In vitro antimalarial activity of inhibitors of the human GTPase Rac1

Antimicrob Agents Chemother. 2021 Nov 1:AAC0149821. doi: 10.1128/AAC.01498-21. Online ahead of print.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 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 IC50 (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.PMID:34723630 | DOI:10.1128/AAC.01498-21
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Source Type: research