Attenuation of TNF-α secretion by l-proline-based cyclic dipeptides produced by culture broth of Pseudomonas aeruginosa

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• 作者：Rukaiyya Khan^a ; Ameer Basha^b ; Ragavendra Goverdhanam^b ; Poorna Chandra Rao^a ; Yuhei Tanemura^c ; Yoshinori Fujimoto^c ; Ahil Sajeli Begum^a ; ^{sajeli@hyderabad.bits-pilani.ac.in" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TNF-α inhibitor ; Cyclic dipeptide ; Pseudomonas aeruginosa ; Interleukin-1β ; Interleukin-6
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 December 2015
• 年：2015
• 卷：25
• 期：24
• 页码：5756-5761
• 全文大小：1164 K

文摘

To identify small molecule inhibitors of TNF-α, bioassay- and LC–MS-guided chemical investigation on EtOAc extract of Pseudomonas aeruginosa ABS-36 culture broth (EEPA) was performed, which yielded four proline-based cyclic dipeptides, cyclo(Gly-l-Pro) (1), cyclo(l-Pro-l-Phe) (2), cyclo(trans-4-hydroxy-l-Pro-l-Phe) (3) and cyclo(trans-4-hydroxy-l-Pro-l-Leu) (4). Compounds 1 and 3 exhibited potent inhibition of TNF-α release with IC₅₀ values of 4.5 and 14.2 μg/mL, respectively, while EEPA showed IC₅₀ of 38.8 μg/mL under lipopolysaccharide treated RAW 264.7 cell ELISA assay. Also, marked attenuation of mRNA-expression of TNF-α was shown by all compounds. In vivo testing in rats of EEPA and chemically synthesized 4 validated significant TNF-α reduction with 51% (500 mg/kg) and 79% (50 mg/kg), respectively. In addition, all compounds exhibited significant diminution of IL-1β and IL-6 mRNA-expression levels and NO production. All samples displayed only weak toxicity to lipopolysaccharide-induced RAW 264.7 cells.