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 - Funding Information:
Toita, Mr. Tzu-Tshin Wong, Dr. John Ginn, Dr. Andrew Stamford, and Dr. Peter Meinke at Tri-Institutional Therapeutics Discovery for medicinal chemistry discussions; Dr. J. David Warren at The Abby and Howard P. Milstein Synthetic Chemistry Core Facility at Weill Cornell Medicine for assistance; Dr. Hao Li and Dr. Matthew Bogyo for advice and sharing reagents; Ms. Stephanie A. Rasmussen (Dominican University) and Amanda Chan (Weill Cornell Medicine) for technical assistance; Jamie Bean (Memorial Sloan Kettering Cancer Center, MSKCC) for assistance with whole-genome sequencing; Dr. Angelika Sturm, Dr. Koen Dechering, and Mr Rob Henderson at TropIQ Health Sciences for providing parasite biomass; and Dr. Katja Becker at Justus Liebig University Giessen for sharing reagents. This work was supported by NIH Grants 1R21AI123794 (to G.L. and L.A.K.), R21 AI101393 (to G.L.), 1R21AI094167 (to P.B.), AI075045 (to P.J.R. and R.A.C.),
Funding Information:
We thank Takeda Pharmaceuticals, Inc. for providing pharmacokinetic analyses and GlaxoSmithKline’s Diseases of the Developing World campus at Tres Cantos, Spain for providing gamete activation and pharmacokinetic assays as gifts-in-kind; Dr. Takafumi Yukawa, Dr. Akinori Toita, Mr. Tzu-Tshin Wong, Dr. John Ginn, Dr. Andrew Stamford, and Dr. Peter Meinke at Tri-Institutional Therapeutics Discovery for medicinal chemistry discussions; Dr. J. David Warren at The Abby and Howard P. Milstein Synthetic Chemistry Core Facility at Weill Cornell Medicine for assistance; Dr. Hao Li and Dr. Matthew Bogyo for advice and sharing reagents; Ms. Stephanie A. Rasmussen (Dominican University) and Amanda Chan (Weill Cornell Medicine) for technical assistance; Jamie Bean (Memorial Sloan Kettering Cancer Center, MSKCC) for assistance with whole-genome sequencing; Dr. Angelika Sturm, Dr. Koen Dechering, and Mr Rob Henderson at TropIQ Health Sciences for providing parasite biomass; and Dr. Katja Becker at Justus Liebig University Giessen for sharing reagents. This work was supported by NIH Grants 1R21AI123794 (to G.L. and L.A.K.), R21 AI101393 (to G.L.), 1R21AI094167 (to P.B.), AI075045 (to P.J.R. and R.A.C.), and T37MD003407 (to L.F.G. and D.J.M.); National Science Foundation Grant IOS-1146221 (to P.B.); the Department of Medicine, Weill Cornell Medicine Seed Fund (L.A.K.); the Tri-Institutional Therapeutics Discovery Institute and Weill Cornell Medicine Matching Fund (G.L.); Medicines for Malaria Venture RD/15/0001 (R.A.C. and P.J.R.); and United States Department of Veterans Affairs Biomedical Laboratory Research and Development Grant BX002440 (to J.S.D.). We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the National Cancer Institute Cancer Center Support Grant P30 CA08748, Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (MSKCC). The Department of Microbiology and Immunology at Weill Cornell Medicine is supported by the William Randolph Hearst Trust. L.A.K. is a Hearst Clinical Scholar.
Funding Information:
and T37MD003407 (to L.F.G. and D.J.M.); National Science Foundation Grant IOS-1146221 (to P.B.); the Department of Medicine, Weill Cornell Medicine Seed Fund (L.A.K.); the Tri-Institutional Therapeutics Discovery Institute and Weill Cornell Medicine Matching Fund (G.L.); Medicines for Malaria Venture RD/15/0001 (R.A.C. and P.J.R.); and United States Department of Veterans Affairs Biomedical Laboratory Research and Development Grant BX002440 (to J.S.D.). We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the National Cancer Institute Cancer Center Support Grant P30 CA08748, Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (MSKCC). The Department of Microbiology and Immunology at Weill Cornell Medicine is supported by the William Randolph Hearst Trust. L.A.K. is a Hearst Clinical Scholar.
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
UR - http://www.scopus.com/inward/record.url?scp=85050031731&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050031731&partnerID=8YFLogxK
U2 - 10.1073/pnas.1806109115
DO - 10.1073/pnas.1806109115
M3 - Review article
C2 - 29967165
AN - SCOPUS:85050031731
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
SN - 0027-8424
IS - 29
ER -