In Vitro Antimalarial Activity of Inhibitors of the Human GTPase Rac1

• Published in: Antimicrobial agents and chemotherapy Vol. 66; no. 1; p. e0149821
• Main Authors: Parapini, Silvia, Paone, Silvio, Erba, Emanuela, Cavicchini, Loredana, Pourshaban, Manoochehr, Celani, Francesco, Contini, Alessandro, D'Alessandro, Sarah, Olivieri, Anna
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 18-01-2022
• Subjects: Antimalarials - pharmacology; Antimalarials - therapeutic use; Antimicrobial Chemotherapy; Chloroquine - pharmacology; Chloroquine - therapeutic use; Experimental Therapeutics; GTP Phosphohydrolases - antagonists & inhibitors; Humans; Malaria, Falciparum - drug therapy; Plasmodium falciparum; rac1 GTP-Binding Protein - antagonists & inhibitors; Plasmodium; antimalarial drug; Rac1
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01498-21

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.
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
, with nanomolar 50% inhibitory concentrations (IC
s) (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.