1. Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice
- Author
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Roland A. Cooper, Thijs Beuming, Philip J. Rosenthal, Jeremie Vendome, Laura A. Kirkman, Akinori Toita, Ryoma Hara, John Ginn, Annie Leung, Maria Jose Lafuente-Monasterio, Takafumi Yukawa, Wenhu Zhan, Gang Lin, Kazuyoshi Aso, Patrick K Tumwebaze, Mayako Michino, Carl Nathan, Kenjiro Sato, Hao Zhang, Yi J. Liu, Toshihiro Imaeda, Maria Santos Martinez-Martinez, Peter T. Meinke, Rei Okamoto, Sevil Chelebieva, and Tzu-Tshin Wong
- Subjects
Models, Molecular ,Proteasome Endopeptidase Complex ,Plasmodium falciparum ,Molecular Conformation ,Parasitemia ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Plasmodium ,Catalysis ,Article ,Antimalarials ,Mice ,Drug Development ,Parasitic Sensitivity Tests ,parasitic diseases ,medicine ,Gametocyte ,Animals ,Malaria, Falciparum ,biology ,010405 organic chemistry ,Chemistry ,General Medicine ,General Chemistry ,biology.organism_classification ,medicine.disease ,In vitro ,0104 chemical sciences ,Proteasome ,Proteasome inhibitor ,Proteasome Inhibitors ,Malaria ,medicine.drug - Abstract
Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages - erythrocytic stages, gametocyte stages, liver stages and gamete activation, indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the b5 subunit of the Plasmodium falciparum proteasome, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum -infected mice.
- Published
- 2020