2. Academic Validation
  3. Attenuation of TNF-α secretion by L-proline-based cyclic dipeptides produced by culture broth of Pseudomonas aeruginosa

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

  • Bioorg Med Chem Lett. 2015 Dec 15;25(24):5756-61. doi: 10.1016/j.bmcl.2015.10.075.
Rukaiyya Khan 1,  Ameer Basha 2,  Ragavendra Goverdhanam 2,  Poorna Chandra Rao 1,  Yuhei Tanemura 3,  Yoshinori Fujimoto 3,  Ahil Sajeli Begum 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India.
  • 2 Regional Agricultural Research Station, Professor Jayashankar Telangana State Agricultural University, Palem 509 215, Mahaboobnagar District, Telangana State, India.
  • 3 Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro, Tokyo 152-8551, Japan.
  • 4 Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India. Electronic address: sajeli@hyderabad.bits-pilani.ac.in.
PMID: 26546220 DOI: 10.1016/j.bmcl.2015.10.075
Abstract

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 14.2μg/mL, respectively, while EEPA showed IC50 of 38.8μg/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% (500mg/kg) and 79% (50mg/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.

Keywords

Cyclic dipeptide; Interleukin-1β; Interleukin-6; Pseudomonas aeruginosa; TNF-α inhibitor.

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