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The SUB1 protease, which is essential for parasite egress in both hepatic and blood stages, would meet these criteria. We previously reported the structure\u2010activity relationship analysis of \u03b1\u2010ketoamide\u2010containing inhibitors encompassing positions P4\u2010P2\u2019. Despite compounds with high inhibitory potencies were identified, their antiparasitic activity remained limited, probably due to insufficient cell permeability. Here, we present our efforts to improve it through the <jats:italic>N<\/jats:italic>\u2010terminal introduction of basic or hydrophobic moieties and\/or cyclization. Compared to our previous reference compounds <jats:bold>1<\/jats:bold>\/<jats:bold>2<\/jats:bold> (Ac\u2010Ile\/Cpg\u2010Thr\u2010Ala\u2010AlaCO\u2010Asp\u2010Glu (Oall)\u2010NH<jats:sub>2<\/jats:sub>), we identified analogues with improved Pf\u2010\/PvSUB1 inhibition (IC<jats:sub>50<\/jats:sub> values in the 10\u201320\u2005nM range) and parasite growth inhibition (up to 98\u2009% at 100\u2005\u03bcM). The increase in potency was mainly observed when increasing the overall hydrophobicity of the compounds. Conjugation to the cell penetrating peptide octa\u2010arginine was also favorable. Finally, the crystal structure of PvSUB1 in complex with compound\u2005<jats:bold>15<\/jats:bold> has been determined at 1.6\u2005\u00c5 resolution. Compared to compound\u2005<jats:bold>1<\/jats:bold>, this structure extended to the P5 residue and revealed two additional hydrogen bonds.<\/jats:p>","DOI":"10.1002\/cmdc.202400924","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T12:49:23Z","timestamp":1737377363000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Towards Improved Peptidic \u03b1\u2010Ketoamide Inhibitors of the Plasmodial Subtilisin\u2010Like SUB1: Exploration of <i>N<\/i>\u2010Terminal Extensions and Cyclic Constraints"],"prefix":"10.1002","volume":"20","author":[{"given":"Anna K.","family":"Puszko","sequence":"first","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron (IBMM) CNRS Univ Montpellier ENSCM  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando A.","family":"Batista","sequence":"additional","affiliation":[{"name":"Structural Microbiology 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