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Proc Natl Acad Sci U S A ; 115(29): E6863-E6870, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29967165

RESUMO

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) ß5 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 ß5 inhibitors synergize with a ß2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA ß5 inhibitor surprisingly harbored a point mutation in the noncatalytic ß6 subunit. The ß6 mutant was resistant to the species-selective Pf20S ß5 inhibitor but remained sensitive to the species-nonselective ß5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S ß5 inhibitor was accompanied by increased sensitivity to a Pf20S ß2 inhibitor. Finally, the ß5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S ß5 and ß2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.


Assuntos
Antimaláricos/química , Plasmodium falciparum/enzimologia , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/química , Proteínas de Protozoários/antagonistas & inibidores , Artemisininas/química , Bortezomib/química , Resistência Microbiana a Medicamentos , Humanos , Lactonas/química , Oligopeptídeos/química , Proteínas de Protozoários/química
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