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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Singh P,Kaur S,Kaur J,Singh G,Bhatti R

doi

10.1021/acs.jmedchem.6b00134

subject

Has Abstract

pub_date

2016-04-28 00:00:00

pages

3920-34

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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