In Vitro Antimalarial Activity of Inhibitors of the Human GTPase Rac1.

Silvia Parapini,Emanuela Erba,Francesco Celani,Anna Olivieri,Loredana Cavicchini,Sarah D’Alessandro,Silvio Paone,Alessandro Contini,Manoochehr Pourshaban

doi:10.1128/aac.01498-21

Abstract

ABSTRACTMalaria 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 to all 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, the involvement of Rac1 during both the invasion process and parasite intracellular development was suggested. The 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 50% inhibitory concentrations (IC50s) (138.8 ± 16.0 nM on the chloroquine-sensitive D10 strain and 321.5 ± 28.5 nM on the chloroquine-resistant W2 strain) and a 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 promising activity that raises attention to this class of molecules as potential antimalarials and deserves further investigation.

Highlights

Malaria accounts for millions of cases and thousands of deaths every year
We showed that Rac1 is recruited in proximity to the site of parasite entry during the invasion process and that it subsequently localizes to the parasitophorous vacuole membrane, the membrane surrounding the parasite during its whole intraerythrocytic life
Three different inhibitors of Rac1 guanosine nucleotide exchange activity and 11 inhibitors of the interaction between Rac1 and its guanine nucleotide exchange factors (GEFs) were tested against asexual parasites of the chloroquine (CQ)-sensitive D10 and CQ-resistant W2 strains

Summary

Introduction

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 to all classes of known antimalarial drugs. In Plasmodium falciparum, the involvement of Rac during both the invasion process and parasite intracellular development was suggested. The aim of this work is to test a panel of Rac inhibitors as potential antimalarial drugs. Among the tested Rac inhibitors, EHop-016 showed promising activity that raises attention to this class of molecules as potential antimalarials and deserves further investigation. Malaria is a vector-borne parasitic disease, which accounts for more than 200 million cases in tropical and subtropical regions. After a single replicative cycle in hepatocytes, Plasmodium parasites invade erythrocytes and develop inside red blood cells (RBCs) through two developmental stages, named trophozoites and schizonts. Some of the parasites inside RBCs develop into sexual forms called gametocytes, which can start replication in the mosquito vector.

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