{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T21:23:21Z","timestamp":1792531401421,"version":"4.5.0"},"reference-count":48,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"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":[[2026,7,29]]},"abstract":"<jats:p>\n                    Malaria remains a significant global health burden, increasingly threatened by the emergence of artemisinin\u2010resistant\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    strains that compromise the efficacy of frontline combination therapies. Hemoglobin digestion constitutes a central metabolic pathway sustaining intraerythrocytic parasite growth, in which the terminal processing of hemoglobin\u2010derived peptides and liberation of free amino acids are mediated by two zinc\u2010dependent metalloaminopeptidases, PfA\u2010M1 (M1 alanyl aminopeptidase) and PfA\u2010M17 (M17 leucyl aminopeptidase). This review synthesizes current evidence supporting PfA\u2010M17 and PfA\u2010M1 as validated antimalarial targets, with particular emphasis on the structural biology, catalytic regulation, and cellular essentiality of PfA\u2010M17. We discuss how the oligomerization\u2010dependent activation of PfA\u2010M17, governed by metal\u2010ion\u2010mediated quaternary assembly and a dynamic regulatory loop (L13), imposes structural constraints that may limit resistance evolution. We further evaluate selective and dual\u2010target inhibitors, including MMV1557817 and compound 26, that demonstrate cross\u2010species antiplasmodial efficacy with substantial fitness costs on resistant parasites. The mechanistic interplay between aminopeptidase inhibition and established antimalarial drug classes, including quinolines and artemisinins, is also examined. This review supports dual PfA\u2010M1\/PfA\u2010M17 inhibition as a promising approach for next\u2010generation antimalarial drug development.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70401","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T01:46:51Z","timestamp":1784857611000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aminopeptidase Inhibition in Drug\u2010Resistant\n                    <i>Plasmodium falciparum<\/i>\n                    : Structural, Functional, and Pharmacological Rationale for Targeting PfA\u2010M1 and PfA\u2010M17"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9787-3996","authenticated-orcid":false,"given":"Sharoen Yu Ming","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences Faculty of Medicine and Health Sciences Universiti Malaysia Sarawak  Kota Samarahan Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"WHO Malaria (2025). 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