFP | Green fluorescent protein |
GST | Glutathione S-transferase |
HDAC | Histone deacetylase |
HEA | Hydroxyethylamine |
HMT | Histone methyltransferase |
IAP | Inhibitor of apoptosis |
IC50 | 50% inhibitory concentration |
IF | Immunofluorescence |
iPanAms | Inverted pantothenamides |
JmjC | Jumonji C |
KDM | Lysine demethylase |
LDH | Lactate dehydrogenase |
MMV | Medicines for Malaria Venture |
ODA | Ookinete development assay |
PABP1 | Polyadenylate-binding protein 1 complex |
PCNA1 | Proliferating cell nuclear antigen |
PfCLK3 | P. falciparum cyclin-dependent-like kinase |
PfDHFR | P. falciparum dihydrofolate reductase |
PfATP4 | P. falciparum Na+-efflux ATPase ATP4 |
PfPANK1 | P. falciparum pantothenate kinase 1 |
PfPI4Kβ | P. falciparum phosphatidylinositol 4-kinase type III β |
PfeEF2 | P. falciparum translation elongation factor 2 |
PfYRS | P. falciparum tyrosine-tRNA synthetase |
PfvapA | P. falciparum V-type H + -ATPase |
Pf20S | P. falciparum 20S proteasome |
PheRS | Phenylalanyl-tRNA synthetase |
PK | Pharmacokinetics |
PM | Plasmepsins |
PMIX | Plasmepsin IX |
PMX | Plasmepsin X |
PVM | Parasitophorous vacuole membrane |
RBCs | Red blood cells |
SAHA | Suberoylanilide hydroxamic acid |
SaLSSA | Saponin-lysis sexual stage assay |
SAR | Structure–activity relationship |
SMFA | Standard membrane feeding assay |
SPR | Surface plasmon resonance |
TAP | Triaminopyrimidine |
YRS | Tyrosine-tRNA synthetase |
WHO | World Health Organization |
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Compound | Structure | Target Class | Asexual IC50 ± SEM (nM) | Stage I–II Gametocyte IC50 ± SEM (nM) | Stage IV–V Gametocyte IC50 ± SEM (nM) |
---|---|---|---|---|---|
SGI-1027 8 | DNMT | 50.8 ± 0.6 | 18.2 ± 2.1 | 322.4 ± 123.7 | |
Chaetocin 9 | HMT | 775.3 ± 366.0 | 292.3 ± 25.7 | 504.5 ± 92.3 | |
BIX01294 10a | HMT | 10.5 ± 3.6 | 12.3 ± 1.3 | 939.0 ± 84.7 | |
UNC0631 10b | HMT | 28.5 ± 5.9 | 14.8 ± 0.9 | 641.2 ± 83.0 | |
UNC0642 10c | HMT | 19.2 ± 10.4 | 14.6 ± 0.8 | 929.6 ± 199.0 | |
UNC0379 10d | HMT | 50.4 ± 2.3 | 21.3 ± 4.8 | >1000 | |
UNC0638 10e | HMT | 21.6 ± 2.0 | 16.4 ± 1.0 | >1000 | |
UNC0646 10f | HMT | 140.1 ± 3.8 | 66.8 ± 22.6 | >1000 | |
JIB-04 11a | KDM | 470.5 ± 28.3 | 133.1 ± 18.5 | 262.5 ± 113.0 | |
Quisinostat 12a | HDAC | <13 | <13 | 148.1 ± 145.8 | |
Panobinostat 13 | HDAC | 8.7 ± 3.8 | 12.0 ± 4.8 | 515.3 ± 144.7 | |
Apicidin 14 | HDAC | 23.1 ± 15.2 | 103.6 ± 2.9 | 590.2 ± 146.6 | |
HC Toxin 15 | HDAC | 15.1 ± 3.7 | 30.2 ± 0.1 | 351.4 ± 221.3 | |
CUDC-101 16 | HDAC | 35.6 ± 8.4 | 133.1 ± 6.3 | 2150.4 ± 744.3 | |
Trichostatin A 17 | HDAC | 62.3 ± 21.1 | 53.9 ± 5.4 | 3795.5 ± 1576.3 | |
Dacinostat 18 | HDAC | 40.8 ± 19.1 | 45.3 ± 0.9 | 2266.1 ± 843.2 | |
Fedratinib 19 | Kinase | 66.9 ± 2.8 | 96.9 ± 19.7 | >1000 |
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Appetecchia, F.; Fabbrizi, E.; Fiorentino, F.; Consalvi, S.; Biava, M.; Poce, G.; Rotili, D. Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development. Pharmaceuticals 2024, 17, 962. https://doi.org/10.3390/ph17070962
Appetecchia F, Fabbrizi E, Fiorentino F, Consalvi S, Biava M, Poce G, Rotili D. Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development. Pharmaceuticals. 2024; 17(7):962. https://doi.org/10.3390/ph17070962
Chicago/Turabian StyleAppetecchia, Federico, Emanuele Fabbrizi, Francesco Fiorentino, Sara Consalvi, Mariangela Biava, Giovanna Poce, and Dante Rotili. 2024. "Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development" Pharmaceuticals 17, no. 7: 962. https://doi.org/10.3390/ph17070962
APA StyleAppetecchia, F., Fabbrizi, E., Fiorentino, F., Consalvi, S., Biava, M., Poce, G., & Rotili, D. (2024). Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development. Pharmaceuticals, 17(7), 962. https://doi.org/10.3390/ph17070962