UGC Sponsored Centre for Advanced Studies - Department of Chemistry and ‡Department of Pharmaceutical Sciences, Guru Nanak Dev University , Amritsar 143005, India.
J Med Chem. 2016 Apr 28;59(8):3920-34. doi: 10.1021/acs.jmedchem.6b00134. Epub 2016 Apr 6.
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.
在 2-31 个小肽中，（H）甘氨酰-甘氨酰-苯丙氨酰-亮氨酸（OME）（30）对 COX-2 的前列腺素生成的抑制作用的 IC50 为 60 nM，而对 COX-1 的抑制作用的 IC50 为 6000 nM。化合物 30 的 5mg/kg 剂量使辣椒素诱导的舔爪白老鼠的恢复率达到 80%，使角叉菜胶诱导的炎症的恢复率达到 60%。通过使用 P 物质、L-精氨酸和藜芦碱分别作为生物标志物，研究了化合物 30 对 COX-2、iNOS 和 VGSC 的作用模式。等温量热实验支持 30 与 COX-2 的相互作用，其 Ka 值为 6.10±1.10×10(4)M(-1)，ΔG 值为-100.3kJ/mol(-1)，而 COX-1 的 Ka 值为 0.41×10(3)±0.09M(-1)，ΔG 值为-19.2±0.06kJ/mol(-1)。此外，化合物 30 高达 2000mg/kg 的剂量没有显示出毒性。因此，我们建议将肽 30 作为一种很有前途的候选药物，进一步开发成一种抗炎药物。
