{"doi":"10.1002/chem.202203958","title":"Development of Potent and Highly Selective Epoxyketone‐Based Plasmodium Proteasome Inhibitors","abstract":"Here, we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171-fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.","journal":"Chemistry - A European Journal","year":2023,"id":333005,"datarank":0.6201015798336627,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.13138709913044033,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.13138709913044033,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":11,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":447645,"name":"Pavla Fajtová","orcid":"0000-0002-4029-0706","position":1,"is_corresponding":false},{"id":883284,"name":"Jaeson Calla","orcid":"0000-0003-4812-3168","position":2,"is_corresponding":false},{"id":323858,"name":"Gregory LaMonte","orcid":"0000-0002-6036-4063","position":3,"is_corresponding":false},{"id":356691,"name":"Mudong Feng","orcid":"0000-0003-1686-0454","position":4,"is_corresponding":false},{"id":323859,"name":"Frances Rocamora","orcid":"0000-0002-2579-6733","position":5,"is_corresponding":false},{"id":288356,"name":"Sabine Ottilie","orcid":"0000-0001-9797-2612","position":6,"is_corresponding":false},{"id":262004,"name":"Evgenia Glukhov","orcid":"0000-0001-6513-9909","position":7,"is_corresponding":false},{"id":550573,"name":"Evžen Bouřa","orcid":"0000-0002-9652-4065","position":8,"is_corresponding":false},{"id":314429,"name":"Raymond T. Suhandynata","orcid":"0000-0002-4767-7639","position":9,"is_corresponding":false},{"id":330629,"name":"Jeremiah D. Momper","orcid":"0000-0002-3154-6685","position":10,"is_corresponding":false},{"id":263938,"name":"Michael K. Gilson","orcid":"0000-0002-3375-1738","position":11,"is_corresponding":false},{"id":79127,"name":"Elizabeth A. Winzeler","orcid":"0000-0002-4049-2113","position":12,"is_corresponding":false},{"id":108307,"name":"William H. Gerwick","orcid":"0000-0003-1403-4458","position":13,"is_corresponding":false},{"id":241385,"name":"Anthony J. O’Donoghue","orcid":"0000-0001-5695-0409","position":14,"is_corresponding":false},{"id":261990,"name":"Jehad Almaliti","orcid":"0000-0002-3562-0846","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:35.125543Z","pmid":"36617500","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}