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

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.