Poster Presentation 10th Australian Peptide Conference 2013

2-Oxoamides based on dipeptides and pseudodipeptides as inhibitors of Ca2+-independent phospholipase A2 (#148)

Anneta Smyrniotou 1 , Ishita Shah 2 , Edward A Dennis 2 , George Kokotos 3 , Violetta Constantinou-Kokotou 1
  1. Agricultural University of Athens, Athens, Greece
  2. Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA
  3. Department of Chemistry, University of Athens, Athens, Greece

Phospholipases A2 (PLA2) hydrolyze phospholipids to release free fatty acids and lysophospholipids, some of which can mediate inflammation and demyelination, two hallmarks of the autoimmune disease multiple sclerosis. We have developed polyfluoroketones which are selective inhibitors of Ca2+-independent phospholipase A2 (GVIA iPLA2)1 and we have shown that such selective inhibitors reduce the severity and progression of experimental autoimmune encephalomyelitis (EAE).2 Most recently, the interactions between a polyfluoroketone inhibitor and the active site of GVIA iPLA2 have been studied.3 Our studies have shown that an aromatic ring attached to a four-carbon linker fits very well to one of the binding sites of GVIA iPLA2. To increase the binding of the inhibitor to the target enzyme, we decided to develop new 2-oxoamides containing an aromatic ring attached to four-carbon linker in combination with a small peptide chain. Thus, a series of 2-oxoamides based on dipeptides and pseudodipeptides have been synthesized and their activities towards the two human intracellular GIVA cPLA2 and GVIA iPLA2 and the human secreted GV sPLA2 have been evaluated. tert-Butyl esters of 2-oxoamides based on either Nle-Gly or a corresponding ether pseudodipeptide were found to present interesting inhibition of GVIA iPLA2.
This work was supported by the European Social Fund and National Resources Herakleitos II.

  1. Kokotos, G.; Hsu, Y. H.; Burke, J. E.; Baskakis, C.; Kokotos, C. G.; Magrioti, V.; Dennis, E. A. J. Med. Chem. 2010, 53, 3602-3610.
  2. Kalyvas, A.; Baskakis, C.; Magrioti, V.; Constantinou-Kokotou, V.; Stephens, D.; Lopez-Vales, R.; Lu, J. Q.; Yong, V. W.; Dennis, E. A.; Kokotos, G.; David, S. Brain 2009, 132, 1221-1235.
  3. Hsu, Y.-H.; Bucher, D.; Cao, J.; Li, S.; Yang, S.-W.; Kokotos, G.; Woods, Jr, V. L., McCammon, J. A.; Dennis, E. A. J. Am. Chem. Soc. 2013, 135, 1330-1337