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Improvement of Asparagine Ethylenediamines as Anti-malarial
Natural Sciences and Mathematics | Faculty Scholarship
  • Wenhu Zhan, Department of Microbiology & Immunology , Weill Cornell Medicine
  • Joseph Visone, Department of Microbiology & Immunology , Weill Cornell Medicine
  • Tierra Ouellette, Department of Microbiology & Immunology , Weill Cornell Medicine
  • Jacob C. Harris, Department of Microbiology & Immunology , Weill Cornell Medicine
  • Rong Wang, NMR Analytical Core Facility , Memorial Sloan Kettering Cancer Center
  • Hao Zhang, Department of Microbiology & Immunology , Weill Cornell Medicine
  • Pradeep K. Singh, Chemical Core Facility, Department of Biochemistry , Weill Cornell Medicine
  • John Ginn, Tri-Institutional Therapeutics Discovery Institute
  • George Sukenick, NMR Analytical Core Facility , Memorial Sloan Kettering Cancer Center
  • Tzu-Tshin Wong, Takeda Pharmaceutical Company Ltd.
  • Judith I Okoro, Infectious Diseases Research Collaboration
  • Ryan M Scales, Department of Public Health , University of North Carolina
  • Patrick K Tumwebaze, Infectious Diseases Research Collaboration
  • Philip J Rosenthal, Department of Medicine, University of California, San Francisco
  • Björn F. C. Kafsack, Department of Microbiology & Immunology , Weill Cornell Medicine
  • Roland A. Cooper, Department of Natural Sciences and Mathematics, Dominican University of California
  • Peter T. Meinke, Tri-Institutional Therapeutics Discovery Institute
  • Laura A. Kirkman, Department of Microbiology & Immunology , Weill Cornell Medicine
  • Gang Lin, Department of Microbiology & Immunology , Weill Cornell Medicine
Department
Natural Sciences and Mathematics
Document Type
Article
Source
Journal of Medicinal Chemistry
Publication Date
7-11-2019
Abstract

The Plasmodium proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors. Here, we report further a structure–activity relationship study of AsnEDAs for selective inhibition of Pf20S over human proteasomes. Additionally, we show new mutation that conferred resistance to AsnEDAs and collateral sensitivity to an inhibitor of the Pf20S β2 subunit, the same as previously identified resistant mutation. This resistance could be overcome through the use of the structure-guided inhibitor design. Collateral sensitivity to inhibitors among respective proteasome subunits underscores the potential value of treating malaria with combinations of inhibitors of different proteasome subunits to minimize the emergence of drug resistance.

PubMed ID
31177777
Rights
Copyright © 2019 American Chemical Society
Citation Information
Wenhu Zhan, Joseph Visone, Tierra Ouellette, Jacob C. Harris, et al.. "Improvement of Asparagine Ethylenediamines as Anti-malarial" Vol. 62 Iss. 13 (2019) p. 6137 - 6145 ISSN: 1520-4804
Available at: http://works.bepress.com/roland_cooper/48/