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The causative agents, Plasmodium parasites, are highly resilient and have developed resistance to nearly all existing antimalarial drugs. The Plasmodium 20S proteasome core (Pf20S), a central component of the parasite\u2019s proteostasis pathway, has emerged as a promising therapeutic target. Inhibiting Pf20S effectively suppresses parasite growth at multiple stages of the parasite life cycle, synergizes with artemisinin-based therapies, and shows no cross-resistance with other antimalarial drug classes. Previously, we identified a novel class of proteasome inhibitors with potent activity against Pf20S, which we subsequently optimized for improved potency and selectivity over human proteasomes. However, these inhibitors exhibited suboptimal pharmacokinetic properties, potentially attributable to a high number of rotatable bonds and hydrogen bond donors. Here, we describe further optimization of this inhibitor class and provide structural insights into Pf20S-inhibitor interactions. Cryo-EM structural studies reveal a novel binding pose of the inhibitor at the Pf20S \u03b25 active site, explaining the enhanced activity of an N-cap sulfonamide modification compared to an N-cap amide. These findings offer insights into the development of next-generation antimalarial Pf20S-targeting compounds with improved drug-like properties.<\/jats:p>","DOI":"10.1021\/acsomega.6c06226","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:53:11Z","timestamp":1784652791000},"page":"45549-45559","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2013Activity Relationship Study of Antimalarial\nAsparagine-Derived Proteasome Inhibitors"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1187-5844","authenticated-orcid":true,"given":"Hao","family":"Zhang","sequence":"first","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daqiang","family":"Li","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Chi","family":"Hsu","sequence":"additional","affiliation":[{"name":"Van Andel Institute , , , ,","place":["Grand Rapids, Michigan, United States, 49503"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay","family":"Vishwanatha","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhu","family":"Zhan","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Yukawa","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Visone","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Imaeda","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavla","family":"Fajtova","sequence":"additional","affiliation":[{"name":"University of California, San Diego , , 9500 Gilman Drive , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoma","family":"Hara","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Kawasaki","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0674-0239","authenticated-orcid":true,"given":"Kenjiro","family":"Sato","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5469-025X","authenticated-orcid":true,"given":"Mayako","family":"Michino","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreeya","family":"Garg","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriana","family":"Kreutzfeld","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick K.","family":"Tumwebaze","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration , ,","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Orena","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration , ,","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Okitwi","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration , ,","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyoshi","family":"Aso","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland A.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Dominican University of California , , , ,","place":["San Rafael, California, United States, 94901"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["San Francisco, California, United States, 94143"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7548-6215","authenticated-orcid":true,"given":"Peter T.","family":"Meinke","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Foley","sequence":"additional","affiliation":[{"name":"Sanders Tri-Institutional Therapeutics Discovery Institute , 1230 York Ave. , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"O\u2019Donoghue","sequence":"additional","affiliation":[{"name":"University of California, San Diego , , 9500 Gilman Drive , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8085-8928","authenticated-orcid":true,"given":"Huilin","family":"Li","sequence":"additional","affiliation":[{"name":"Van Andel Institute , , , ,","place":["Grand Rapids, Michigan, United States, 49503"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Kirkman","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]},{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4797-7073","authenticated-orcid":true,"given":"Gang","family":"Lin","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Ave , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"2026080409261748000_cit1","volume-title":"World\nMalaria Report 2022","author":"WHO.","year":"2022"},{"issue":"6","key":"2026080409261748000_cit2","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/s41579-024-01008-2","article-title":"Emergence, transmission dynamics\nand mechanisms of artemisinin partial resistance in malaria parasites\nin Africa","volume":"22","author":"Rosenthal","year":"2024","journal-title":"Nat. Rev. Microbiol."},{"issue":"9","key":"2026080409261748000_cit3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(24)00141-5","article-title":"The emergence of\nartemisinin partial resistance in\nAfrica: how do we respond?","volume":"24","author":"Rosenthal","year":"2024","journal-title":"Lancet Infect. Dis."},{"issue":"9","key":"2026080409261748000_cit4","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(22)00155-0","article-title":"Pre-existing partner-drug\nresistance to artemisinin combination therapies facilitates the emergence\nand spread of artemisinin resistance: a consensus modelling study","volume":"3","author":"Watson","year":"2022","journal-title":"Lancet Microbe."},{"key":"2026080409261748000_cit5","doi-asserted-by":"publisher","first-page":"102193","DOI":"10.1016\/j.mib.2022.102193","article-title":"Plasmodium falciparum resistance to artemisinin-based combination\ntherapies","volume":"69","author":"Ward","year":"2022","journal-title":"Curr. Opin. Microbiol."},{"issue":"12","key":"2026080409261748000_cit6","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/j.medj.2021.11.005","article-title":"Artemisinin\nresistance in Africa: How urgent is the\nthreat?","volume":"2","author":"Fidock","year":"2021","journal-title":"Med"},{"key":"2026080409261748000_cit7","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.pt.2021.04.006","article-title":"Assessing risks of Plasmodium falciparum resistance\nto select next-generation antimalarials","volume":"37","author":"Duffey","year":"2021","journal-title":"Trends\nParasitol."},{"issue":"6473","key":"2026080409261748000_cit8","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1126\/science.aax4735","article-title":"A Kelch13-defined\nendocytosis pathway mediates artemisinin resistance in malaria parasites","volume":"367","author":"Birnbaum","year":"2020","journal-title":"Science"},{"issue":"6706","key":"2026080409261748000_cit9","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1126\/science.adp5137","article-title":"Artemisinin-resistant\nmalaria in Africa demands urgent action","volume":"385","author":"Dhorda","year":"2024","journal-title":"Science"},{"issue":"22","key":"2026080409261748000_cit10","doi-asserted-by":"publisher","first-page":"6511","DOI":"10.1002\/ange.201512062","article-title":"A Click\nChemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and\nArtemisinin Antimalarials Share a Common Protein Alkylation Profile","volume":"128","author":"Ismail","year":"2016","journal-title":"Angew. Chem. Weinheim Bergstr. Ger."},{"issue":"8","key":"2026080409261748000_cit11","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1073\/pnas.1600459113","article-title":"Artemisinin activity-based\nprobes identify multiple\nmolecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7","volume":"113","author":"Ismail","year":"2016","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"6951","key":"2026080409261748000_cit12","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1038\/nature01813","article-title":"Artemisinins target\nthe SERCA of Plasmodium falciparum","volume":"424","author":"Eckstein-Ludwig","year":"2003","journal-title":"Nature"},{"key":"2026080409261748000_cit13","doi-asserted-by":"publisher","first-page":"10111","DOI":"10.1038\/ncomms10111","article-title":"Haem-activated promiscuous targeting\nof artemisinin in Plasmodium falciparum","volume":"6","author":"Wang","year":"2015","journal-title":"Nat. Commun."},{"issue":"1","key":"2026080409261748000_cit14","doi-asserted-by":"publisher","first-page":"3801","DOI":"10.1038\/s41467-018-06221-1","article-title":"Artemisinin kills malaria\nparasites by damaging proteins and inhibiting the proteasome","volume":"9","author":"Bridgford","year":"2018","journal-title":"Nat. Commun."},{"issue":"6388","key":"2026080409261748000_cit15","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap7847","article-title":"Uncovering the essential\ngenes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis","volume":"360","author":"Zhang","year":"2018","journal-title":"Science"},{"issue":"2","key":"2026080409261748000_cit16","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1021\/acs.jmedchem.2c01651","article-title":"Structure-Activity\nRelationship Studies of Antimalarial Plasmodium Proteasome\nInhibitors horizontal line Part II","volume":"66","author":"Zhang","year":"2023","journal-title":"J. Med.\nChem."},{"issue":"13","key":"2026080409261748000_cit17","doi-asserted-by":"publisher","first-page":"9350","DOI":"10.1021\/acs.jmedchem.2c00611","article-title":"Design, Synthesis,\nand Optimization of Macrocyclic Peptides as Species-Selective Antimalaria\nProteasome Inhibitors","volume":"65","author":"Zhang","year":"2022","journal-title":"J. Med. Chem."},{"issue":"10","key":"2026080409261748000_cit18","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00817-22","article-title":"Susceptibilities\nof Ugandan Plasmodium falciparum Isolates to Proteasome\nInhibitors","volume":"66","author":"Garg","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"issue":"17","key":"2026080409261748000_cit19","doi-asserted-by":"publisher","first-page":"9279","DOI":"10.1002\/anie.202015845","article-title":"Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria\nActivity in Humanized Mice","volume":"60","author":"Zhan","year":"2021","journal-title":"Angew. Chem., Int.\nEd. Engl."},{"issue":"13","key":"2026080409261748000_cit20","doi-asserted-by":"publisher","first-page":"6137","DOI":"10.1021\/acs.jmedchem.9b00363","article-title":"Improvement of Asparagine Ethylenediamines\nas Anti-malarial Plasmodium-Selective Proteasome\nInhibitors","volume":"62","author":"Zhan","year":"2019","journal-title":"J. Med. Chem."},{"issue":"29","key":"2026080409261748000_cit21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1806109115","article-title":"Antimalarial\nproteasome inhibitor reveals collateral sensitivity from intersubunit\ninteractions and fitness cost of resistance","volume":"115","author":"Kirkman","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"36","key":"2026080409261748000_cit22","doi-asserted-by":"publisher","first-page":"11424","DOI":"10.1021\/jacs.8b06656","article-title":"Defining the Determinants of Specificity\nof Plasmodium Proteasome Inhibitors","volume":"140","author":"Yoo","year":"2018","journal-title":"J. Am. Chem. Soc."},{"issue":"7589","key":"2026080409261748000_cit23","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nature16936","article-title":"Structure- and function-based design of Plasmodium-selective proteasome inhibitors","volume":"530","author":"Li","year":"2016","journal-title":"Nature"},{"issue":"39","key":"2026080409261748000_cit24","doi-asserted-by":"publisher","first-page":"13562","DOI":"10.1021\/ja507692y","article-title":"Identification of potent and selective non-covalent inhibitors of\nthe Plasmodium falciparum proteasome","volume":"136","author":"Li","year":"2014","journal-title":"J. Am. Chem. Soc."},{"issue":"39","key":"2026080409261748000_cit25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2107213118","article-title":"Design\nof proteasome\ninhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome","volume":"118","author":"Xie","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"22","key":"2026080409261748000_cit26","doi-asserted-by":"publisher","first-page":"10053","DOI":"10.1021\/acs.jmedchem.8b01161","article-title":"Target Validation\nand Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome","volume":"61","author":"Xie","year":"2018","journal-title":"J. Med. Chem."},{"key":"2026080409261748000_cit27","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1016\/j.chembiol.2024.07.001","article-title":"Identification\nof potent and reversible piperidine carboxamides that are species-selective\norally active proteasome inhibitors to treat malaria","volume":"31","author":"Lawong","year":"2024","journal-title":"Cell Chem. Biol."},{"issue":"1","key":"2026080409261748000_cit28","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.tibs.2013.10.004","article-title":"The unique functions of tissue-specific proteasomes","volume":"39","author":"Kniepert","year":"2014","journal-title":"Trends Biochem. Sci."},{"issue":"2","key":"2026080409261748000_cit29","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.coi.2008.03.002","article-title":"Thymoproteasome:\nprobable role in\ngenerating positively selecting peptides","volume":"20","author":"Murata","year":"2008","journal-title":"Curr.\nOpin. Immunol."},{"issue":"5","key":"2026080409261748000_cit30","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1016\/j.cell.2013.04.032","article-title":"Acetylation-mediated\nproteasomal degradation of core\nhistones during DNA repair and spermatogenesis","volume":"153","author":"Qian","year":"2013","journal-title":"Cell"},{"issue":"8","key":"2026080409261748000_cit31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008316","article-title":"The PSMA8 subunit of\nthe spermatoproteasome is essential for proper meiotic exit and mouse\nfertility","volume":"15","author":"Gomez","year":"2019","journal-title":"PLoS Genet."},{"issue":"5","key":"2026080409261748000_cit32","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.chembiol.2023.04.006","article-title":"Dual-pharmacophore\nartezomibs hijack the Plasmodium ubiquitin-proteasome\nsystem to kill malaria parasites while overcoming\ndrug resistance","volume":"30","author":"Zhan","year":"2023","journal-title":"Cell Chem. 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