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Papers of the Week

2019 Jul 11

J Med Chem



Engineered Substrate for Cyclooxygenase-2: A Pentapeptide Isoconformational to Arachidonic Acid for Managing Inflammation.


Kaur B, Kaur M, Kaur N, Garg S, Bhatti R, Singh P
J Med Chem. 2019 Jul 11; 62(13):6363-6376.
PMID: 31244108.


Beyond the conventional mode of working of anti-inflammatory agents through enzyme inhibition, herein, COX-2 was provided with an alternate substrate. A proline-centered pentapeptide isoconformational to arachidonic acid, which exhibited appreciable selectivity for COX-2, overcoming acetic acid- and formalin-induced pain in rats to almost 80%, was treated as a substrate by the enzyme. Remarkably, COX-2 metabolized the pentapeptide into small fragments consisting mainly of di- and tripeptides that ensured the safe breakdown of the peptide under in vivo conditions. The kinetic parameter K/ K for COX-2-mediated metabolism of the peptide (6.3 × 10 M s) was quite similar to 9.5 × 10 M s for arachidonic acid. Evidenced by the molecular dynamic studies and the use of Y385F COX-2, it was observed that the breakage of the pentapeptide has probably been taken place through H-bond activation of the peptide bond by the side chains of Y385 and S530.