{"id":4204,"date":"2023-08-01T10:46:55","date_gmt":"2023-08-01T08:46:55","guid":{"rendered":"https:\/\/ospt.osi.lv\/2023\/08\/01\/the-emission-efficiency-of-cationic-solid-state-luminophores-is-directly-proportional-to-the-intermolecular-charge-transfer-intensity-2\/"},"modified":"2023-08-16T14:54:34","modified_gmt":"2023-08-16T12:54:34","slug":"macrocyclic-peptidomimetic-plasmepsin-x-inhibitors-with-potent-in-vitro-and-in-vivo-antimalarial-activity","status":"publish","type":"post","link":"https:\/\/ospt.osi.lv\/macrocyclic-peptidomimetic-plasmepsin-x-inhibitors-with-potent-in-vitro-and-in-vivo-antimalarial-activity\/","title":{"rendered":"46. Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity"},"content":{"rendered":"<div class=\"wpb-content-wrapper\"><p>[vc_row][vc_column][vc_column_text]Kovada, V.; Withers-Martinez, C.; Bobrovs, R.; Ce\u0305rule, H.; Liepins, E.; Grinberga, S.; Hackett, F.; Collins, C. R.; Kreicberga, A.; Jim\u00e9nez-D\u00edaz, M. B.; Angulo-Barturen, I.; Rasina, D.; Suna, E.; Jaudzems, K.; Blackman, M. J.; Jirgensons, A.<em> J. Med. Chem.<\/em> <strong>2023<\/strong>, 66, 15, 10658\u201310680.<br \/>\nDOI: <a href=\"https:\/\/doi.org\/10.1021\/acs.jmedchem.3c00812\">https:\/\/doi.org\/10.1021\/acs.jmedchem.3c00812<\/a>.<\/p>\n<p>&nbsp;<\/p>\n<p><!--more--><\/p>\n<h4>Abstract<\/h4>\n<p style=\"text-align: justify;\">The <i>Plasmodium falciparum<\/i> aspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in <i>in vitro<\/i> parasite growth inhibition. Inhibitor <b>7k<\/b> cleared blood-stage <i>P. falciparum<\/i> in a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound <b>7k<\/b> represents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.<\/p>\n<p>[\/vc_column_text][\/vc_column][\/vc_row]<\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>[vc_row][vc_column][vc_column_text]Kovada, V.; Withers-Martinez, C.; Bobrovs, R.; Ce\u0305rule, H.; Liepins, E.; Grinberga, S.; Hackett, F.; Collins, C. R.; Kreicberga, A.; Jim\u00e9nez-D\u00edaz, M. B.; Angulo-Barturen, I.; Rasina, D.; Suna, E.; Jaudzems, K.; Blackman, M. J.; Jirgensons, A. J. Med. Chem. 2023, 66, 15, 10658\u201310680. DOI: https:\/\/doi.org\/10.1021\/acs.jmedchem.3c00812. &nbsp;<\/p>\n","protected":false},"author":5,"featured_media":4207,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"image","meta":{"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[38,16],"tags":[],"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/4204"}],"collection":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/comments?post=4204"}],"version-history":[{"count":5,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/4204\/revisions"}],"predecessor-version":[{"id":4206,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/4204\/revisions\/4206"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/media\/4207"}],"wp:attachment":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/media?parent=4204"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/categories?post=4204"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/tags?post=4204"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}