Table 1.
Select high-value, chemically validated targets for malaria. Listed tool compounds were used to establish on-target activity using reverse chemical genetics, usually using in vitro evolution and whole-genome sequencing.
| Gene | Product Description | Tool Compound | Structure | Ref |
|---|---|---|---|---|
| AcAS (PF3D7_0627800) | Acetyl-CoA synthetase | MMV019721 MMV693183 |
[50–52] | |
| ACS11 (PF3D7_1238800) | Acyl-CoA synthetase | MMV019719 | [53] | |
| ATP4 (PF3D7_1211900) | Non-SERCA-type Ca2+ -transporting P-ATPase | KAE609, SJ733 | [10] | |
| cIRS (PF3D7_1332900) | Isoleucine tRNA synthetase | MMV1081413, thiaisoleucine | [10,54] | |
| CLK3 (PF3D7_1114700) | Cyclin-like kinase 3 | TCMDC135051 | [26] | |
| CPSF3 (PF3D7_1438500) | Cleavage and polyadenylation specificity factor subunit 3, putative | AN13762 | [••55] | |
| CYTB (mal_mito_3) | Cytochrome bc1 complex | Atovaquone, DDD01061024, MMV008149, MMV1427995, MMV1432711 | 4PD4 | [10,54] |
| DHFR-TS (PF3D7_0417200) | Bifunctional dihydrofolate reductase-thymidylate synthase | MMV027634(TS), pyrimethamine (DHFR), P218 | 3QGT | [56] |
| DHODH (PF3D7_0603300) | Dihydroorotate dehydrogenase | DSM265, BRD7539, BRD9185, DSM1 | 4CQ8 | [10,57,58] |
| DPCK (PF3D7_1443700) | Dephospho-CoA kinase, putative | Amb3377585, STK740987 | [59–61] | |
| eEF2 (PF3D7_1451100) | Elongation factor 2 | M5717 (DDD498) | [10] | |
| Ftbeta (PF3D7_1147500) | Protein farnesyltransferase subunit beta | MMV019066, BMS-388891 | [10] | |
| GCN5 (PF3D7_0823300) | Histone acetyltransferase GCN5 | SGC-CBP30 | PQNS | [62] |
| GGPPS (PF3D7_1128400) | Geranylgeranyl pyrophosphate synthase, putative | GDI11–078A, MMV019313 | 3CC9 | [63] |
| HT1 (PF3D7_0204700) | Hexose transporter | C3361 | 6M2L | [64,65] |
| KRS1 (PF3D7_1350100) | Lysine tRNA synthetase | Cladosporin | 6KAB 4H02 |
[35,66] |
| NCR1 (PF3D7_0107500) | Lipid/sterol:H+ symporter | MMV009108, MMV019662, MMV028038 | [67] | |
| NMT (PF3D7_1412800) | Glycylpeptide N-tetradecanoyltransferase (NMT) | IMP-1002 | 6MB1 | [68] |
| PFK9 (PF3D7_0915400) | 6-phosphofructokinase | PS-3 | [69] | |
| PheRS (PF3D7_0109800) | Phenylalanine--tRNA synthetase (α subunit) | BRD1095, BRD3444 | 7BY6 7DPI |
[70] |
| PI4K (PF3D7_0509800) | Phosphatidylinositol 4-kinase | BRD9685, MMV390048, KAI407 | [71,72] | |
| PKG (PF3D7_1436600) | cGMP-dependent protein kinase | ML10 | 5DYK | [24] |
| PMX (PF3D7_0808200) | Plasmepsin X | WM382 | 7RY7 | [21] |
| PNP (PF3D7_0513300) | Purine nucleoside phosphorylase | DADMe-ImmG | [73] | |
| PPPK-DHPS (PF3D7_0810800) | 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK)–dihydropteroate synthase (DHPS) | Pterin/pHBA, Sulfadoxine- dihydropteroate | 6KCM 6JWX |
[74] |
| Proteasome (PF3D7_1011400) | Proteasome subunit beta type-5 | Bortezomib | 7LXT | [34] |
| Proteasome (PF3D7_1328100) | Proteasome subunit beta type-7, putative | WLW | 5FMG | [75] |
| Proteosome (PF3D7_0518300) | Proteasome subunit beta type-1, putative | WLL | 5FMG | [75] |
| PRS (PF3D7_1213800) | Proline--tRNA synthetase | Compound 1S, Halofuginone | 4TWA 4WI1 |
[10,76] |
| TyrRS (PF3D7_0807900) | Tyrosine--tRNA synthetase | ML901 | 7ROR 3VGJ |
[••36] |