title: A novel non-agonist peroxisome proliferator-activated receptor γ (PPARγ) ligand UHC1 blocks PPARγ phosphorylation by cyclin-dependent kinase 5 (CDK5) and improves insulin sensitivity.
abstract: Thiazolidinedione class of anti-diabetic drugs which are known as peroxisome proliferator-activated receptor γ (PPARγ) ligands have been used to treat metabolic disorders, but thiazolidinediones can also cause several severe side effects, including congestive heart failure, fluid retention, and weight gain. In this study, we describe a novel synthetic PPARγ ligand UNIST HYUNDAI Compound 1 (UHC1) that binds tightly to PPARγ without the classical agonism and which blocks cyclin-dependent kinase 5 (CDK5)-mediated PPARγ phosphorylation. We modified the non-agonist PPARγ ligand SR1664 chemically to improve its solubility and then developed a novel PPARγ ligand, UHC1. According to our docking simulation, UHC1 occupied the ligand-binding site of PPARγ with a higher docking score than SR1664. In addition, UHC1 more potently blocked CDK5-mediated PPARγ phosphorylation at Ser-273. Surprisingly, UHC1 treatment effectively ameliorated the inflammatory response both in vitro and in high-fat diet-fed mice. Furthermore, UHC1 treatment dramatically improved insulin sensitivity in high-fat diet-fed mice without causing fluid retention and weight gain. Taken together, compared with SR1664, UHC1 exhibited greater beneficial effects on glucose and lipid metabolism by blocking CDK5-mediated PPARγ phosphorylation, and these data indicate that UHC1 could be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea.
authors.forename: Sun-Sil
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea.
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Seoul National University, Seoul 151-747, Korea.
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu 701-310, Korea.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea.
authors.forename: Yong Ryoul
authors.initials: YR
authors.lastname: Yang
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea.
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Department of Biophysics and Chemical Biology/Bio-MAX Institute, Seoul National University, Seoul 151-747, Korea, and.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Seo
authors.affiliation: Department of Biophysics and Chemical Biology/Bio-MAX Institute, Seoul National University, Seoul 151-747, Korea, and.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Min
authors.affiliation: Department of Medical Chemistry, Hyundai Pharm Co., Ltd., Suwon, Gyonggi 443-270, Korea.
authors.forename: In Hee
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Seoul National University, Seoul 151-747, Korea,; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu 701-310, Korea.
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea.
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea,. Electronic address: janghchoi@unist.ac.kr.
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017207:Rats, Sprague-Dawley
chemical_list: C561901:(S)-4'-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid; C000594850:4'-((2,3-dimethyl-5-(pyridin-3-ylmethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylic acid; D000893:Anti-Inflammatory Agents; D001565:Benzoates; D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D007211:Indoles; D018836:Inflammation Mediators; D047495:PPAR gamma; D051360:Cyclin-Dependent Kinase 5
keywords: Adipose Tissue; Diabetes; Drug Action; Inflammation; Ligand; Non-agonist; PPARγ; Peroxisome Proliferator-activated Receptor (PPAR); Rational Drug Design
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