Table 2.
Select Antiplasmodial Compounds Identified by Recent Drug Discovery Efforts
| Compound ID | Compound Class | Stage in Development | Putative Target | Target Location | Biological pathway | Pf Strain(s) for ABS | Resistance Mediator(s) | Refs |
|---|---|---|---|---|---|---|---|---|
| ACT-451840 | Piperazine | Phase I (NCT02223871, NCT02186002a) | Multidrug resistance 1 (PfMDR1)b | DV membrane | Unknown | Dd2, 7G8, NF54 | pfmdr1 (PF3D7_0523000) | [82] |
| AN13762 | Benzoxaborole | Pre-clinical | Cleavage and specificity factor homolog (PfCPSF3) | Nucleus | mRNA maturation | Dd2, 3D7 | Prodrug activation and resistance esterase (pfpare, PF3D7_0709700); SUMO-activating enzyme subunit 2 (pfuba2, Pf3D7_123700); E3 SUMO ligase (pfpias, Pf3D7_1360700), ring zinc-finger E3 ubiquitin ligase (Pf3D7_0529900); ubiquitin-activating enzyme 1 (Pf3D7_1350400); cleavage and polyadenylation specificity factor subunit 3 (pfcpsf3, PF3D7_1438500) | [57] |
| Bortezomib, WLL, WLW | Bortezomib: peptidyl boronic acid; WLL and WLW: peptide vinyl sulfones | Pre-clinical | P. falciparum 20S proteasome (β5 for bortezomib, β5 and β2 for WLL, β2 for WLW) | Proteasome | Ubiquitin-regulated protein degradation | Bortezomib: 3D7; WLL and WLW: Cam3.II K13WT, Cam3.II K13C580Y, V1/S K13WT, V1/S K13C580Y | Bortezomib: Pf 20S β5 (PF3D7_1011400); WLL: Pf 20S β6 (PF3D7_0518300) and β5; WLW: Pf 20S β2 (PF3D7_1328100), Pf 26S proteasome 19S regulatory particles (pfrpt4, PF3D7_1306400), (pfrpt5, PF3D7_1130400), (pfrpn6, PF3D7_1402300) | [59–61] |
| DSM265 | Triazolopyrimidine | Phase I/II (NCT02389348, NCT02573857, NCT02123290a) | Dihydroorotate dehydrogenase (PfDHODH) | Mitochondrion | Pyrimidine biosynthesis | Dd2, K1 | pfdhodh (PF3D7_0603300) | [58] |
| GNF-Pf-5640 | Hexahydroquinoline | Pre-clinical | Unknown | Unknown | Unknown | Dd2-B2 | pfmdr1 (PF3D7_0523000) | [65] |
| KAF156 and GNF179 | Imidazolopiperazines | KAF156: Phase II (NCT01753323, NCT04546633, NCT03167242a); GNF179: Pre-clinical | Unknown | Endoplasmic Reticulum/Golgi apparatus | Endoplasmic Reticulum-dependent protein processing | 3D7, Dd2 | Cyclic amine resistance locus (pfcarl, Pf3D7_0321900); UDP-galactose transporter (pfugt, PF3D7_1113300); acetyl-CoA transporter (pfact, PF3D7_1036800) | [20] |
| MB14 | 4-cyano-3-methylisoquinoline | Pre-clinical | Na+ efflux pump (PfATP4) | Parasite plasma membrane | ATP4-regulated Na+ homeostasis | 3D7 | non-SERCA-type Ca2+-transporting P-ATPase (pfatp4, PF3D7_1211900) | [66] |
| ML10 and MMV030084 | ML10: imidazopyridine; MMV030084: trisubstituted imidazole | Pre-clinical | cGMP-dependent protein kinase (PfPKG) | Cytosol and early secretory pathway | Parasite egress and host cell invasion | Dd2-B2 WT, Dd2-B2 TKL3KO | Tyrosine kinase-like protein 3 (tkl3, PF3D7_1349300) | [18, 68] |
a
ClinicalTrials.gov Identifier
b
Unknown if this is the primary target or resistance mediator