Authors

Laura A. Kirkman, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine
Wenhu Zhan, Department of Microbiology and Immunology, Weill Cornell Medicine
Joseph Visone, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine
Alexis Dziedziech, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine
Pradeep K. Singh, Chemical Core Facility, Department of Biochemistry, Weill Cornell Medicine
Hao Fan, Department of Microbiology and Immunology, Weill Cornell Medicine
Xinran Tong, Department of Microbiology and Immunology, Weill Cornell Medicine
Igor Bruzual, Department of Research and Development, Portland Veterans Affairs Medical Center
Ryoma Hara, Tri-Institutional Therapeutics Discovery Institute
Masanori Kawasaki, Tri-Institutional Therapeutics Discovery Institute
Toshihiro Imaeda, Tri-Institutional Therapeutics Discovery Institute
Rei Okamoto, Tri-Institutional Therapeutics Discovery Institute
Kenjiro Sato, Tri-Institutional Therapeutics Discovery Institute
Mayako Michino, Tri-Institutional Therapeutics Discovery Institute
Elena Fernandez Alvaro, Diseases of the Developing World (DDW)
Liselle F. Guiang, Department of Natural Sciences and Mathematics, Dominican University of California
Laura Sanz, Diseases of the Developing World (DDW)
Daniel J. Mota, Department of Medicine, University of California, San Francisco
Kavitha Govindasamy, Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School
Rong Wang, NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center
Yan Ling, Department of Microbiology and Immunology, Weill Cornell Medicine
Patrick K. Tumwebaze, Infectious Diseases Research Collaboration
George Sukenick, NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center
Lei Shi, Department of Biophysics, Weill Cornell Medicine
Jeremie Vendome, Schrödinger, Inc.
Purnima Bhanot, Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School
Philip J. Rosenthal, Department of Medicine, University of California, San Francisco
Kazuyoshi Aso, Tri-Institutional Therapeutics Discovery Institute
Michael A. Foley, Tri-Institutional Therapeutics Discovery Institute
Roland A. Cooper, Department of Natural Sciences and Mathematics, Dominican University of CaliforniaFollow
Bjorn Kafsack, Department of Microbiology and Immunology, Weill Cornell Medicine
J Stone Doggett, Department of Research and Development, Portland Veterans Affairs Medical Center
Carl F. Nathan, Department of Microbiology and Immunology, Weill Cornell Medicine
Gang Lin, Department of Microbiology and Immunology, Weill Cornell Medicine

Department

Natural Sciences and Mathematics

Document Type

Article

Source

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

7-17-2018

ISSN

1091-6490

Volume

115

Issue

29

First Page

6863

Last Page

6863

Digital Object Identifier / DOI

https://doi.org/10.1073/pnas.1806109115

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.

PubMed ID

29967165

Rights

Copyright © 2018 the Author(s). Published by PNAS

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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