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Background: Glutathione (GSH) is an essential antioxidant that protects against oxidative stress, but its oral bioavailability is below 1% due to enzymatic degradation and poor gastrointestinal absorption. Improving the oral bioavailability of GSH could significantly enhance its therapeutic efficacy. Methods: This study synthesised GSH analogues with chemical modifications to improve bioavailability. Seven GSH derivatives were designed: three analogues with altered stereochemistry (1.62, 1.63, and 1.64) and three N-methylated derivatives (1.65, 1.70, and 1.71), alongside a native GSH (1.61). The analogues were synthesised via Fmoc-solid-phase peptide synthesis, and they were characterised using reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionisation mass spectrometry (ESI-MS), Fourier-transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR) spectroscopy. Their toxicity was assessed on Caco-2 cells for viability, and their antioxidant activity was assessed on UVA-irradiated fibroblast cells, enzymatic resistance, and interactions with GSH-metabolising enzymes. Results: Among the tested analogues, the N-methylated cysteine Compound (1.70) emerged as the most promising candidate. Compound 1.70 demonstrated superior resistance to enzymatic degradation, as well as showing enhanced cell viability and improved antioxidant activity. In vivo studies revealed a 16.8-fold increase in plasma half-life (t½) and a 16.1-fold increase in oral bioavailability compared to native GSH. Conclusions: Chemical modification strategies, particularly the N-methylation of GSH, present a viable approach to enhancing oral bioavailability. Compound 1.70 showed significant potential for therapeutic applications, warranting further investigation and development in clinical settings.
Yin et al. (Tue,) studied this question.