In Vitro Antimalarial Activity of Inhibitors of the Human GTPase Rac1

Abstract

Malaria accounts for millions of cases and thousands of deaths every year. In the absence of an effective vaccine, drugs are still the most important tool in the fight against the disease. Plasmodium parasites developed resistance for all the classes of known antimalarial drugs. Thus, the search for antimalarial drugs with novel mechanisms of action is compelling. The human GTPase Rac1 plays a role in parasite invasion of the host cell in many intracellular pathogens. Also in Plasmodium falciparum , it was suggested an involvement of Rac1 both during the invasion process and parasite intracellular development. Aim of this work is to test a panel of Rac1 inhibitors as potential antimalarial drugs. Fourteen commercially available or newly synthesized inhibitors of Rac1 were tested for antimalarial activity. Among these, EHop-016 was the most effective against P. falciparum in vitro, with nanomolar IC 50 (138.8 ± 16.0 nM on the chloroquine-sensitive D10 strain and 321.5 ± 28.5 nM on the chloroquine-resistant W2 strain), and Selectivity Index of 37.8. EHop-016 did not inhibit parasite invasion of red blood cells but affected parasite growth inside them. Among the tested Rac1 inhibitors, EHop-016 showed a promising activity that raises attention on this class of molecules as potential antimalarials and deserves further investigation.

NPM1-Mutated Patient-Derived AML Cells Are More Vulnerable to Rac1 Inhibition

“…In that study, it was hypothesized that resistance is led via an increased number of actin filaments, adhesion forces, and increased cell stiffness in the AML cell. In our study, we intended to investigate the inhibitors thought to be more specific for Rac1, thus avoiding, e.g., EHT-1864, which inhibits nucleotide-binding and activation of Rac1 but also the GTPases Rac2 and Rac3 [ 27 ], and inhibitors of the GTPase Cdc42, e.g., Aza-1 [ 28 ].…”

Role of Host Small GTPases in Apicomplexan Parasite Infection

“…In our recent work, we proposed the Rho GTPase Rac1 as a potential host target for the development of novel antimalarial drugs [ 72 , 73 ] and EHop-016, the most efficient Rac1 inhibitor against P. falciparum , as a promising starting molecule for the development of novel, more effective compounds [ 131 , 132 ]. Moreover, the Rho modulator CNF from E. coli was proposed as a treatment against severe malaria, specifically targeting the adhesion of infected erythrocytes to endothelia [ 75 ].…”

“…Because of their role in actin cytoskeleton modulation, GTPases belonging to the Rho family are involved in infection by many intracellular pathogens [ 40 , 48 , 49 , 50 , 58 , 59 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ], including several apicomplexan parasites, such as Plasmodia [ 72 , 73 , 74 , 75 ], T. gondii [ 76 , 77 ], C. parvum [ 78 , 79 ] and Theileria annulata [ 80 ]. Moreover, several commercially available inhibitors of Rho GTPases have shown in vitro efficacy against intracellular pathogens, including bacteria [ 81 , 82 ], viruses [ 83 , 84 ] and protozoan parasites [ 85 , 86 ].…”

“…Among them, three showed a half inhibitory concentration below 1 μM. The most efficient inhibitors were also tested for their cytotoxicity, giving good results on human microvascular endothelial cells (HMEC-1) [ 73 ].…”