title: Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent.
abstract: Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg(-1) dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 10(4) M(-1) and ΔG of -100.3 kJ mol(-1) in comparison to a Ka 0.41 × 10(3) ± 0.09 M(-1) and ΔG of -19.2 ± 0.06 kJ mol(-1) for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg(-1) dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.
authors.affiliation: UGC Sponsored Centre for Advanced Studies - Department of Chemistry and ‡Department of Pharmaceutical Sciences, Guru Nanak Dev University , Amritsar 143005, India.
authors.forename: Palwinder
authors.initials: P
authors.lastname: Singh
authors.affiliation: UGC Sponsored Centre for Advanced Studies - Department of Chemistry and ‡Department of Pharmaceutical Sciences, Guru Nanak Dev University , Amritsar 143005, India.
authors.forename: Sukhmeet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: UGC Sponsored Centre for Advanced Studies - Department of Chemistry and ‡Department of Pharmaceutical Sciences, Guru Nanak Dev University , Amritsar 143005, India.
authors.forename: Jagroop
authors.initials: J
authors.lastname: Kaur
authors.affiliation: UGC Sponsored Centre for Advanced Studies - Department of Chemistry and ‡Department of Pharmaceutical Sciences, Guru Nanak Dev University , Amritsar 143005, India.
authors.forename: Gurjit
authors.initials: G
authors.lastname: Singh
authors.affiliation: UGC Sponsored Centre for Advanced Studies - Department of Chemistry and ‡Department of Pharmaceutical Sciences, Guru Nanak Dev University , Amritsar 143005, India.
authors.forename: Rajbir
authors.initials: R
authors.lastname: Bhatti
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D002151:Calorimetry; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D021281:Quantitative Structure-Activity Relationship; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D010455:Peptides