Table 1.

Experimentally characterized inhibitors of PfHSP90, PfHSP70, PfHSP40, and their complexes.

PfHSPa	Inhibitor	Biochemical activityb	Biological activity	Ref.c
PfHSP90	Beta carboline alkaloids (Harmine analogs; 17A and 21A)	Moderate affinity but greater affinity for the ATP-binding site of PfHSP90 than human HSP90	Inhibit in vitro growth of parasite-infected erythrocytes; reduce parasitemia and extend survival of parasite-infected mice in combination with DHA	21, 22
	2-Aminobenzamides (SNX-0723)	High affinity for the ATP-binding site of PfHSP90	Inhibit in vitro growth of parasite-infected erythrocytes and parasite-infected liver cells; inhibit parasite growth in liver cells synergistically with PIK-75 (phosphatidylinositol 3-kinase inhibitor); inhibit in vivo growth of parasite-infected mice	23
	Amino-alcohol carbazoles (N-CBZ; compound 5B)	Moderate affinity binding to a PfHSP90-specific hydrophobic extension of the ATP-binding site; no binding to human HSP90	Inhibit in vitro growth of parasite-infected erythrocytes	24
	Pyrimidinediones (compound FM2, which is MMV Malaria Box compound MMV019066)	Moderate affinity binding to PfHSP90 (Surface Plasmon Spectroscopy), and no binding to human HSP90 (competition binding assays with geldanamycin); inhibit ATPase activity of PfHSP90	Inhibit in vitro growth of parasite-infected erythrocytes; high selectivity index from in vitro cytotoxicity assays with mammalian cells	25, 26
	Terpenoids (IMA; UAA)	Bind to PfHSP90 with moderate affinity (binding site not experimentally determined); inhibit ATPase activity and protein aggregation suppression activity of PfHSP90	Inhibit in vitro growth of parasite-infected erythrocytes; inhibit in vivo growth of parasite-infected mice	27
PfHSP70	Polymyxin B	Bind to PfHSP70-1 (primarily ATPase domain) with high affinity and to PfHSP70-z with moderate-to-high affinity; inhibit ATPase activity and protein aggregation suppression activity of PfHSP70-1 and PfHSP70-z; disrupt the interaction of PfHSP70-1 with PfHSP70-z and PfHOP	Not determined	28
	(−)-Epigallocatechin-3-gallate	Bind to PfHSP70-1 (primarily ATPase domain) and PfHSP70-z with high affinity; inhibit ATPase activity and protein aggregation suppression activity of PfHSP70-1 and PfHSP70-z; disrupt the interaction of PfHSP70-1 with PfHSP70-z and PfHOP	Inhibit in vitro growth of parasite-infected erythrocytes	29
	Terpenoids (IMA; UAA)	Bind to PfHSP70-1 (affinity and binding site not experimentally determined). IMA Inhibits ATPase activity and protein aggregation suppression activity of PfHSP70-1; UAA inhibits protein aggregation suppression activity of PfHSP70-1	Inhibit in vitro growth of parasite-infected erythrocytes; inhibit in vivo growth of parasite-infected mice	30
	Malonganenones A, B, and C (MalA, B, and C)	MalA–C inhibit the protein aggregation suppression activity of PfHSP70-1; MalA also inhibits the protein aggregation suppression activity of PfHSP70-x; MalA does not inhibit the basal ATPase activity of PfHSP70-1, PfHSP70-x, and human HSP70, but does inhibit the HSP40-stimulated ATPase activity of PfHSP70-1 and PfHSP70-x, but not human HSP70	MalA and C inhibit in vitro growth of parasite-infected erythrocytes	31, 32
	1,4 Naphthoquinones (lapachol)	Preferentially inhibit protein aggregation suppression activity of PfHSP70-1 compared to a “human-like” HSP70 control; inhibit the basal and HSP40-stimulated ATPase activity of PfHSP70-x but not that of PfHSP70-1 and human HSP70	Inhibit in vitro growth of parasite-infected erythrocytes	31, 32
	Pyrimidinones (DMT002264)	Inhibit PfHSP40-stimulated ATPase activity of PfHSP70-1 (single turnover assay); inhibit HSP40-stimulated ATPase activity of human HSP70 (steady state assay)	Inhibit in vitro growth of parasite-infected erythrocytes	33
	Quinoline–pyrimidine hybrids (compound 7a)	Bind to PfHSP70-1 and PfHSP70-z with high affinity (binding site not experimentally determined)	Inhibit in vitro growth of parasite-infected erythrocytes	34
	2-Phenylthynesulfonamide	Bind with high affinity to PfHSP70-1 (primarily the substrate binding domain) and with moderate affinity to PfHOP; disrupt the interaction of PfHSP70-1 with PfHOP; inhibit protein aggregation suppression activity of PfHSP70-1	Inhibit in vitro growth of parasite-infected erythrocytes	35
PfHSP40	Chalcones (C86)	A pan-inhibitor of all classes of human HSP40, binding specifically to the J domain; inhibited the PFE0055c-stimulated ATPase activity of PfHSP70-x but not its basal ATPase activity	Not determined	36, 37

Abbreviations used: DHA, dihydroartemisinin; HSP, heat shock protein; IMA, iso-mukaadial acetate; PfHSP, Plasmodium falciparum heat shock protein; UAA, ursolic acid acetate.

^aThe title “PfHSP” refers to the PfHSP family that is the primary target of the indicated inhibitors.

^bHigh affinity indicates submicromolar or nanomolar affinity, while moderate affinity indicates micromolar affinity.

^cThe title “Ref.” refers to reference citations.