{"doi":"10.1016/j.chembiol.2024.07.001","title":"Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria","abstract":"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.","journal":"Cell chemical biology","year":2024,"id":432398,"datarank":0.42498200160843247,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.0,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":369677,"name":"Suraksha Gahalawat","orcid":"0000-0002-8004-0322","position":1,"is_corresponding":false},{"id":706683,"name":"S. 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