Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance

Laura A. Kirkman, Wenhu Zhan, Joseph Visone, Alexis Dziedziech, Pradeep K. Singh, Hao Fan, Xinran Tong, Igor Bruzual, Ryoma Hara, Masanori Kawasaki, Toshihiro Imaeda, Rei Okamoto, Kenjiro Sato, Mayako Michino, Elena Fernandez Alvaro, Liselle F. Guiang, Laura Sanz, Daniel J. Mota, Kavitha Govindasamy, Rong Wang & 14 others Yan Ling, Patrick K. Tumwebaze, George Sukenick, Lei Shi, Jeremie Vendome, Purnima Bhanot, Philip J. Rosenthal, Kazuyoshi Aso, Michael A. Foley, Roland A. Cooper, Bjorn Kafsack, Joseph Doggett, Carl F. Nathan, Gang Lin

Research output: Contribution to journalReview article

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E6863-E6870
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number29
DOIs
StatePublished - Jul 17 2018

Fingerprint

ethylenediamine
Proteasome Inhibitors
Antimalarials
Plasmodium falciparum
Asparagine
Proteasome Endopeptidase Complex
Costs and Cost Analysis
Artemisinins
Parasites
Point Mutation
Liver

Keywords

  • Artemisinin
  • Collateral sensitivity
  • Malaria
  • Plasmodium
  • Proteasome inhibitors

ASJC Scopus subject areas

  • General

Cite this

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance. / Kirkman, Laura A.; Zhan, Wenhu; Visone, Joseph; Dziedziech, Alexis; Singh, Pradeep K.; Fan, Hao; Tong, Xinran; Bruzual, Igor; Hara, Ryoma; Kawasaki, Masanori; Imaeda, Toshihiro; Okamoto, Rei; Sato, Kenjiro; Michino, Mayako; Alvaro, Elena Fernandez; Guiang, Liselle F.; Sanz, Laura; Mota, Daniel J.; Govindasamy, Kavitha; Wang, Rong; Ling, Yan; Tumwebaze, Patrick K.; Sukenick, George; Shi, Lei; Vendome, Jeremie; Bhanot, Purnima; Rosenthal, Philip J.; Aso, Kazuyoshi; Foley, Michael A.; Cooper, Roland A.; Kafsack, Bjorn; Doggett, Joseph; Nathan, Carl F.; Lin, Gang.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 29, 17.07.2018, p. E6863-E6870.

Research output: Contribution to journalReview article

Kirkman, LA, Zhan, W, Visone, J, Dziedziech, A, Singh, PK, Fan, H, Tong, X, Bruzual, I, Hara, R, Kawasaki, M, Imaeda, T, Okamoto, R, Sato, K, Michino, M, Alvaro, EF, Guiang, LF, Sanz, L, Mota, DJ, Govindasamy, K, Wang, R, Ling, Y, Tumwebaze, PK, Sukenick, G, Shi, L, Vendome, J, Bhanot, P, Rosenthal, PJ, Aso, K, Foley, MA, Cooper, RA, Kafsack, B, Doggett, J, Nathan, CF & Lin, G 2018, 'Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 29, pp. E6863-E6870. https://doi.org/10.1073/pnas.1806109115
Kirkman, Laura A. ; Zhan, Wenhu ; Visone, Joseph ; Dziedziech, Alexis ; Singh, Pradeep K. ; Fan, Hao ; Tong, Xinran ; Bruzual, Igor ; Hara, Ryoma ; Kawasaki, Masanori ; Imaeda, Toshihiro ; Okamoto, Rei ; Sato, Kenjiro ; Michino, Mayako ; Alvaro, Elena Fernandez ; Guiang, Liselle F. ; Sanz, Laura ; Mota, Daniel J. ; Govindasamy, Kavitha ; Wang, Rong ; Ling, Yan ; Tumwebaze, Patrick K. ; Sukenick, George ; Shi, Lei ; Vendome, Jeremie ; Bhanot, Purnima ; Rosenthal, Philip J. ; Aso, Kazuyoshi ; Foley, Michael A. ; Cooper, Roland A. ; Kafsack, Bjorn ; Doggett, Joseph ; Nathan, Carl F. ; Lin, Gang. / Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 29. pp. E6863-E6870.
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abstract = "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.",
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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 - Doggett, Joseph

AU - Nathan, Carl F.

AU - Lin, Gang

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

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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

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