科研之友
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摘要
We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) beta 5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The beta 5 inhibitors synergize with a beta 2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA beta 5 inhibitor surprisingly harbored a point mutation in the noncatalytic beta 6 subunit. The beta 6 mutant was resistant to the species-selective Pf20S beta 5 inhibitor but remained sensitive to the species-nonselective beta 5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S beta 5 inhibitor was accompanied by increased sensitivity to a Pf20S beta 2 inhibitor. Finally, the beta 5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S beta 5 and beta 2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.
- 出版日期2018-7-17
