Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria

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Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum ( Pf ) parasites revealed point mutations in the Pf_ proteasome β5 active-site ( Pf β5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >10 9 ) and was synergistic with dihydroartemisinin. Pf_ proteasome purification was facilitated by His 8 -tag introduction onto β7. Inhibition of Pf β5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_ proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the β5/β6/β3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.

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