TY - JOUR
T1 - Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance
AU - Kirkman, Laura A.
AU - Zhan, Wenhu
AU - Visone, Joseph
AU - Dziedziech, Alexis
AU - Singh, Pradeep K.
AU - Fan, Hao
AU - Tong, Xinran
AU - Bruzual, Igor
AU - Hara, Ryoma
AU - Kawasaki, Masanori
AU - Imaeda, Toshihiro
AU - Okamoto, Rei
AU - Sato, Kenjiro
AU - Michino, Mayako
AU - Alvaro, Elena Fernandez
AU - Guiang, Liselle F.
AU - Sanz, Laura
AU - Mota, Daniel J.
AU - Govindasamy, Kavitha
AU - Wang, Rong
AU - Ling, Yan
AU - Tumwebaze, Patrick K.
AU - Sukenick, George
AU - Shi, Lei
AU - Vendome, Jeremie
AU - Bhanot, Purnima
AU - Rosenthal, Philip J.
AU - Aso, Kazuyoshi
AU - Foley, Michael A.
AU - Cooper, Roland A.
AU - Kafsack, Bjorn
AU - Stone Doggett, J.
AU - Nathan, Carl F.
AU - Lin, Gang
N1 - Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.
PY - 2018/7/17
Y1 - 2018/7/17
N2 - 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.
AB - 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.
KW - Artemisinin
KW - Collateral sensitivity
KW - Malaria
KW - Plasmodium
KW - Proteasome inhibitors
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U2 - 10.1073/pnas.1806109115
DO - 10.1073/pnas.1806109115
M3 - Review article
C2 - 29967165
AN - SCOPUS:85050031731
SN - 0027-8424
VL - 115
SP - E6863-E6870
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -