Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemical Compounds
2.2. Parasite Culture
2.3. Standard Chemosensitivity Assay
2.4. Cytotoxicity Evaluation
2.5. Quiescent-Stage Survival Assay (QSA)
2.6. Determination of Abundance of Methylated and Acetylated Histone
3. Results and discussion
3.1. Antiplasmodial Activity of Some Epidrugs
3.2. Specific Antiplasmodial Activity of Certain Epidrugs
3.3. Some Epidrugs Are Active against ART-Resistant Parasites in a Quiescent State
3.4. Effects of Some Epidrugs on Histone Methylation and Acetylation in DHA-Treated Parasites
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug | Antiplasmodial Activity: IC50 (nM) | p-Value 1 (F32-ART vs. F32-TEM) | Cytotoxicity: CC50 (µM) (Cell Type) | Selectivity Index 2 CC50/IC50 | ||
---|---|---|---|---|---|---|
F32-ART | F32-TEM | |||||
HDAC inhibitors | Trichostatin A | 29 ± 12 | 30 ± 3 | 0.8 | 0.2 (NFF) [40] 3 | 7 |
Apicidin | 36 ± 9 | 36 ± 5 | >0.99 | 10 (Jurkat) [41] 3 | 280 | |
JAHA | 460 ± 30 | 690 ± 80 | 0.1 | 2.4 (MCF7 cancer) [42] 3 | 5 | |
SAHA | 540 ± 55 | 390 ± 10 | 0.1 | 5.5 (NFF) [43] 3 | 10 | |
Tubastatin A | 7 × 103 * | 8 × 103 * | >10 (661W) [44] 3 | >1.4 | ||
PCI 34051 | 8 × 103 * | 9 × 103 * | >20 (MCF7) [45] 3 | >2.5 | ||
TC-H 106 | >10 × 103 * | >10 × 103 * | 6.3 (GM15850) [46] 3 | <0.6 | ||
MC 1568 | >10 × 103 * | >10 × 103 * | 10 (monocytes) [47] 3 | <1 | ||
HMT inhibitors | BI × -01294 | 56 ± 8 | 55 ± 14 | >0.99 | 6.1 (HFF) [48] 3 | 110 |
TM2-115 | 128 ± 30 | 104 ± 32 | 0.4 | 5.7 (HFF) [48] 3 | 45 | |
Chaetocin | 640 ± 160 | 730 ± 90 | >0.99 | 0.13 (HL-60) [49] 3 | 0.2 | |
HAT inhibitors | CB3717 | 1 × 103 ± 0.16 × 103 | 1 × 103 ± 0.11 × 103 | >0.99 | >20 (NIH3T3) [50] 3 | >20 |
MG149 | >10 × 103 | >10 × 103 | 51 (NOMO1) [51] 3 | <1.7 | ||
C646 | >10 × 103 | >10 × 103 | Between 10 and 20 (WM983A) [52] 3 | <1 | ||
HDM inhibitor | JIB-04 | 560 ± 80 | 940 ± 30 | 0.1 | >10 (human mesenchymal stem) [53] 3 | >18 |
DNMT inhibitors | SGI-1027 | 63 ± 13 | 54 ±22 | 0.7 | >50 (H4IIErat) [54] 3 | >790 |
MLo1302 | 7 × 103 ± 2 × 103 | 8 × 103 * | 6.5 * (Vero) | 0.9 | ||
Hydralazine | >10 × 103 | >10 × 103 | 0.4 | 40 (HeLa) [55] 3 | <4 | |
Flv69 | >10 × 103 * | >10 × 103 * | >50 * (Vero) | |||
Flv880 | >10 × 103 * | >10 × 103 * | >50 * (Vero) | |||
MLo1401 | >10 × 103 * | >10 × 103 * | 20 * (Vero) | <2 | ||
MLo1406 | >10 × 103 * | >10 × 103 * | >50 * (Vero) | |||
MLo1502 | >10 × 103 | >10 × 103 * | >50 * (Vero) | |||
MLo1507 | >10 × 103 * | >10 × 103 * | 40 * (Vero) | <4 | ||
MLo1508 | >10 × 103 * | >10 × 103 * | 36 * (Vero) | <3.6 | ||
MLo1509 | >10 × 103 * | >10 × 103 * | >50 (Vero) | |||
NFlav2018 | >10 × 103 * | >10 × 103 * | >50 * (Vero) | |||
Bromodomain inhibitors | (+)-JD-1 | 6 × 103 * | 4.5 × 103 * | 0.6 * (Vero) | 0.1 | |
SHH-878-1 | 10 × 103 * | 10 × 103 * | 3 * (Vero) | 0.3 | ||
(+)-JQ-1 | >10 × 103 * | >10 × 103 * | 0.2 * (Vero) | <0.02 | ||
AKE-040 | >10 × 103 * | >10 × 103 * | 24 * (Vero) | <2.4 | ||
PROTAC BRD4 degrader | MZ1 | 1.7 × 103 ± 0.3 × 103 | 1.3 × 103 * | >50 * (Vero) | >30 | |
Control drug | artemisinin | 14 ± 3 | 13±3 | 0.5 | >100 (Vero) | >7500 |
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Reyser, T.; Paloque, L.; Nguyen, M.; Augereau, J.-M.; Fuchter, M.J.; Lopez, M.; Arimondo, P.B.; Hassell-Hart, S.; Spencer, J.; Di Stefano, L.; et al. Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites. Pharmaceutics 2023, 15, 2440. https://doi.org/10.3390/pharmaceutics15102440
Reyser T, Paloque L, Nguyen M, Augereau J-M, Fuchter MJ, Lopez M, Arimondo PB, Hassell-Hart S, Spencer J, Di Stefano L, et al. Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites. Pharmaceutics. 2023; 15(10):2440. https://doi.org/10.3390/pharmaceutics15102440
Chicago/Turabian StyleReyser, Thibaud, Lucie Paloque, Michel Nguyen, Jean-Michel Augereau, Matthew John Fuchter, Marie Lopez, Paola B. Arimondo, Storm Hassell-Hart, John Spencer, Luisa Di Stefano, and et al. 2023. "Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites" Pharmaceutics 15, no. 10: 2440. https://doi.org/10.3390/pharmaceutics15102440