Table 1.
Historical and current MMV portfolio of clinical antimalarial projects and their in vitro resistance-associated parameters.
| Molecular target | Project/Compound | Stage in portfolio | Targeted parasite stage | Resistance associated characteristics | ||||
|---|---|---|---|---|---|---|---|---|
| Resistance gene(s) | EC50 fold Pressure | MIR | EC50 fold shift | Ref. | ||||
| PfATP4 | SJ733 | Patient exploratory - halted (Eisai/St Jude/Kentucky) | ABS, transmission | pfatp4 (Pf3D7_1211900) | 5 | 9 | 3 – 7 | [70] |
| Cipargamin (KAE609) | Patient exploratory | ABS, transmission | pfatp4 (Pf3D7_1211900) | 3 | 7 | 7 – 10 | [71] | |
| PfDHODH | DSM265 | Patient exploratory - halted | ABS, prophylaxis | pfdhodh (Pf3D7_0603300) | 3 | 5.5 | 3.5 | [26] |
| PfDHFR | P218 | Human volunteers | ABS, transmission, prophylaxis | pfdhfr (PF3D7_041720) | 3 | 8 | 3 | N/A |
| PfPi4K | MMV390048 | Patient exploratory - halted | ABS, transmission, prophylaxis | pfpi4k (Pf3D7_0509800) | 3 | 6 | 3 – 7 | [57] |
| PfEF2 | M5717 (DDD107498) | Human volunteers | ABS, transmission, prophylaxis | pfeef2 (Pf3D7_1451100) | 5 | 6 | 7 –5500 | [41] |
| Pf Cyt-bc1 | Atovaquone | Approved | Prophylaxis | Pfcytb (mal_mito_3) | 3 | 7 | 10 – 60 | N/A |
| PfACoAS | Pantothenate series | Preclinical development | ABS, transmission | pfAcCoaS (Pf3D7_0627800) | 3 | 9 | 15 | [72] |
| Unknown | Ganaplacide (KAF156) | Patient exploratory | ABS, transmission, prophylaxis | pfcarl (Pf3D7_0321900) pfugt (Pf3D7_1113300) pfact (Pf3D7_1036800) | 3 | 8 | 10 | [56] |
MIR: in vitro logarithmic value of the minimum inoculum for resistance obtained in Pf Dd2 with a drug pressure corresponding to a designated multiple of the EC50 (or more recently EC90); DHODH, dihydroorotate dehydrogenase; DHFR, dihydrofolate reductase; PI4K, phosphatidylinositol-4-kinase; EF2, elongation factor 2; AcCoAS, acetyl-CoA synthetase; N/A: non-available. The current portfolio is listed in Resources ii, on 20.12.2020. Some compounds displaying log10MIR3xEC50 > 9 in the MMV portfolio are not described here because the data are unpublished to date.