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

TitleImprovement of Asparagine Ethylenediamines as Anti-malarial -Selective Proteasome Inhibitors.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhan W, Visone J, Ouellette T, Harris JC, Wang R, Zhang H, Singh PK, Ginn J, Sukenick G, Wong T-T, Okoro JI, Scales RM, Tumwebaze PK, Rosenthal PJ, Kafsack BFC, Cooper RA, Meinke PT, Kirkman LA, Lin G
JournalJ Med Chem
Volume62
Issue13
Pagination6137-6145
Date Published2019 07 11
ISSN1520-4804
KeywordsAntimalarials, Asparagine, Drug Resistance, Ethylenediamines, Humans, Malaria, Falciparum, Mutation, Plasmodium falciparum, Proteasome Endopeptidase Complex, Proteasome Inhibitors
Abstract

The 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.

DOI10.1021/acs.jmedchem.9b00363
Alternate JournalJ Med Chem
PubMed ID31177777
PubMed Central IDPMC7104388
Grant ListR21 AI101393 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R21 AI123794 / AI / NIAID NIH HHS / United States
R01 AI075045 / AI / NIAID NIH HHS / United States
R56 AI075045 / AI / NIAID NIH HHS / United States

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