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. 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.

In Vitro Antimalarial Activity of Inhibitors of the Human GTPase Rac1 / S. Parapini, S. Paone, E. Erba, L. Cavicchini, M. Pourshaban, F. Celani, A. Contini, S. D'Alessandro, A. Olivieri. - In: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. - ISSN 0066-4804. - 66:1(2022 Jan 18), pp. e01498-21.1-e01498-21.10. [10.1128/AAC.01498-21]

In Vitro Antimalarial Activity of Inhibitors of the Human GTPase Rac1

Parapini S.;Paone S.;Erba E.;Cavicchini L.;Contini A.;D'Alessandro S.;
2022-01-18

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 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.
Antimalarial drug; Plasmodium; Rac1
Settore MED/04 - Patologia Generale
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
Settore MED/07 - Microbiologia e Microbiologia Clinica
CAR_RIC18SDALE_01 - Modulation of bone marrow macrophage plasticity by gametocytes, the transmission stages of malaria parasite - D'ALESSANDRO, SARAH - CAR_RIC - Bandi Fondazione Cariplo - 2018
1-nov-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/900820
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