American Chemical Society
jm9b00363_si_002.pdf (5.93 MB)

Improvement of Asparagine Ethylenediamines as Anti-malarial Plasmodium-Selective Proteasome Inhibitors

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journal contribution
posted on 2019-06-09, 00:00 authored by Wenhu Zhan, Joseph Visone, Tierra Ouellette, Jacob C. Harris, Rong Wang, Hao Zhang, Pradeep K. Singh, John Ginn, George Sukenick, Tzu-Tshin Wong, Judith I. Okoro, Ryan M. Scales, Patrick K. Tumwebaze, Philip J. Rosenthal, Björn F. C. Kafsack, Roland A. Cooper, Peter T. Meinke, Laura A. Kirkman, Gang Lin
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.