Peroxisome Proliferator-Activated Receptors: Difference between revisions
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A number of synthetic agonists have been developed to bind to <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/2'>PPAR</scene> to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([http://www.rezulin.com Rezulin]), [http://en.wikipedia.org/wiki/pioglitazone pioglitazone] ([http://www.actos.com Actos]), and [http://en.wikipedia.org/wiki/Rosiglitazone rosiglitazone] ([http://www.avandia.com Avandia]). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a <scene name='Peroxisome_Proliferator-Activated_Receptors/Rosiglitazone_binding/3'>number of interactions that stabilize the agonist</scene>. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its [http://en.wikipedia.org/wiki/Thiazolidinedione TZD] group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364.<ref name="Nolte"/> | A number of synthetic agonists have been developed to bind to <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/2'>PPAR</scene> to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([http://www.rezulin.com Rezulin]), [http://en.wikipedia.org/wiki/pioglitazone pioglitazone] ([http://www.actos.com Actos]), and [http://en.wikipedia.org/wiki/Rosiglitazone rosiglitazone] ([http://www.avandia.com Avandia]). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a <scene name='Peroxisome_Proliferator-Activated_Receptors/Rosiglitazone_binding/3'>number of interactions that stabilize the agonist</scene>. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its [http://en.wikipedia.org/wiki/Thiazolidinedione TZD] group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364.<ref name="Nolte"/> | ||
[[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | [[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | ||
Despite their structural similarities, each member of the PPAR family is localized to certain parts of the body. Location of receptor partially determines their function in the body and also the different roles they can play in medicine as drug targets. PPARγ is responsible for lipid metabolism and cellular energy homeostasis. It binds genes that transcribe proteins which act as fatty acid transporters, are critical in insulin signaling and glucose transport, catalyze glycerol synthesis from triglycerides, and catabolize lipids. This makes PPARγ an ideal target to treat Diabetes.<ref name="Berger">PMID:11818483</ref> Also, recent research has indicated that some PPAR agonists like Rosiglitazone can induce apoptosis of macrophages and would thus serve as excellent anti-inflammatory targets. <ref>PMID: | Despite their structural similarities, each member of the PPAR family is localized to certain parts of the body. Location of receptor partially determines their function in the body and also the different roles they can play in medicine as drug targets. PPARγ is responsible for lipid metabolism and cellular energy homeostasis. It binds genes that transcribe proteins which act as fatty acid transporters, are critical in insulin signaling and glucose transport, catalyze glycerol synthesis from triglycerides, and catabolize lipids. This makes PPARγ an ideal target to treat Diabetes.<ref name="Berger">PMID:11818483</ref> Also, recent research has indicated that some PPAR agonists like Rosiglitazone can induce apoptosis of macrophages and would thus serve as excellent anti-inflammatory targets. <ref>PMID:12079620</ref> PPARα has been shown to play a critical role in the regulation of uptake and oxidation of fatty acids. This makes PPARα an excellent target for Atherosclerosis drugs which aim to reduce [http://en.wikipedia.org/wiki/Low-density_lipoprotein LDL cholesterol] and increase [http://en.wikipedia.org/wiki/High-density_lipoprotein HDL cholesterol], the two most common traits of atherosclerosis. The fibrates are a class of amphipathic carboxylic acids that are PPARα agonists used to treat hypercholesterolemia and hyperlipidemia along with the [[HMGR]] inhibitor statins . Some fibrates are [http://en.wikipedia.org/wiki/Bezafibrate Bezafibrate] (Marketed by Roche as [http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20B)/BEZALIP.html Bezalip]) and [http://en.wikipedia.org/wiki/Ciprofibrate Ciprofibrate] ([http://www.netdoctor.co.uk/medicines/100001714.html Modalim]).<ref name="Berger"/> PPARδ is broadly expressed across the human body and thus is suspected to play a role in a number of diseases. It has been implicated in disorders ranging from fertility problems to types of cancer. Perhaps the most important use of PPARδ agonists will be in treating [http://en.wikipedia.org/wiki/Central_nervous_system central nervous system] (CNS) diseases as PPARδ has been implicated in neuron [http://en.wikipedia.org/wiki/Myelin myelinogenesis] and neuronal signaling as well as lipid metabolism in the CNS. <ref name="Berger"/> | ||
Most drugs target the PPARγ LBD, as ligands that bind to RXRα are likely to inadvertently act on other RXRα complexes, resulting in unexpected side effects. <ref>PMID:19043829</ref> Sales of Avandia, marketed by GlaxoSmithKline peaked at $2.5 billion in 2006 but have since dipped dramatically due to health concerns. In response to the health concerns, sales of Actos, marketed by Takeda, have grown to block buster status.<ref>http://uk.reuters.com/article/idUKT7482820080131</ref> | Most drugs target the PPARγ LBD, as ligands that bind to RXRα are likely to inadvertently act on other RXRα complexes, resulting in unexpected side effects. <ref>PMID:19043829</ref> Sales of Avandia, marketed by GlaxoSmithKline peaked at $2.5 billion in 2006 but have since dipped dramatically due to health concerns. In response to the health concerns, sales of Actos, marketed by Takeda, have grown to block buster status.<ref>http://uk.reuters.com/article/idUKT7482820080131</ref> | ||