Medicinal Chemistry and Drug Design

Biography

Biography: Shimon Ben-Shabat

Abstract

Phospholipase A2 (PLA2) expression/activity is significantly elevated in inflamed intestinal tissue in inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis. PLA2 hydrolyses the sn-2 fatty acyl bond of phospholipids (PL) liberating a fattyacid and a lysophospholipid. By replacing the sn-2 positioned fatty-acid with a drug, PLA2 may be exploited as a prodrug activating enzyme, liberating the free drug from the PL-complex. Therefore, orally delivered PL-based prodrugs will release the free drug at the inflamed sites, effectively targeting the regions of intestinal inflammation. We have utilized a modern computational approach to simulate the PLA2-mediated activation using the candidate drug, and to predict the most appropriate linker length. We have synthesized PL-diclofenac conjugates and shown in-vitro activation of these synthesized conjugates by isolated bee venom PLA2 and conditioned medium from inflamed Caco-2 cell line. We showed that depending on the linker length between the PL and diclofenac, PLA2 could be exploited as the activating enzyme in-vitro, liberating the free diclofenac from the PL complex. We have compared the computational calculations to our experimental data, and obtained excellent correlation between the in-silico predictions and the in-vitro experiments. The proposed research may significantly improve drug therapy in IBD patients, enabling higher efficacy and lower toxicity profiles.

Recent Publications

1. A Dahan, S Ben-Shabat, N Cohen, S Keinan, I Kurnikov, A Aponick, E M Zimmermann (2016) Phospholipid-based prodrugs for drug targeting in inflammatory bowel disease: Computational optimization and in-vitro correlation. Curr. Top. Med. Chem. 16: 2543-8.

2. A Dahan, E Zimmermann, S Ben-Shabat (2014) Modern prodrug design for targeted oral drug delivery. Molecules 19: 16489-16505.

3. Wolk, S Epstein, V Ioffe-Dahan, S Ben-Shabat, A Dahan (2013) New targeting strategies in drug therapy of inflammatory bowel disease: Mechanistic approaches and opportunities, Expert Opin. Drug Deliv. 10: 1275-1286.

4. A Dahan, G L Amidon, E M Zimmermann (2010) Drug targeting strategies for the treatment of inflammatory bowel disease: A mechanistic update. Expert Rev. Clin. Immunol. 6: 543-550.

5. A Dahan, R Duvdevani, E Dvir, A Elmann, A Hoffman (2007) A novel mechanism for oral controlled release of drugs by continuous degradation of a phospholipid prodrug along the intestine: In-vivo and in-vitro evaluation of an indomethacin-lecithin conjugate. J. Control Release 119: 86-93.