1区 · 综合性期刊
Article
作者: Kawasaki, Masanori ; Mota, Daniel J. ; Lin, Gang ; Wang, Rong ; Aso, Kazuyoshi ; Michino, Mayako ; Tong, Xinran ; Ling, Yan ; Sukenick, George ; Bruzual, Igor ; Visone, Joseph ; Guiang, Liselle F. ; Alvaro, Elena Fernandez ; Foley, Michael A. ; Singh, Pradeep K. ; Fan, Hao ; Okamoto, Rei ; Sato, Kenjiro ; Zhan, Wenhu ; Hara, Ryoma ; Rosenthal, Philip J. ; Tumwebaze, Patrick K. ; Nathan, Carl F. ; Govindasamy, Kavitha ; Imaeda, Toshihiro ; Kafsack, Bjorn ; Shi, Lei ; Cooper, Roland A. ; Kirkman, Laura A. ; Dziedziech, Alexis ; Vendome, Jeremie ; Bhanot, Purnima ; Sanz, Laura ; Doggett, J. Stone
We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 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 β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.
