{"id":3195,"date":"2018-12-06T16:29:15","date_gmt":"2018-12-06T14:29:15","guid":{"rendered":"https:\/\/ospt.osi.lv\/?p=3195"},"modified":"2022-01-11T12:15:17","modified_gmt":"2022-01-11T10:15:17","slug":"peptidomimetic-plasmepsin-inhibitors-with-potent-anti-malarial-activity-and-selectivity-against-cathepsin-d","status":"publish","type":"post","link":"https:\/\/ospt.osi.lv\/peptidomimetic-plasmepsin-inhibitors-with-potent-anti-malarial-activity-and-selectivity-against-cathepsin-d\/","title":{"rendered":"23. Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D"},"content":{"rendered":"<p>Zogota, R.; Kinena, L.; Withers-Martinez, C.; Blackman, M., J.; Bobrovs, R.; Pantelejevs, T.; Kanepe-Lapsa, I.; Ozola, V.; Jaudzems, K.; Suna, E.; Jirgensons, A. <em>Eur. J. Med. Chem.<\/em> <strong>2019<\/strong>, <em>163<\/em>, 344-352.<\/p>\n<p>DOI: <a href=\"https:\/\/doi.org\/10.1016\/j.ejmech.2018.11.068\" target=\"_blank\" rel=\"noopener noreferrer\">10.1016\/j.ejmech.2018.11.068<\/a><\/p>\n<p><!--more--><\/p>\n<h4>Abstract<\/h4>\n<p>Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite <em>Plasmodium falciparum<\/em> at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity <em>versus<\/em> the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This resulted in potent anti-malarials with an up to 50-fold Plm IV\/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the <em>P.\u00a0falciparum<\/em> subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Zogota, R.; Kinena, L.; Withers-Martinez, C.; Blackman, M., J.; Bobrovs, R.; Pantelejevs, T.; Kanepe-Lapsa, I.; Ozola, V.; Jaudzems, K.; Suna, E.; Jirgensons, A. Eur. J. Med. Chem. 2019, 163, 344-352. DOI: 10.1016\/j.ejmech.2018.11.068<\/p>\n","protected":false},"author":1,"featured_media":3198,"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\/3195"}],"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\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/comments?post=3195"}],"version-history":[{"count":1,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/3195\/revisions"}],"predecessor-version":[{"id":3996,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/3195\/revisions\/3996"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/media\/3198"}],"wp:attachment":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/media?parent=3195"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/categories?post=3195"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/tags?post=3195"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}