Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria
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ABSTRACT: Malaria remains a global health threat 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 5 active-site. 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 of Resistance >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto 7. Inhibition of Pf5 correlated with parasite killing, without inhibiting the human proteasome or showing cytotoxicity. The Pf_proteasome_SW584 cryo-EM structure showed SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the 5/6/3 subunit interface that shows 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.
INSTRUMENT(S): Q TRAP
ORGANISM(S): Homo Sapiens (human) Plasmodium Falciparum (isolate 3d7)
TISSUE(S): Erythrocyte
SUBMITTER: Andrew Lemoff
LAB HEAD: Margaret A. Phillips
PROVIDER: PXD052830 | Pride | 2024-07-30
REPOSITORIES: Pride
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