{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:54:41Z","timestamp":1791438881546,"version":"4.3.3"},"reference-count":36,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>\n                    Malaria, caused by the\n                    <jats:italic>Plasmodium parasites<\/jats:italic>\n                    , remains a major global health burden, and resistance to current antimalarials drives the need for drugs with new mechanisms of action. Plasmepsin V (PMV), an essential aspartic protease required for PEXEL processing and protein export, is structurally divergent from human aspartic proteases, offering a path to selective inhibition. Here, we applied a structure\u2010informed, deconstruction\u2010based approach to identify non\u2010peptidomimetic PMV inhibitors by mining catalytic dyad\u2010binding motifs from experimentally solved aspartic protease\u2013inhibitor complexes and assembling a focused fragment\u2010like library. Fragment\u2010inspired model compounds based on pyrrolidine, piperidine, and piperazine cores showed measurable PMV inhibition in a Forster resonance energy transfer (FRET)\u2010based assay, and a\n                    <jats:italic>trans<\/jats:italic>\n                    \u20103,4\u2010disubstituted pyrrolidine hit (\n                    <jats:bold>7a<\/jats:bold>\n                    ; IC\n                    <jats:sub>50<\/jats:sub>\n                    70\u2009 \u00b5M) was selected for optimization. Guided by PMV structural data and a renin cocrystal structure of a related pyrrolidine inhibitor, we explored SAR around substituents intended to engage the S1 and S2 regions. Optimization identified\n                    <jats:italic>N\u2010<\/jats:italic>\n                    sulfonamide analogs bearing two aromatic substituents as a preferred chemotype, with\n                    <jats:italic>meta<\/jats:italic>\n                    \u2010substitution on the\n                    <jats:italic>N\u2010<\/jats:italic>\n                    aryl group improving potency to the low micromolar range. The most potent compounds obtained displayed ~10 \u00b5M potency, establishing a promising non\u2010peptidomimetic scaffold for further development of selective PMV inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70420","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:10:59Z","timestamp":1786594259000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deconstruction of Aspartic Protease Inhibitors Enables Fragment\u2010Based Discovery of Plasmepsin V Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0081-426X","authenticated-orcid":false,"given":"Marija","family":"Skvorcova","sequence":"first","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rudu\u0161a","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6931-2294","authenticated-orcid":false,"given":"Diana","family":"Zelencova\u2010Gopejenko","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"},{"name":"Molport Inc.  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aigars","family":"Jirgensons","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0221-8658","authenticated-orcid":false,"given":"Raitis","family":"Bobrovs","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"World Health Organisation (WHO) World Malaria Report 2025 (World Health Organization 2025)."},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2007.05999.x"},{"key":"e_1_2_8_4_1","unstructured":"World Health Organisation (WHO) Global Report on Insecticide Resistance in Malaria Vectors: 2010\u20102016 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