Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent

详细信息    查看全文

• 作者：Palwinder Singh ; Sukhmeet Kaur ; Jagroop Kaur ; Gurjit Singh ; Rajbir Bhatti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3920-3934
• 全文大小：913K
• 年卷期：0
• ISSN：1520-4804

文摘

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 K_a of 6.10 ± 1.10 × 10⁴ M^–1 and ΔG of −100.3 kJ mol^–1 in comparison to a K_a 0.41 × 10³ ± 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.