{"id":1458,"date":"2023-09-04T05:43:46","date_gmt":"2023-09-04T05:43:46","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/medphc\/?p=1458"},"modified":"2023-09-04T05:43:46","modified_gmt":"2023-09-04T05:43:46","slug":"degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy","status":"publish","type":"post","link":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/","title":{"rendered":"Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy"},"content":{"rendered":"\r\n<p><strong><span style=\"font-size: 18pt;\">Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy<\/span><\/strong><\/p>\r\n<p style=\"text-align: left;\">Quy T.N. Tran a,b,c,1, Phyllis X.L. Gan a,2, Wupeng Liao a,d,3, Yu Keung Mok e,4, Christina L.L. Chai b,c,*,5, W.S. Fred Wong<\/p>\r\n<p><span style=\"font-size: 10pt;\"><em>a Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore<\/em><\/span><br \/><span style=\"font-size: 10pt;\"><em>b Department of Pharmacy, Faculty of Science, National University of Singapore, 117543, Singapore<\/em><\/span><br \/><span style=\"font-size: 10pt;\"><em>c Drug Discovery and Optimization Platform (DDOP), Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore<\/em><\/span><br \/><span style=\"font-size: 10pt;\"><em>d Singapore-HUJ Alliance for Research and Enterprise (SHARE), National University of Singapore, Singapore<\/em><\/span><br \/><span style=\"font-size: 10pt;\"><em>e Department of Biological Sciences, Faculty of Science, National University of Singapore, 117543, Singapore<\/em><\/span><\/p>\r\n<p>A B S T R A C T<\/p>\r\n<p>The p38MAPK-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38MAPK-MK2 signaling axis represents a direct therapeutic intervention of inflammatory diseases. We described here a novel role of andrographolide (AG), a small-molecule ent-labdane natural compound, as an inhibitor of p38MAPK-MK2 axis via MK2 degradation. AG was found to bind to the activation loop of MK2, located at the interface of the p38MAPKMK2 biomolecular complex. This interaction disrupted the complex formation and predisposed MK2 to proteasome-mediated degradation. We showed that AG induced MK2 degradation in a concentration- and timedependent manner and exerted its anti-inflammatory effects by enhancing the mRNA-destabilizing activity of tristetraprolin, thereby inhibiting pro-inflammatory mediator production (e.g., TNF-\u03b1, MCP-1). Administration of AG via intratracheal (i.t.) route to mice induced MK2 downregulation in lung alveolar macrophages, but not lung tissues, and prevented macrophage activation. Our study also demonstrated that the anti-inflammatory effects achieved by AG via MK2 degradation were more durable and sustained than that achieved by the conventional MK2 kinase inhibitors (e.g., PF-3644022). Taken together, our findings illustrated a novel mode of action of AG by modulating the p38MAPK-MK2 signaling axis and would pave the way for the development of a novel class of anti-inflammatory agents targeting MK2 for degradation by harnessing the privileged scaffold of AG.<\/p>\r\n","protected":false},"excerpt":{"rendered":"<p>Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy Quy T.N. Tran a,b,c,1, Phyllis X.L. Gan a,2, Wupeng Liao a,d,3, Yu Keung Mok e,4, Christina L.L. Chai b,c,*,5, W.S. Fred Wong a Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singaporeb Department of Pharmacy, Faculty [&hellip;]<\/p>\n","protected":false},"author":9345,"featured_media":1459,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"default","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"default","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[5],"tags":[],"class_list":["post-1458","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.4 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy - Pharmacology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy - Pharmacology\" \/>\n<meta property=\"og:description\" content=\"Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy Quy T.N. Tran a,b,c,1, Phyllis X.L. Gan a,2, Wupeng Liao a,d,3, Yu Keung Mok e,4, Christina L.L. Chai b,c,*,5, W.S. Fred Wong a Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singaporeb Department of Pharmacy, Faculty [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/\" \/>\n<meta property=\"og:site_name\" content=\"Pharmacology\" \/>\n<meta property=\"article:published_time\" content=\"2023-09-04T05:43:46+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2023\/09\/20230904-FW-title.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1654\" \/>\n\t<meta property=\"og:image:height\" content=\"746\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Woon Fei\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Woon Fei\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/\"},\"author\":{\"name\":\"Woon Fei\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#\/schema\/person\/ea3ccd10ab2f2bba51fd804396287cb0\"},\"headline\":\"Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy\",\"datePublished\":\"2023-09-04T05:43:46+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/\"},\"wordCount\":352,\"publisher\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#organization\"},\"image\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2023\/09\/20230904-FW-title.jpg\",\"articleSection\":[\"Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/\",\"url\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/degradation-of-mk2-with-natural-compound-andrographolide-a-new-modality-for-anti-inflammatory-therapy\/\",\"name\":\"Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy - 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Tran a,b,c,1, Phyllis X.L. Gan a,2, Wupeng Liao a,d,3, Yu Keung Mok e,4, Christina L.L. Chai b,c,*,5, W.S. 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