Design of Chirality-Controlled Ketorolac-Peptide Conjugates for Selective COX-2 Inhibition and Localized Drug Release

Area of Science:

• Medicinal Chemistry
• Supramolecular Chemistry
• Pharmacology

Background:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like Ketorolac (Ket) inhibit cyclooxygenase (COX) enzymes to reduce pain and inflammation.
• Non-selective COX inhibition by Ketorolac can cause adverse effects.
• Improving COX-2 selectivity is crucial for developing safer anti-inflammatory therapeutics.

Purpose of the Study:

• To synthesize and analyze Ketorolac-tripeptide conjugates with controlled chirality.
• To enhance COX-2 selectivity of Ketorolac.
• To explore the potential of self-assembled supramolecular hydrogels for drug delivery.

Main Methods:

• Synthesis of amphiphilic Ketorolac-capped peptide conjugates.
• Controlled chirality was incorporated into the peptide sequences.
• Self-assembly in water to form supramolecular hydrogels at pH 7.0.
• Evaluation of COX-2/COX-1 selectivity ratios for synthesized compounds.

Main Results:

• Ketorolac-tripeptide conjugates self-assembled into supramolecular hydrogels.
• Ket-Gly-D-Phe-D-Phe exhibited significantly higher COX-2 selectivity compared to Ketorolac.
• Ket-Gly-D-Phe-D-Phe achieved a COX-2/COX-1 ratio of 5.8, indicating enhanced selectivity.
• Most Ket-peptides showed a COX-2/COX-1 ratio below 1.

Conclusions:

• Chirality control is critical for enhancing COX-2 selectivity in Ketorolac derivatives.
• Ket-Gly-D-Phe-D-Phe represents a promising candidate for safer anti-inflammatory therapeutics.
• Supramolecular hydrogels of Ket-Gly-D-Phe-D-Phe may be suitable for topical and controlled drug-release applications, minimizing systemic toxicity.