{"id":1040,"date":"2020-07-07T11:51:48","date_gmt":"2020-07-07T09:51:48","guid":{"rendered":"https:\/\/covid.si\/?p=1040"},"modified":"2020-10-29T21:11:41","modified_gmt":"2020-10-29T20:11:41","slug":"mission-2-search-for-selective-modulators-ppar%ce%b3","status":"publish","type":"post","link":"https:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar%ce%b3\/","title":{"rendered":"Mission 2: Search for selective modulators PPAR\u03b3"},"content":{"rendered":"\t\t
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Mission 2: Search for selective modulators PPAR\u03b3<\/h1>\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t
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MISSION STATUS:\u00a0PROCESSING RESULTS<\/span><\/h5>
MISSION PLAN:\u00a0Filip Cernati\u010d, dr. \u010crtomir Podlipnik<\/span><\/h5><\/div>
Target number: 4<\/strong><\/h5>
Target identifiers:\u00a022-25<\/b><\/span><\/h5>
Number of compounds:\u00a010.000.000<\/b><\/span><\/h5>
Total dockings:\u00a04<\/b>0.000.000<\/strong><\/h5>
Mission duration:\u00a007.05.2020 –\u00a0<\/strong><\/h5>
Results:\u00a0<\/span>in processing<\/b><\/h5>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t
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OPIS MISIJE:<\/p>

PPAR\u03b3 is a nuclear receptor that plays a central role in promoting adipocyte growth and differentiation and regulating blood glucose and triglyceride levels. PPAR\u03b3 exists in two isoforms, PPAR\u03b31 and PPAR\u03b32, of which PPAR\u03b31 is ubiquitous and PPAR\u03b32 is expressed predominantly in adipose tissue. Under normal physiological conditions, PPAR\u03b3 is the target of a number of post-translational modifications that regulate the transcriptional activity of this receptor. Posttranslational modification of PPAR\u03b3 by cyclin-dependent kinase 5 (CDK5) leads to suppression of specific genes that increase insulin sensitivity. In obese individuals, proinflammatory cytokines, such as TNF-\u03b1, IL-6, and IL-1\u03b2, invade adipose tissue. Such cytokines accelerate the cleavage of the p35 protein, the CDK5 binding partner, into a more stable and biologically active p25 subunit, which increases CDK5 activity, leading to an excessive extent of PPAR\u03b3 phosphorylation at the Ser245 site (Ser273 in PPAR\u03b32). The end result of the described course of events is the insulin resistance of the individual – a condition that significantly increases the likelihood of developing type 2 diabetes and cardiovascular disease. Inhibition of PPAR\u03b3 phosphorylation by CDK5, by binding the ligand to the active site of PPAR\u03b3, restores the basal level of transcription and again increases insulin sensitivity [1,2].<\/p>

In previous decades, several groups of active substances have been developed and approved for the treatment of obesity-related diseases, the most important of which is probably the group of thiazolodindiones (TZDs), full of PPAR\u03b3 agonists. Due to many side effects of TZD drugs, such as weight gain, excessive water retention, bone loss and anemia, attention has been shifted to the development of selective PPAR\u03b3 modulators (SPPARMs) in the development of such active substances. , which express a smaller extent of harmful side effects, but still retain strong antidiabetic properties [1,2,3].<\/p>

References:<\/p>

[1] Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466(7305):451\u2010456. doi:10.1038\/nature09291<\/p>

[2] Zieleniak, A., W\u00f3jcik, M. & Wo\u017aniak, L.A. Structure and physiological functions of the human peroxisome proliferator-activated receptor \u03b3. Arch. Immunol. Ther. Exp. 56, 331 (2008). https:\/\/doi.org\/10.1007\/s00005-008-0037-y<\/p>

[3] Zhang F, Lavan BE, Gregoire FM. Selective Modulators of PPAR-gamma Activity: Molecular Aspects Related to Obesity and Side-Effects. PPAR Res. 2007;2007:32696. doi:10.1155\/2007\/3269<\/p>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"

MISSION STATUS: PROCESSING RESULTS MISSION PLAN: Filip Cernati\u010d, dr. \u010crtomir Podlipnik Target number: 4 Target identifiers: 22-25 Number of compounds: 10.000.000 Total dockings: 40.000.000 Mission […]<\/p>\n","protected":false},"author":5,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[27],"tags":[],"yoast_head":"\nMission 2: Search for selective modulators PPAR\u03b3 - COVID.SI<\/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:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar\u03b3\/\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Mission 2: Search for selective modulators PPAR\u03b3 - COVID.SI\" \/>\n<meta property=\"og:description\" content=\"MISSION STATUS: PROCESSING RESULTS MISSION PLAN: Filip Cernati\u010d, dr. \u010crtomir Podlipnik Target number: 4 Target identifiers: 22-25 Number of compounds: 10.000.000 Total dockings: 40.000.000 Mission […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar\u03b3\/\" \/>\n<meta property=\"og:site_name\" content=\"COVID.SI\" \/>\n<meta property=\"article:published_time\" content=\"2020-07-07T09:51:48+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2020-10-29T20:11:41+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/covid.si\/wp-content\/uploads\/2020\/05\/ppargama.png\" \/>\n<meta name=\"author\" content=\"Bostjan Laba\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Bostjan Laba\" \/>\n\t<meta name=\"twitter:label2\" content=\"Estimated 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:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar%ce%b3\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar%ce%b3\/\"},\"author\":{\"name\":\"Bostjan Laba\",\"@id\":\"https:\/\/covid.si\/#\/schema\/person\/c5be130409669c048f1af4bc6ba2060e\"},\"headline\":\"Mission 2: Search for selective modulators PPAR\u03b3\",\"datePublished\":\"2020-07-07T09:51:48+00:00\",\"dateModified\":\"2020-10-29T20:11:41+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar%ce%b3\/\"},\"wordCount\":401,\"publisher\":{\"@id\":\"https:\/\/covid.si\/#organization\"},\"image\":{\"@id\":\"https:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar%ce%b3\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/covid.si\/wp-content\/uploads\/2020\/05\/ppargama.png\",\"articleSection\":[\"Project missions\"],\"inLanguage\":\"en-GB\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar%ce%b3\/\",\"url\":\"https:\/\/covid.si\/en\/mission-2-search-for-selective-modulators-ppar%ce%b3\/\",\"name\":\"Mission 2: Search for selective modulators PPAR\u03b3 - 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