title: Identification of novel protein tyrosine phosphatase sigma inhibitors promoting neurite extension.
abstract: Protein tyrosine phosphatase sigma (PTPσ) is a potential target for the therapeutic treatment of neurological deficits associated with impaired neuronal recovery, as this protein is the receptor for chondroitin sulfate proteoglycan (CSPG), which is known to inhibit neuronal regeneration. Through a high-throughput screening approach started from 6400 representative compounds in the Korea Chemical Bank chemical library, we identified 11 novel PTPσ inhibitors that can be classified as flavonoid derivatives or analogs, with IC50 values ranging from 0.5 to 17.5μM. Biochemical assays and structure-based active site-docking simulation indicate that our inhibitors are accommodated at the catalytic active site of PTPσ as surrogates for the phosphotyrosine group. Treatments of these compounds on PC-12 neuronal cells led to the recovery of neurite extension attenuated by CSPG treatment, demonstrating their potential as antineurodegenerative agents.
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea; Department of Biology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Hye Seon
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
authors.forename: Bonsu
authors.initials: B
authors.lastname: Ku
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Park
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Republic of Korea.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Joong-Kwon
authors.initials: JK
authors.lastname: Choi
authors.affiliation: National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 363-883, Republic of Korea.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Chang
authors.affiliation: Department of Biology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Seong Eon
authors.initials: SE
authors.lastname: Ryu
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea. Electronic address: ksj@kribb.re.kr.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D054852:Small Molecule Libraries; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: High-throughput screening; Inhibitor; PTPσ; Protein tyrosine phosphatase; Receptor type PTP