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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, J Stone; Nathan, Carl F; Lin, Gang.
Afiliación
  • Kirkman LA; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, NY 10065; lak9015@med.cornell.edu cnathan@med.cornell.edu gal2005@med.cornell.edu.
  • Zhan W; Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065.
  • Visone J; Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065.
  • Dziedziech A; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, NY 10065.
  • Singh PK; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, NY 10065.
  • Fan H; Chemical Core Facility, Department of Biochemistry, Weill Cornell Medicine, NY 10065.
  • Tong X; Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065.
  • Bruzual I; Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065.
  • Hara R; Department of Research and Development, Portland Veterans Affairs Medical Center, Oregon Health and Science University, Portland, OR 97239.
  • Kawasaki M; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Imaeda T; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Okamoto R; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Sato K; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Michino M; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Alvaro EF; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Guiang LF; Diseases of the Developing World (DDW), Tres Cantos Medicine Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
  • Sanz L; Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA 94901.
  • Mota DJ; Diseases of the Developing World (DDW), Tres Cantos Medicine Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
  • Govindasamy K; Department of Medicine, University of California, San Francisco, CA 94143.
  • Wang R; Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 11201.
  • Ling Y; NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • Tumwebaze PK; Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065.
  • Sukenick G; Infectious Diseases Research Collaboration, Kampala, Uganda.
  • Shi L; NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • Vendome J; Department of Biophysics, Weill Cornell Medicine, NY 10065.
  • Bhanot P; Schrödinger, Inc., New York, NY 10036.
  • Rosenthal PJ; Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 11201.
  • Aso K; Department of Medicine, University of California, San Francisco, CA 94143.
  • Foley MA; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Cooper RA; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065.
  • Kafsack B; Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA 94901.
  • Doggett JS; Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065.
  • Nathan CF; Department of Research and Development, Portland Veterans Affairs Medical Center, Oregon Health and Science University, Portland, OR 97239.
  • Lin G; Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065; lak9015@med.cornell.edu cnathan@med.cornell.edu gal2005@med.cornell.edu.
Proc Natl Acad Sci U S A ; 115(29): E6863-E6870, 2018 07 17.
Article en En | MEDLINE | ID: mdl-29967165
We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) ß5 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 ß5 inhibitors synergize with a ß2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA ß5 inhibitor surprisingly harbored a point mutation in the noncatalytic ß6 subunit. The ß6 mutant was resistant to the species-selective Pf20S ß5 inhibitor but remained sensitive to the species-nonselective ß5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S ß5 inhibitor was accompanied by increased sensitivity to a Pf20S ß2 inhibitor. Finally, the ß5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S ß5 and ß2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Proteínas Protozoarias / Complejo de la Endopetidasa Proteasomal / Inhibidores de Proteasoma / Antimaláricos Tipo de estudio: Diagnostic_studies / Health_economic_evaluation Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Proteínas Protozoarias / Complejo de la Endopetidasa Proteasomal / Inhibidores de Proteasoma / Antimaláricos Tipo de estudio: Diagnostic_studies / Health_economic_evaluation Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos