Identification of novel protein tyrosine phosphatase sigma inhibitors promoting neurite extension

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• 作者：Hye Seon Lee^a ; ^b ; ^&dagger ; ; Bonsu Ku^a ; ^&dagger ; ; Tae Hyun Park^c ; Hwangseo Park^d ; Joong-Kwon Choi^e ; Kyu-Tae Chang^f ; Cheol-Hee Kim^b ; Seong Eon Ryu^c ; Seung Jun Kim^a ; ^{ksj@kribb.re.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PTPσ ; protein tyrosine phosphatase sigma ; CSPG ; chondroitin sulfate proteoglycan ; PTP ; protein tyrosine phosphatase ; HSPG ; heparan sulfate proteoglycan ; IC50 ; half-maximal inhibitory concentration ; HTS ; high-throughput screening ; KCB ; Korea Chemical Bank ; pNPP ; para-nitrophenylphosphate ; NGF ; nerve growth factor
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：26
• 期：1
• 页码：87-93
• 全文大小：1694 K

文摘

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 17.5 μM. 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.