Trifluoromethylthio and Trifluoromethyl Functionalization of Endomorphin-1 Enhances its Hydrophobicity and Plasma...

Area of Science:

• Medicinal Chemistry
• Peptide Chemistry
• Pharmacology

Background:

• Bioactive peptides often have poor metabolic stability, limiting their therapeutic use.
• Fluorinated amino acids offer a strategy to enhance peptide pharmacokinetic properties.
• Endomorphin-1 (EM1) is a potent μ-opioid receptor (μOR) agonist with a short plasma half-life.

Purpose of the Study:

• To synthesize and evaluate SCF3- or CF3-modified neuropeptide analogs based on endomorphin-1.
• To assess the impact of fluorination on the pharmacokinetic profile and μOR activity of EM1 analogs.
• To explore the potential of SCF3-containing amino acids in therapeutic peptide development.

Main Methods:

• Solid-phase synthesis (SPPS) of ten SCF3- or CF3-modified EM1 analogs.
• Development and incorporation of eight novel fluorinated amino acid building blocks.
• In vitro μOR binding and functional activity assays.
• Plasma stability studies to determine half-life.

Main Results:

• Most fluorinated analogs retained μOR binding affinity and potency.
• Fluorination increased peptide hydrophobicity.
• The analog with l-Dmt(3-SCF3) modification at Tyr1 showed the most favorable profile (Ki = 1.4 nM, EC50 = 0.9 nM).
• This lead analog exhibited a significantly increased half-life (72-fold vs. EM1).

Conclusions:

• SCF3 and CF3 functionalization can improve the pharmacokinetic stability of short bioactive peptides.
• The l-Dmt(3-SCF3) modified EM1 analog demonstrates significant potential for therapeutic applications.
• SCF3-containing amino acids are valuable tools for designing metabolically stable peptide therapeutics.